Inhibitors of Brain Phospholipase A2 Activity: Their Neuropharmacological Effects and Therapeutic Importance for the Treatment of Neurologic Disorders

Akhlaq A. Farooqui; Wei-Yi Ong; Lloyd A. Horrocks

doi:10.1124/pr.58.3.7

Abstract

The phospholipase A₂ family includes secretory phospholipase A₂, cytosolic phospholipase A₂, plasmalogen-selective phospholipase A₂, and calcium-independent phospholipase A₂. It is generally thought that the release of arachidonic acid by cytosolic phospholipase A₂ is the rate-limiting step in the generation of eicosanoids and platelet activating factor. These lipid mediators play critical roles in the initiation and modulation of inflammation and oxidative stress. Neurological disorders, such as ischemia, spinal cord injury, Alzheimer's disease, multiple sclerosis, prion diseases, and epilepsy are characterized by inflammatory reactions, oxidative stress, altered phospholipid metabolism, accumulation of lipid peroxides, and increased phospholipase A₂ activity. Increased activities of phospholipases A₂ and generation of lipid mediators may be involved in oxidative stress and neuroinflammation associated with the above neurological disorders. Several phospholipase A₂ inhibitors have been recently discovered and used for the treatment of ischemia and other neurological diseases in cell culture and animal models. At this time very little is known about in vivo neurochemical effects, mechanism of action, or toxicity of phospholipase A₂ inhibitors in human or animal models of neurological disorders. In kainic acid-mediated neurotoxicity, the activities of phospholipase A₂ isoforms and their immunoreactivities are markedly increased and phospholipase A₂ inhibitors, quinacrine and chloroquine, arachidonyl trifluoromethyl ketone, bromoenol lactone, cytidine 5-diphosphoamines, and vitamin E, not only inhibit phospholipase A₂ activity and immunoreactivity but also prevent neurodegeneration, suggesting that phospholipase A₂ is involved in the neurodegenerative process. This also suggests that phospholipase A₂ inhibitors can be used as neuroprotectants and anti-inflammatory agents against neurodegenerative processes in neurodegenerative diseases.

I. Introduction

Phospholipases A₂ (PLA₂¹; EC 3.1.1.4) form an expanding superfamily of esterases that specifically cleave the acyl ester bond at the sn-2 position of membrane phospholipids to produce a free fatty acid and lysophospholipid (Farooqui et al., 2000b). Because a large proportion of cellular arachidonic acid is found esterified at the sn-2 position of membrane phospholipids, arachidonic acid and lysophospholipid are the major products of the PLA₂-catalyzed reaction. Under normal conditions, some arachidonic acid is converted to inflammatory mediators, prostaglandins, leukotrienes, and thromboxanes, whereas a majority of arachidonic acid is reincorporated into the brain phospholipids (Rapoport, 1999; Leslie, 2004). Arachidonic acid not only acts via conversion to inflammatory metabolites, but can also directly modulate neuronal function by various mechanisms, such as altering membrane fluidity and polarization state, activating protein kinase C, and regulating gene transcription (Katsuki and Okuda, 1995; Farooqui et al., 1997b). Another product of PLA₂ catalyzed reactions, 1-alkyl-2-lysophospholipid, is the immediate precursor of platelet-activating factor (PAF), another potent inflammatory mediator (Farooqui and Horrocks, 2004b).

Lysophospholipids may also change membrane fluidity and permeability. These metabolites are also involved in phospholipid remodeling and membrane perturbation. Accumulation of lysophospholipids is controlled by either reacylation to native phospholipids (Farooqui et al., 2000b) or by metabolism to water-soluble glycerophosphodiesters such as glycerophosphocholine by lysophospholipases (Farooqui et al., 1985). Thus, tight regulation of PLA₂ activity is necessary for maintaining basal levels of arachidonic acid, lysophospholipid, and PAF for performing normal brain function.

Increased PLA₂ activity and excessive production of proinflammatory mediators, eicosanoids, and platelet-activating factor, may potentially lead to disease states and neuronal injury. Collective evidence from many recent studies suggests that increased PLA₂ activity and PLA₂-generated mediators play a central role not only in acute inflammatory responses in brain but also in oxidative stress associated with neurological disorders such as ischemia, Alzheimer's disease (AD), Parkinson's disease (PD), and multiple sclerosis (MS) (Kalyvas and David, 2004; Phillis and O'Regan, 2004; Sun et al., 2004). PLA₂ contributes to the pathogenesis of the above disorders by attacking neural membrane phospholipids and releasing proinflammatory lipid mediators such as prostaglandins, leukotrienes, and thromboxanes, and PAF, and also by generating 4-hydroxynonenal (4-HNE). Thus, inhibition of cPLA₂ activity provides an attractive approach for designing novel drugs for the treatment of inflammation and oxidative stress associated with acute neural trauma such as ischemia, spinal cord injury, and head injury and some neurodegenerative disorders such as AD, PD, and MS. A definitive proof of whether enhanced PLA₂ activity represents a part of the cellular defense mechanism or whether increased PLA₂ activities contribute to the pathology of the neurological disorder awaits the development of a potent, specific, and clinically useful PLA₂ inhibitor for the treatment of inflammation and oxidative stress associated with neurological disorders. The purpose of this review is to describe the current knowledge of PLA₂ involvement in neurological disorders and the usefulness of PLA₂ inhibitors in preventing neurotoxin-mediated damage to neurons, glial cells, and the myelin sheath in brain tissue. This discussion should initiate more studies on not only the involvement of PLA₂-mediated inflammation and oxidative stress in neurological disorders but also on the development of potent, specific, and nontoxic inhibitors of PLA₂ activity that can cross the blood-brain barrier without harm and can be used for the treatment of neurological disorders.

II. Multiplicity of Phospholipases A₂ in Brain

Recent advances in molecular and cellular biology of PLA₂ have led to the identification of more than 20 isoforms with PLA₂ activity. PLA₂ enzymes are subdivided into several groups depending upon their structure, enzymic properties, subcellular localization, and cellular function (Table 1) (Farooqui et al., 1997c; Chakraborti, 2003; Phillis and O'Regan, 2004; Sun et al., 2004). These groups include secretory phospholipase A₂ (sPLA₂), cytosolic phospholipase A₂ (cPLA₂), plasmalogen-selective phospholipase A₂ (PlsEtn-PLA₂), and calcium-independent phospholipase A₂ (iPLA₂). Each class of PLA₂ is further subdivided into isozymes of which there are 14 for sPLA₂, at least 4 for cPLA₂, and 2 for iPLA₂. Genes coding for sPLA₂, cPLA₂, and iPLA₂ have been shown to occur in different regions of brain, in neurons, microglia, and astrocytes (Molloy et al., 1998; Zanassi et al., 1998; Balboa et al., 2002). PLA₂ isoforms have been partially purified and characterized from brain tissue (Hirashima et al., 1992; Ross et al., 1995; Yang et al., 1999), but none have been cloned and fully characterized. The following section briefly describes properties of brain PLA₂ isoforms, their roles, and importance in signal transduction processes in brain metabolism (Fig. 1).

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TABLE 1

Properties of various isoforms of brain PLA₂ Data summarized from Hirashima et al. (1992); Matsuzawa et al. (1996); Yang et al. (1999); and Farooqui et al. (2000b).

A. Secretory Phospholipase A₂

sPLA₂ is synthesized intracellularly; then it is secreted and acts extracellularly. sPLA₂ has a molecular mass of 14 kDa and is mainly associated with synaptosomes and synaptic vesicle fractions (Kim et al., 1995; Matsuzawa et al., 1996). PLA₂ binds to two types of cell surface receptors, namely the N type, identified in neurons, and the M type, identified in skeletal muscles, of sPLA₂ receptors (Hanasaki and Arita, 2002). Brain sPLA₂ contains a secretion peptide and requires millimolar concentrations of Ca²⁺ for enzymic activity. It shows no selectivity for particular fatty acyl chains in the phospholipids. This enzyme is present in all regions of mammalian brain. The highest activities of sPLA₂ are found in medulla oblongata, pons, and hippocampus, moderate activities in the hypothalamus, thalamus, and cerebral cortex, and low activities in the cerebellum and olfactory bulb (Thwin et al., 2003). At the cellular level, the sPLA₂ transcript is found in astrocytes (Mosior et al., 1998b; Zanassi et al., 1998). sPLA₂ is present in differentiated PC12 cells and in rat brain synaptic vesicles, indicating that neurons also express sPLA₂ activity (Matsuzawa et al., 1996).

Rat brain synaptosomes or differentiated PC12 cells release sPLA₂ upon stimulation via acetylcholine and glutamate receptors or via voltage-dependent calcium channels through depolarization. Thus, sPLA₂ may play an important role in neuronal metabolism (Kim et al., 1995; Matsuzawa et al., 1996). Based on pharmacological studies, the sPLA₂ released from neuronal cells may modulate the degranulation process leading to the release of neurotransmitters. Inhibitors of sPLA₂ activity block this release. For the expression of neurotoxicity, the released sPLA₂ binds to the presynaptic membrane, enters the lumen of the synaptic vesicle during retrieval of the vesicle from the plasma membrane, and hydrolyzes phospholipids of the inner leaflet of synaptic vesicles, changing the phospholipid composition and thus impairing its endocytosis. The stimulation of sPLA₂ in synaptic vesicles correlates with the induction of vesicle-vesicle aggregation. This process plays a central role in presynaptic neurotransmission (Moskowitz et al., 1983; Matsuzawa et al., 1996; Wei et al., 2003). In brain, astrocytes express sPLA₂, which can be induced in response to proinflammatory cytokines such as tumor necrosis factor-α and interleukin-1β (Lin et al., 2004).

Fig. 1.

A hypothetical diagram showing interplay among lipid mediators generated by sPLA₂, cPLA₂, PlsEtn-PLA₂, and iPLA₂ in brain tissue. PM, plasma membrane; A1, agonist; R1, receptor; A2, agonist; R2, receptor; A3, agonist; R3, receptor; sPLA₂-R, sPLA₂ receptor; PtdCho, phosphatidylcholine; PlsEtn, ethanolamine plasmalogen; LysoPtdCho, lysophosphatidylcholine; LysoPlsEtn, lysoethanolamine plasmalogen; AA, arachidonic acid; FFA, free fatty acid; (+), stimulation; (-), inhibition.

Mitochondrial fractions from rat brain, PC12, and U251 astrocytoma cell cultures contain significant sPLA₂ and iPLA₂ activities (Macchioni et al., 2004). The mechanism for a secretory protein (like sPLA₂) targeting an intracellular organelle (like mitochondria) remains unknown. However, it is proposed that at the molecular level, heparan sulfate, a glycosaminoglycan, may play an important role in internalization and attachment of PLA₂ isoforms to intracellular organelles (Farooqui et al., 1994b; Boilard et al., 2003). A reduction in the mitochondrial membrane potential causes the release of sPLA₂ and this sPLA₂ along with other PLA₂ isoforms may be involved in neural cell injury (Farooqui et al., 1997d; Macchioni et al., 2004).

Glutamate and its analogs stimulate sPLA₂ activity in a dose- and time-dependent manner (Kim et al., 1995; Xu et al., 2003). The neurotoxicity of glutamate is synergistically increased with the addition of sPLA₂ to cortical cultures. This observation suggests that glutamatergic synaptic activity may be modulated by sPLA₂ and its receptors on the neuronal surface (DeCoster et al., 2002; Kolko et al., 2002). In PC12 cells, sPLA₂ induces neurite outgrowth. Mutants with reduced sPLA₂ activity exhibit a comparable reduction in neurite-inducing activity (Nakashima et al., 2003), indicating that sPLA₂ performs a neurotrophin-like role in the central nervous system.

B. Cytosolic Phospholipases A₂

Although brain tissue contains cPLA₂ activity, it has never been purified to homogeneity and characterized from brain. The cytosolic fraction from rat brain contains two forms of PLA₂ activity, PLA₂-H and PLA₂-L. PLA₂-H has an apparent molecular mass of 200 to 500 kDa. Its activity is partially inhibited by Ca²⁺. In contrast, PLA₂-L has a molecular mass of 100 kDa and requires Ca²⁺ (Yoshihara and Watanabe, 1990). Based on several enzymic properties such as Ca²⁺ sensitivity, molecular mass, and Ca²⁺-mediated translocation, PLA₂-L seems to be identical to cPLA₂ (Yoshihara et al., 1992). cPLA₂ prefers arachidonic acid over other fatty acids and does not use Ca²⁺ for catalysis, although submicromolar Ca²⁺ concentrations are needed for membrane binding (Clark et al., 1987; Farooqui et al., 2000b). Owing to the presence of a Ca²⁺-dependent phospholipid-binding domain at the N-terminal region, cPLA₂ is translocated in a Ca²⁺-dependent manner from cytosol to the nuclear or other cellular membranes (Clark et al., 1987; Hirabayashi et al., 2004), in which other downstream enzymes, including the cyclooxygenases and lipoxygenases responsible for the metabolism of arachidonic acid to eicosanoids, are located. This gives cPLA₂ access to its membrane-associated phospholipid substrate. However, we do not know the manner in which cPLA₂ is activated by extracellular stimuli and whether this activation occurs at specific sites. The C-terminal region of cPLA₂ contains the phosphorylation site and catalytic site. These sites may be involved in regulation of the enzymic activity. The activation of cPLA₂ can be through serine residues, notably Ser-505 and Ser-727, by mitogen-activated protein kinase and protein kinase C (PKC) (Hirabayashi and Shimizu, 2000; Hirabayashi et al., 2004). In neural membranes, cPLA₂ activity and arachidonic acid release are linked to dopamine, glutamate, serotonin, P2-purinergic, muscarinic, cytokine, and growth factor receptors through different coupling mechanisms (Table 2). Some receptors involve G-proteins and others do not. The ligand-mediated stimulation of the above receptors modulates the release of arachidonic acid and levels of other second messengers in brain tissue (Farooqui et al., 2000b).

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TABLE 2

Coupling of PLA₂ isoforms with various receptors in brain tissue.

cPLA₂ activity can also be modulated through a cooperative binding mechanism with glycerophospholipids containing arachidonic acid (Burke et al., 1995) or through binding of anionic phospholipids, such as phosphatidylinositol 4,5-bisphosphate, phosphatidylinositol 3,4,5-trisphosphate, and ceramide 1-phosphate (Hirabayashi et al., 2004; Pettus et al., 2004), to a pleckstrin homology domain (Mosior et al., 1998a). Three paralogs of cPLA₂ occur in brain and other non-neural tissues (Diaz-Arrastia and Scott, 1999; Farooqui et al., 2000b; Hirabayashi et al., 2004). They are cPLA₂-α (molecular mass 85 kDa), cPLA₂-β (molecular mass 114 kDa), and cPLA₂-γ (molecular mass 61 kDa). cPLA₂-β is found mainly in the cerebellum and shares more similarities with cPLA₂-α than with cPLA₂-γ. cPLA₂-γ lacks the C2 domain, but contains a prenyl group-binding motif that behaves as a lipid anchor and allows binding of the enzyme to the membrane.

Recombinantly expressed cPLA₂-γ liberates arachidonic acid from phosphatidylcholine. Unlike cPLA₂-α, cPLA₂-γ also acts on other fatty acid residues at the sn-2 and sn-1 positions of glycerophospholipids. cPLA₂-α hydrolyzes fatty acids at the sn-2 position, cPLA₂-β prefers to cleave fatty acids at the sn-1 position, and cPLA₂-γ efficiently hydrolyzes fatty acid at the sn-1 as well as sn-2 positions of the glycerol moiety (Song et al., 1999). The overexpression of cPLA₂-γ increases the proportions of polyunsaturated fatty acids in phosphatidylethanolamine, indicating that this paralog can modulate the phospholipid composition (Asai et al., 2003). cPLA₂-γ is constitutively expressed in the endoplasmic reticulum where it is involved in remodeling and maintaining membrane phospholipid composition under oxidative stress.

cPLA₂-β displays much lower activity with [2-arachidonyl]PtdCho than do the other two paralogs. The genes for human cPLA₂-α, -β, and -γ map to chromosomes 1, 15, and 19, respectively. Mitogen-activated protein kinase phosphorylation sites are only present in cPLA₂-α and are not conserved in cPLA₂-β and cPLA₂-γ. cPLA₂-α activity is uniformly distributed in various regions of rat brain (Farooqui et al., 2000b). Recent studies have indicated the presence of a new paralog of cPLA₂. This paralog is mainly found in skin and has been named cPLA₂-δ (molecular mass 109 kDa) (Chiba et al., 2004). In contrast with other cPLA₂ paralogs, cPLA₂-δ has a preference for linoleic acid release instead of arachidonic acid release.

Considerable information is available on cPLA₂-α. From immunolabeling and in situ hybridization studies, cPLA2-α is localized in somata and dendrites of Purkinje cells, whereas cPLA2-β is present in the granule cells of rat brain (Shirai and Ito, 2004). In addition, cPLA₂-α is predominantly found in astrocytes of gray matter (Farooqui et al., 2000b; Pardue et al., 2003), as well as in hippocampal neurons (Sandhya et al., 1998; Kishimoto et al., 1999; Strokin et al., 2003), in which under physiological conditions cPLA₂-α may be involved in second-messenger generation and long-term potentiation (LTP), a mechanism involved in memory storage. More recently, the mRNAs for cPLA₂-β and cPLA₂-δ have been identified by reverse transcription-polymerase chain reaction analysis in human brain tissue (Pickard et al., 1999; Song et al., 1999; Hirabayashi et al., 2004), but the role of these paralogs of cPLA₂ in brain tissue remains speculative. Because cPLA₂-δ mainly occurs in skin, it is proposed that this paralog plays a critical role in inflammation in psoriatic lesions (Chiba et al., 2004).

Even though cPLA₂ isozymes are often considered to be the enzymes responsible for stimulus-mediated arachidonic acid release and eicosanoid formation, several studies also implicate sPLA₂ activation. cPLA₂ and sPLA₂ may modulate arachidonic acid metabolism in the astrocytoma cell line 1321N1 via the mitogen-activated protein kinase pathway (Hernandez et al., 2000). At the cellular level, interactions and interplay among calcium mobilization, cPLA₂ phosphorylation, and extracellular receptors of sPLA₂ may be responsible for increased eicosanoid production (Fig. 1). cPLA₂ may be a good candidate for triggering down-regulation of nitricoxide synthase activity and may thus be an important component of the cross-talk between calcium and nitric oxide-regulated signal transduction pathways in neuronal cells (Palomba et al., 2004). Under pathological conditions, the interactions among calcium, cPLA₂, and nitric-oxide synthase may play an important role in the pathophysiology of neurological disorders associated with oxidative stress and inflammation (see below).

C. Plasmalogen-Selective Phospholipase A₂

This enzyme hydrolyzes arachidonic acid and docosahexaenoic acid from the sn-2 position of plasmalogens, a special type of glycerophospholipid with a vinyl ether linkage at the sn-1 position of the glycerol backbone (Farooqui and Horrocks, 2001). This enzyme has been purified and characterized from bovine brain cytosol (Hirashima et al., 1992), rabbit kidney (Portilla and Dai, 1996), and rabbit heart (Hazen and Gross, 1993). Bovine brain PlsEtn-PLA₂ has an apparent molecular mass of 39 kDa. Nonionic detergents, Triton X-100 and Tween 20, stimulate the enzymic activity. It is not inhibited by bromoenol lactone, an inhibitor that markedly inhibits iPLA₂. Low micromolar concentrations of ATP have no effect on PlsEtn-PLA₂ activity, but 2 mM ATP markedly inhibits its activity. Bovine brain PlsEtn-PLA₂ is inhibited by 5,5′-dithiobis(2-nitrobenzoic acid, iodoacetate, and N-ethylmaleimide in a dose-dependent manner (Farooqui et al., 1995). Various polyvalent anions, citrate > sulfate > phosphate, and metal ions, Ag⁺, Hg²⁺, and Fe³⁺, also inhibit this enzyme in a dose-dependent manner. Glycosaminoglycans markedly inhibit bovine brain PlsEtn-PLA₂ with an inhibition pattern of heparan sulfate > hyaluronic acid > chondroitin sulfate > heparin. This PLA₂ is also inhibited by N-acetylneuraminic acid, gangliosides, and sialoglycoproteins (Yang et al., 1994b). Other glycosphingolipids, such as cerebrosides and sulfatides, have no effect. However, ceramide markedly stimulates PlsEtn-PLA₂ activity in a time-and dose-dependent manner (Latorre et al., 2003). Treatment of rat brain slices with Staphylococcus aureus sphingomyelinase or C2-ceramide produces a marked decrease in PlsEtn levels, suggesting stimulation of PlsEtn-PLA₂ activity. Bromoenol lactone, a potent inhibitor of iPLA₂, does not affect this stimulation, but quinacrine and gangliosides, nonspecific inhibitors of PlsEtn-PLA₂, completely block it (Latorre et al., 2003; Yang et al., 1994a,b). These studies have led to the suggestion that the degradation of plasmalogen by PlsEtn-PLA₂ is a receptor-mediated process (Farooqui and Horrocks, 2001; Farooqui et al., 2003a; Latorre et al., 2003) and may involve an interaction between plasmalogen metabolism and sphingolipid metabolism.

PlsEtn-PLA₂ has been localized immunochemically in neurons and astrocytes (Farooqui and Horrocks, 2001). The colocalization of PlsEtn-PLA₂ with glial fibrillary acidic protein suggests that this PLA₂ is predominantly associated with astrocytes. This is in contrast with cPLA₂-α, which is present in neurons as well as astrocytes (Sandhya et al., 1998; Kishimoto et al., 1999). cPLA₂ (molecular mass 85 kDa) and PlsEtn-PLA₂ (molecular mass 39-42 kDa) release arachidonic acid and docosahexaenoic acid in rat brain astrocytes and cyclic AMP and Ca²⁺ regulate these enzymes differentially (Strokin et al., 2003). Because plasmalogens are major phospholipids of neural membranes, PlsEtn-PLA₂ may be mainly involved in generating docosahexaenoic acid (DHA), a 22-carbon essential fatty acid with 6 double bonds. This fatty acid is highly enriched in synaptosomal membranes, synaptic vesicles, and growth cones and accounts for >17% by weight of the total fatty acids in the brain of adult rats (Hamano et al., 1996).

D. Calcium-Independent Phospholipases A₂

The brain cytosolic fraction contains an 80-kDa Ca²⁺-independent PLA₂ activity. This enzyme has been purified from rat brain to homogeneity using multiple column chromatographic procedures with a very low yield. The purified enzyme has a specific activity of 4.3 μmol/min/mg. The peptide sequence of this enzyme has considerable homology to sequences of the iPLA₂ from P388D1 macrophages, Chinese hamster ovary cells, and human B lymphocytes (Yang et al., 1999). This iPLA₂ hydrolyzes the sn-2 fatty acid from PtdCho with preferences linoleoyl > palmitoyl > oleoyl > arachidonyl group. iPLA₂ has an unique amino acid sequence containing a lipase consensus sequence and eight ankyrin repeats. This enzyme is strongly inhibited by bromoenol lactone, and ATP augments its activity. iPLA₂ is present in all brain regions with the highest activity in striatum, hypothalamus, and hippocampus. The gene encoding iPLA₂ has been identified (Molloy et al., 1998). Alternative splicing can generate multiple iPLA₂ isoforms with distinct tissue distribution and localization (Larsson et al., 1998). Truncated splice variant proteins that prevent the formation of active iPLA₂ tetramers may negatively regulate iPLA₂ (Larsson et al., 1998; Seashols et al., 2004). Native iPLA₂ is a homotetramer that is potentially formed through interactions between N-terminal ankyrin repeats (Ackermann and Dennis, 1995). Five splice variants of iPLA₂ occur in various tissues (Larsson et al., 1998; Shirai and Ito, 2004). One splice variant (iPLA₂-1) lacks exon 9 (165 base pairs), whereas the other four variants (iPLA₂-2, iPLA₂-3, iPLA₂-ankyrin-1, and iPLA₂-ankyrin-2) contain exon 9. The presence of this exon makes these splice variants membrane-bound because exon 9 encodes hydrophobic amino acids (Larsson et al., 1998; Shirai and Ito, 2004). Rat cerebellum contains iPLA₂-1 and iPLA₂-2 or iPLA₂-3, but not iPLA₂-ankyrin-1 or iPLA₂-ankyrin-2. From immunolabeling studies in rat brain, granule cells, stellate cells, and the nucleus of Purkinje cells contain iPLA₂ (Shirai and Ito, 2004). Strong signals of iPLA₂ immunoreactivity are observed in olfactory bulb, hippocampus CA1-3, dentate gyrus, and brain stem. In non-neural cells, the cleavage of iPLA₂ by caspase-3 is associated with the execution of apoptosis (Atsumi et al., 1998, 2000). The proposed role of iPLA₂ in phospholipid remodeling and apoptosis is based on the use of bromoenol lactone, thought to be a specific inhibitor, but this compound actually inhibits other enzymes such as diacylglycerol lipase and phosphatidate phosphohydrolase (see below). This makes it difficult to define the role of iPLA₂ in phospholipid metabolism (Farooqui et al., 2000a; Pérez et al., 2004). iPLA₂ may play an important role not only in long-term potentiation and long-term depression and activity-dependent changes in synaptic strength believed to underlie certain forms of learning and memory in the hippocampus (Fitzpatrick and Baudry, 1994; Wolf et al., 1995; Fujita et al., 2001) but also in neural cell proliferation, apoptosis, and differentiation (Farooqui et al., 2004a).

III. Involvement of Phospholipase A₂ Activity in Brain Injury

A growing body of evidence suggests the involvement of isoforms of PLA₂ in neurotransmitter release, LTP, long-term depression, membrane repair, neurodegeneration, neural cell proliferation, differentiation, and apoptosis (Fig. 2) (Farooqui et al., 1997c). It is not known which PLA₂ isoform performs which central nervous system function. The multiplicity of PLA₂ and the interplay among lipid mediators generated by PLA₂ in brain tissue provide diversity in function and specificity of various isoforms of this family of enzymes in the regulation of enzymic activity in response to a wide range of extracellular signals. However, this diversity complicates the analysis of their function (Fig. 1). The complexity of this problem becomes obvious when one considers the coupling of various isoforms of PLA₂ with different receptors in a single neural cell and tries to associate PLA₂ activity with specific neuronal functions and disease processes.

Isoforms of PLA₂ may not function interchangeably but act in parallel to the transducer signal (Farooqui et al., 1997d). Various isoforms of PLA₂ probably act on different cellular pools of phospholipids located in different types of neural cells and these isoforms may be regulated by different coupling mechanisms involving common second messengers (Sun et al., 2004). The synthesis of eicosanoids depends not only on PLA₂ activity for the generation of arachidonic acid, but also on cyclooxygenase or lipoxygenase activities (Sun et al., 2004). Tight regulation of PLA₂ activity is necessary for normal brain function (Farooqui et al., 2000b; Phillis and O'Regan, 2004).

Fig. 2.

Proposed roles of PLA₂ isoforms in brain.

Activities of PLA₂ isoforms are also regulated through modulation of gene expression. Interleukin (IL)-1α, (Xu et al., 2003), tumor necrosis factor (TNF)-α (Pirianov et al., 1999; Tong et al., 1999; Jupp et al., 2003), interferon-γ (Xu et al., 2003), and several growth factors induce these enzymes (Jupp et al., 2003; Akiyama et al., 2004; Wang et al., 2004b). Regulatory interactions and coupling between PLA₂ activity and the expression of genes encoding cyclooxygenase and lipoxygenases have been suggested (Doug et al., 2003). In brain tissue, the coupling between cPLA₂ depends not only on the type of neural cell but also on the stimulatory status of neural cell involved.

Stimulation of PLA₂ isoforms may contribute to brain damage in several ways:

The loss of essential phospholipids with the accumulation of free fatty acids and lysophospholipids may have a detergent-like effect on neuronal membranes.
Free fatty acids can uncouple oxidative phosphorylation, which results in mitochondrial dysfunction (Schapira, 1996). Arachidonic acid produces mitochondrial swelling in glial cells and induces changes in membrane permeability by regulating ion channels (Farooqui et al., 1997b,c). It also inhibits glutamate uptake. In the nucleus, arachidonic acid may also interact with elements of gene structure, such as promoters, enhancers, suppressors, and others, in a specific manner that is not shared by eicosanoids or other fatty acids. These interactions modulate gene expression (Farooqui et al., 1997c).
Polyunsaturated fatty acid-induced oxidative stress is accompanied by an increase in AP-1 and NF-κB activity and gene expression (Mazière et al., 1999). Another consequence of increased polyunsaturated free fatty acid-induced oxidative stress is the activation and inactivation of redox-sensitive proteins (Wang, 2003).
PAF, formed from the acetylation of lysophospholipids, not only can activate leukocytes and microglia but also can induce inflammation at endothelial and neuronal cell surfaces.
The accumulation of free fatty acids can trigger an uncontrolled “arachidonic acid cascade”. This sets the stage for increased production of prostaglandins, leukotrienes, and thromboxanes. Cyclooxygenases and lipoxygenases catalyze these reactions. Prostaglandins, leukotrienes, and thromboxanes are collectively called eicosanoids. They play important roles in the generation and maintenance of inflammation in neural cells. The arachidonic acid cascade also produces 4-HNE and reactive oxygen species (ROS) such as superoxide anion, hydroxyl, alkoxyl, and peroxyl radicals and hydrogen peroxide.
An uncontrolled sustained increase in calcium influx through increased phospholipid degradation can lead to increased membrane permeability and stimulation of many enzymes associated with lipolysis, proteolysis, and disaggregation of microtubules with a disruption of cytoskeleton and membrane structure (Farooqui and Horrocks, 1991, 1994). The most compelling evidence for the involvement of cPLA₂ in neurodegeneration comes from reports indicating that mice with a targeted deletion of the gene that encodes cPLA₂ show reduced infarct size after cerebral ischemia (Bonventre et al., 1997) and resistance to MPTP-induced neurotoxicity (Klivenyi et al., 1998). Studies on brain lipid metabolism in cPLA₂ knockout mice indicate there is no net change in unesterified arachidonic acid. However, there was a 50% reduction in esterified arachidonic acid in phosphatidylcholine, indicating involvement of cPLA₂ in wild-type mice (Rosenberger et al., 2003). The knockout mice also have reduced rates of arachidonic acid incorporation into ethanolamine and choline glycerophospholipids but elevated rates into phosphatidylinositol. cPLA₂-deficient mice also show a 62% reduction in the rate of formation of prostaglandin (PG) E₂, suggesting a coupling between cPLA₂ and cyclooxygenase activities (Murakami et al., 1997; Bosetti and Weerasinghe, 2003). The deletion of cPLA₂ also causes dysregulation ofinsulin-like growth factor-1 signaling and stimulates striated muscle growth (Obata et al., 2003).

4-HNE has three functional groups that confer to its molecule a very high reactivity toward thiol and amino groups. 4-HNE has been reported to cause a number of deleterious effects in cells including inhibition of DNA synthesis, disturbance in calcium homeostasis, and inhibition of mitochondrial respiration. All of these processes may result in neuronal injury in ischemia and glutamate-mediated neurotoxicity (Farooqui et al., 1997c). In brain tissue, 4-HNE also produces alterations in the function of key membrane proteins including glucose transporter, glutamate transporter, and sodium potassium ATPase (Friguet et al., 1994; Jamme et al., 1995). Thus, high levels of this metabolite are toxic for brain tissue (Farooqui et al., 1997c).

ROS inactivate membrane proteins and DNA (Berlett and Stadtman, 1997). The reaction between ROS and proteins or unsaturated lipids in the plasma membrane leads to a chemical cross-linking of membrane proteins and lipids and a reduction in membrane unsaturation. This depletion of unsaturation in membrane lipids is associated with decreased membrane fluidity and decreases in the activity of membrane-bound enzymes, ion channels, and receptors (Ray et al., 1994).

IV. Physiological and Pharmacological Effects of Phospholipase A₂ Inhibitors

The stimulation of PLA₂ isoforms, release of arachidonic acid, and generation of platelet-activating factor are important events in the inflammation and oxidative stress associated with acute neural trauma and chronic neurological disorders (Farooqui and Horrocks, 1994; Phillis and O'Regan, 2004). Treatment of these disorders requires potent and selective inhibitors of PLA₂ activity that can be used as drugs. The problem with available inhibitors of PLA₂ isoforms has been their specificity. Many PLA₂ inhibitors originally thought to be selective for a specific PLA₂ isoform are now known to not only inhibit other PLA₂ isoforms but also block activities of different enzymes (Farooqui et al., 1999; Cummings et al., 2000; Fuentes et al., 2003). For example, in non-neural cells, arachidonyl trifluoromethyl ketone inhibits not only cPLA₂ activity but also cyclooxygenase and acyltransferase activities (Cummings et al., 2000; Fuentes et al., 2003). Methyl arachidonyl fluorophosphonate, another inhibitor of brain cPLA₂, also inhibits bovine brain iPLA₂.

The discovery of potent and specific inhibitors of PLA₂ isoforms is an important approach, not only for establishing functional roles of a given PLA₂ isoform in a specific type of neural cell in brain tissue but also for treating oxidative stress and inflammation caused by neurodegenerative process. Studies on this important topic are beginning to emerge (Farooqui et al., 1999; Cummings et al., 2000; Miele, 2003a; Scott et al., 2003; Clark and Tam, 2004). These studies are complicated not only by the lack of information on the availability of specific inhibitors but also by the occurrence of isoforms of PLA₂ activity and in vivo effects of PLA₂ inhibitors on enzymic activity. Furthermore, the effect of inhibitors on the physical state of substrate aggregates in neural membranes remains unknown. In searching for good cPLA₂ inhibitors, kinetic analysis is not enough to evaluate whether an inhibitor can block PLA₂ activity by affecting the interfacial quality of phospholipid in lipid bilayer or by directly inhibiting the interaction between the phospholipids and the active site of the enzyme. An ideal inhibitor should have regional specificity and should be able to reach the site where cells are under oxidative stress and inflammatory and neurodegenerative processes are taking place.

Neurons are more susceptible to free radical-mediated neuroinflammation and oxidative stress than glial cells (Adibhatla et al., 2003; Ajmone-Cat et al., 2003). In fact, activated glial cells, including astroglia and microglia, sustain inflammatory processes initiated by arachidonic acid-generated metabolites. This suggests that signals modulating the induction, expression, and stimulation of PLA₂ isoforms may play an important role in neurodegenerative diseases associated with neuroinflammation and oxidative stress (Farooqui and Horrocks, 1994; Farooqui et al., 2003b, 2004b). For the successful treatment of inflammatory and oxidative stress in neurological disorders, timely delivery of a well-tolerated, chronically active, and specific inhibitor of PLA₂ that can bypass or cross the blood-brain barrier without harm is required. Some nonspecific PLA₂ inhibitors (see below) have been used for the treatment of ischemia, spinal cord injury, and AD (Sano et al., 1997), but no compound with real clinical potential has emerged.

A. Arachidonyl Trifluoromethyl Ketone

Arachidonyl trifluoromethyl ketone (Fig. 3) is a potent inhibitor of cPLA₂. NMR studies show that the carbon chain of AACOCF₃ binds in a hydrophobic pocket and the carbonyl group of AACOCF₃ forms a covalent bond with the serine 228 in the active site, generating a charged hemiketal oxoanion that interacts with a positively charged group of the enzyme (Street et al., 1993; Trimble et al., 1993). AACOCF₃ is a 500-fold more potent inhibitor of cPLA₂ than sPLA₂ (Trimble et al., 1993), indicating that it is a more selective inhibitor of cPLA₂ than sPLA₂. This inhibitor also blocks cyclooxygenase activity (Riendeau et al., 1994).

Because of its physicochemical properties, AACOCF₃ can readily penetrate into cell membranes. At 5 to 20 μM it essentially blocks all liberation of arachidonic acid in thrombin-stimulated platelets, in Ca²⁺ ionophore-stimulated human monocytic cells, and in interleukin 1-stimulated mesangial cells (Gronich et al., 1994). AACOCF₃ inhibits bovine brain cPLA₂ and iPLA₂ in a dose-dependent manner with IC₅₀ values of 1.5 and 6.0 μM, respectively.

The treatment of NG 108-15 cells with AACOCF₃ decreases initial neurite formation in a concentration-dependent manner (Smalheiser et al., 1996). The pharmacological blockade of cPLA₂ by a low concentration, 10 μM, of AACOCF₃ significantly inhibits neuronal death in the CA1 region of rat hippocampus. In primary neuronal cultures, this PLA₂ inhibitor prevents caspase-3 activation and neurodegeneration induced by β-amyloid peptide (Aβ) and human prion protein peptide (Bate et al., 2004), suggesting the role of PLA₂ isoforms in neurodegenerative processes (Farooqui and Horrocks, 1994; Farooqui et al., 1997c). In primary neuronal cultures, AACOCF₃ also abolishes methylmercury (MeHg²⁺)-mediated stimulation of cPLA₂ and arachidonic acid release (Shanker et al., 2004), suggesting that cPLA₂ plays an important role in MeHg²⁺-induced neurotoxicity. Similarly, in astrocytes MeHg²⁺-induced ROS generation is strongly inhibited by AACOCF₃ (Shanker and Aschner, 2003). In neural cell cultures AACOCF₃ also shortens the association of PKC-γ with plasma membrane indicating that this isoform of PKC may be involved in neuronal plasticity (Yagi et al., 2004). AACOCF₃ also blocks l-buthionine sulfoximine toxicity in glutathione-depleted mesencephalic cultures (Kramer et al., 2004).

Fig. 3.

Chemical structures of PLA₂ inhibitors. a, arachidonyl trifluoromethyl ketone; b, methyl arachidonyl fluorophosphonate; c, bromoenol lactone; d, 4-alkoxybenzamidine; e, long-chain 2-oxomide; f, quinacrine; and g, 3-(pyrrole)-2-propionic acid.

AACOCF₃ induces the dispersal of Golgi stack and trans-Golgi network resident proteins. This suggests that cPLA₂ isozymes play a crucial role in membrane trafficking and in maintenance of Golgi architecture. In non-neural cultured cells, AACOCF₃ inhibits the expression of IL-2 at both the mRNA and protein levels, indicating that cPLA₂ may have marked effects on T-cell function (Amandi-Burgermeister et al., 1997; Ouyang and Kaminski, 1999). AACOCF₃ inhibited DNA fragmentation during apoptosis in U937 cells, but failed to affect the morphological changes that occur during apoptosis, suggesting that the use of AACOCF₃ may distinguish between cytoplasmic and nuclear events that occur during apoptotic cell death (Vanags et al., 1997). AACOCF₃ is described as a specific inhibitor of cPLA₂, but recent studies in non-neural cells indicate it may also inhibit cyclooxygenases and 5-lipoxygenase (Cummings et al., 2000; Fuentes et al., 2003). These observations strongly suggest that AACOCF₃ is not a specific inhibitor of cPLA₂.

B. Methyl Arachidonyl Fluorophosphonate

MAFP (Fig. 3) is an irreversible inhibitor of bovine brain cPLA₂ (IC₅₀ 0.5 μM) and has no effect on sPLA₂.It inhibits enzymic activity by reacting with a serine residue at the active site. MAFP also inhibits bovine brain iPLA₂ in a dose-dependent manner with an IC₅₀ value of 0.75 μM. At 5.0 μM, MAFP completely inhibits bovine brain iPLA₂ activity. In addition, MAFP inhibits Aβ-mediated stimulation of cPLA₂ activity in cortical neuronal cultures (Kriem et al., 2005).

MAFP induces irreversible inhibition of the enzymic hydrolysis of arachidonyl ethanolamide (anandamide) by fatty acid amide hydrolase. Based on various pharmacological studies with cannabinoid CB₁ receptors and MAFP, it has been suggested that MAFP is an irreversible cannabinoid CB₁ receptor antagonist (Fernando and Pertwee, 1997).

Because MAFP interacts with several PLA₂ isoforms and with fatty amide hydrolase, it cannot be considered as a specific inhibitor of cPLA₂. MAFP also blocks l-buthionine sulfoximine toxicity in glutathione-depleted mesencephalic cultures (Kramer et al., 2004). Intrathecal injections of MAFP in rats produce antinociceptive effects (Ates et al., 2003), suggesting that PLA₂ isoforms may play some role during pain states (see below).

C. Bromoenol Lactone

BEL (Fig. 3) is a potent inhibitor of bovine brain iPLA₂ and PlsEtn-PLA₂ with IC₅₀ values of 60 and 40 nM, respectively. BEL has a structural resemblance to plasmalogen. It inhibits brain cPLA₂ and sPLA₂ at a very high concentration (500 μM). The injection of BEL (10 μM) into postsynaptic CA1 pyramidal neurons produces a robust increase in the amplitude of α-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptor-mediated excitatory postsynaptic currents, suggesting that iPLA₂ plays an important role in AMPA-mediated synaptic plasticity (St-Gelais et al., 2004). AACOCF₃ and palmityl trifluoromethyl ketone, which mainly interact with cPLA₂, have no effect on AMPA-mediated synaptic transmission. The inhibition of iPLA₂ by BEL and the enhancement of AMPA subunit immunoreactivity in brain homogenates and slices support the above electrophysiological studies. Taken together, these results support the hypothesis that BEL-mediated antagonism of AMPA receptors is involved in long-term potentiation and long-term depression during the regulation of synaptic plasticity. Based on the blockage of induction of hippocampal long-term potentiation, brain iPLA₂ may be involved in learning and memory (Wolf et al., 1995; Fujita et al., 2001).

Intracerebroventricular injections of BEL, 3 nmol, markedly affect spatial performance in mice (Fujita et al., 2000), indicating that iPLA₂ is involved in spatial memory formation. BEL also modulates intracellular membrane trafficking (Kuroiwa et al., 2001; Brown et al., 2003) by inhibiting iPLA₂ activity in membrane tubule formation during reassembly of the Golgi complex. In addition, BEL treatment also interferes with membrane fusion events during endocytosis and exocytosis.

D. Benzenesulfonamides and Alkoxybenzamidines

Benzenesulfonamide (Fig. 3) and its piperidine derivative are the most potent inhibitors of membrane-bound heart PLA₂ activity with IC₅₀ values of 28.0 and 9.0 nM, respectively (Oinuma et al., 1991). Intravenous injections of these inhibitors protect rats against ischemic damage in acute myocardial infarction. These compounds are relatively metabolically stable in plasma with half-lives of 1 to 2 h. These compounds also inhibit brain cPLA₂ activity in a dose-dependent manner with IC₅₀ values of 23.0 and 10.0 nM, respectively. Nothing is known about their ability to cross the blood-brain barrier. The synthesis of 4-alkoxybenzamidines as PLA₂ inhibitors has also been described previously (Aitdafoun et al., 1996). These compounds competitively inhibit bovine pancreatic and rabbit platelet PLA₂ activities with IC₅₀ values of 3.0 and 5.0 μM, respectively. It is interesting to note that 4-tetradecyloxybenzamidine has an anti-inflammatory effect in vivo on carrageenan-mediated rat paw edema.

E. 3-(Pyrrol)-2-propionic Acid

Lehr (1996, 1997a,b) has synthesized many compounds (Fig. 3) that inhibit cPLA₂ activity in platelets with IC₅₀ values varying from 0.5 to 10 μM. Effects of these compounds on other isoforms of PLA₂ remain unknown. These inhibitors have not been used to block the activity of brain PLA₂ isoforms and have not been injected into intact animals or animal models of neurological disorders; therefore, nothing is known about their tolerance, half-lives, and toxicity. The ability of these inhibitors to cross the blood-brain barrier also remains unknown.

F. 2-Oxoamide and 1,3-Disubstituted Propan-2-ones

Long-chain 2-oxoamides of γ-aminobutyric acid and γ-norleucine (AX006, AX007, and AX008) (Fig. 3) reversibly inhibit cPLA₂ activity in a dose- and time-dependent manner (Kokotos et al., 2004). These inhibitors block the LPS-mediated release of arachidonic acid due to the stimulation of cPLA₂ in murine P388 D1 macrophages with IC₅₀ values of 8.0, 7.6, and 4.6 μM, respectively. These IC₅₀ values are lower than the IC₅₀ value reported for MAFP (25 μM). This strongly suggests that 2-oxoamides are more potent inhibitors of cPLA₂ than MAFP. Anti-inflammatory and analgesic activities of 2-oxoamide have been tested in the rat paw carrageenan-mediated edema assay. Carrageenan-induced edema in rat paw can be prevented with 2-oxoamides (Kokotos et al., 2004). Effects of these inhibitors on brain cPLA₂ remain unknown.

1,3-Disubstituted propan-2-ones (Fig. 4) were recently synthesized (Connolly et al., 2002). These compounds inhibit cPLA₂ activity with an IC₅₀ value of 0.03 μM in an in vitro assay. They are 10-fold more effective than 2-oxoamides and AACOCF₃ in inhibiting cPLA₂ activity. 1,3-Disubstituted propan-2-ones inhibit arachidonic acid production in HL60 cells with an IC₅₀ value of 2.8 μM. These inhibitors have not been injected into intact animals or animal models of neurological disorders; therefore, nothing is known about their tolerance, half-lives, and toxicity. The ability of these inhibitors to cross the blood-brain barrier also remains unknown.

G. Choline Derivatives with a Long Aliphatic Chain

Recently, a new class of hydrophobic inhibitors that partition into the lipid bilayer and compete with monomers of the glycerophospholipid substrate was described previously (Burke et al., 1999). These compounds include 2-(2-benzyl-4-chlorophenoxy)ethyldimethyl-n-octadecyl-ammonium chloride and 2-(2-benzyl-4-chlorophenoxy)ethyldimethyl-n-octyl-ammonium bromide (Fig. 4). Both compounds inhibit cPLA₂ activity in a competitive manner with IC₅₀ values of 5 and 13 μM, respectively. The length of the N-alkyl chain plays an important role in the degree of inhibition. Shortening of the N-alkyl chain considerably decreases the percentage of inhibitor partitioned into the glycerophospholipid bilayer and increases the IC₅₀ value. These effects may be due to diminished hydrophobic interaction between the shorter alkyl chain and the fatty acid tails of the glycerophospholipids making up the bilayer. In contrast, lengthening of the N-alkyl chain increases the percentage of inhibitor partitioned into the lipid bilayer and decreases the IC₅₀ value. The synthesis of these inhibitors represents an important step in the development of potent in vivo cPLA₂ inhibitors because these compounds inhibit enzymic activity at the interface and provide a weak interaction with the glycerophospholipid bilayer (Burke et al., 1999). Based on kinetic studies, the potential in vivo efficacy of these intracellular inhibitors can be more potent than other inhibitors such as AACOCF₃. These inhibitors have not been used for in vivo studies so nothing is known about their tolerance, toxicity, and half-life. It is also not known whether these inhibitors can cross blood-brain barrier.

Fig. 4.

Chemical structures of PLA₂ inhibitors. a, pyrrolidine-1; b, 2-(2-benzyl-4-chlorophenoxy)ethyldimethyl-n-octyl-ammonium chloride; c, 2-(2-benzyl-4-chlorophenoxy)ethyldimethyl-n-octadecyl-ammonium chloride; and d, AR-C70484XX [4-[3-4-(decyloxy)phenoxy)-2-oxopropoxy]benzoic acid; Connolly et al. (2002)].

H. Pyrrolidine-Based Inhibitors of Phospholipase A₂

Pyrrolidine-containing compounds (Seno et al., 2000; Ghomashchi et al., 2001) markedly inhibit cPLA₂-α in vitro and block arachidonate release in Ca²⁺ ionophore-stimulated non-neural cells (Seno et al., 2000). The structure of the most potent inhibitor, pyrrolidine-1, is shown in Fig. 4. In a fluorometric assay, pyrrolidine-1 inhibits cPLA₂-α activity in a dose-dependent manner with an IC₅₀ value of 0.18 μM. In a mixed-micelle assay system, this compound inhibits cPLA₂-α activity with an IC₅₀ value of 1.8 μM. This difference in the IC₅₀ value may be due to the differences in interface concentrations of pyrrolidine-1 in the different assay systems. The treatment of Chinese hamster ovary cells with pyrrolidine-1 results in marked inhibition of A23187-induced arachidonic acid release with an IC₅₀ value of 0.2 to 0.5 μM. The degree of inhibition approaches 100% with 4 to 10 μM pyrrolidine-1 (Ghomashchi et al., 2001). Similarly the treatment of Madin-Darby canine kidney cells with pyrrolidine-1 also results in marked inhibition of ATP-induced arachidonic acid release with an IC₅₀ value of 0.8 μM. It must be stated here that pyrrolidine-1 also inhibits cPLA₂-γ and iPLA₂-β at a very high concentration but it does not inhibit sPLA₂.

Pyrrophenone, a triphenylmethylthioether derivative of pyrrolidine, is a 39-fold more potent inhibitor (K_i 4.2 nM) of cPLA₂ activity than pyrrolidine-1 (Ono et al., 2002). Pretreatment of rats with pyrrolidine dithiocarbamate, a powerful thiol antioxidant, protects against kainate (KA)-mediated neurotoxicity (Shin et al., 2004). In vitro studies indicate that pyrrophenone may be a potential therapeutic agent for inflammatory diseases (Ono et al., 2002). Pyrrolidine-containing PLA₂ inhibitors have not been injected in animal models of neurological disorders so their half-life and side effects remain unknown.

I. Antimalarial Drugs

All isoforms of bovine brain PLA₂ are strongly inhibited by antimalarial drugs in a dose-dependent manner with rank order potency of chloroquine > quinacrine > hydroxychloroquine > quinine (Lu et al., 2001b). Chloroquine, quinacrine, hydroxychloroquine, and quinine inhibit bovine brain cPLA₂ with IC₅₀ values of 125, 200, 185, and 250 μM. It is suggested that among PLA₂ isoforms, PlsEtn-PLA₂ and cPLA₂ may be associated with proximal events involved in the induction and maintenance of inflammatory processes after ischemic and traumatic brain injuries (Farooqui et al., 2004b) and sPLA₂ may be involved in intensification (Han et al., 2003) of inflammation during later stages of the inflammatory reaction. At low concentrations (<50 μM), these inhibitors have no effect on the growth of neuron-enriched cultures from rat brain cortex, but at high concentrations (>1000 μM), these inhibitors are toxic.

J. Lithium Ion and Carbamazepine

Lithium ion is a mood stabilizer. It has been used for the treatment of bipolar disorders for almost a half-century (Corbella and Vieta, 2003). Lithium ion has a neuroprotective effect on brain tissue. Chronic lithium ion administration in rats result in 50% reduction in mRNA and protein levels of cPLA₂ with no changes observed in iPLA₂ and sPLA₂ protein during these studies (Chang and Jones, 1998; Rintala et al., 1999). Lithium ion does not reduce phosphorylated cPLA₂ protein. Thus, the decrease in brain cPLA₂ enzyme activity induced by chronic lithium ion treatment is due to down-regulation of cPLA₂ transcription (Weerasinghe et al., 2004). This down-regulation of cPLA₂ transcription may be responsible for a selective reduction of arachidonic acid turnover compared with docosahexaenoic acid in rat brain phospholipids (Basselin et al., 2003). The labeling of Purkinje cell dendrites with cPLA₂ and cyclooxygenase (COX-2) antibodies is inhibited by lithium ion, indicating the functional coupling at brain synapses between cPLA₂ and COX-2 enzymes (Weerasinghe et al., 2004).

An anticonvulsant drug, carbamazepine (CBZ), has been used for the treatment of bipolar disorders for many years. Chronic administration of CBZ not only inhibits cPLA₂ activity but also alters its protein and mRNA levels. In contrast, it did not affect iPLA₂ and sPLA₂ activities and protein levels (Ghelardoni et al., 2004). These effects are accompanied by a decrease in COX-2 activity and prostaglandin E₂ levels in brain tissue, suggesting that CBZ blocks the cPLA₂-mediated release of arachidonic acid and its conversion via COX-2 to prostaglandin E₂ (Ghelardoni et al., 2004). The protein levels of other arachidonic acid-metabolizing enzymes such as 5-lipoxygenase and cytochrome P450 and their reaction product leukotriene B₄ are not affected by CBZ. Thus, nonspecific PLA₂ inhibitors, such as lithium ion and CBZ, may have beneficial effects, not only in neurological diseases (see below), but also in bipolar disorders and manic-depressive patients.

K. Vitamin E and Gangliosides

Vitamin E (α-tocopherol) is another nonspecific inhibitor of cPLA₂ activity (Douglas et al., 1986). It modulates the production of arachidonic acid and eicosanoids (Tran et al., 1996). It inhibits bovine brain cPLA₂ and iPLA₂ activities in a dose- and time-dependent manner with IC₅₀ values of 500 and 750 μM, respectively. Vitamin E crosses the blood-brain barrier and with time accumulates in brain (Pentland et al., 1992). It reduces lipid peroxidation and stabilizes neuronal membranes. Several reports indicate that ischemia is accompanied by an increase in PLA₂ activity and a reduction in the levels of vitamin E and glutathione (Farooqui et al., 1994a). A deficiency of vitamin E and selenium in rats leads to a biphasic increase in iPLA₂ activity in non-neural cells (Burgess and Kuo, 1996), once again supporting the view that PLA₂ activity is regulated by vitamin E. Vitamin E may modulate activities of PLA₂ isozymes by two mechanisms: first, by direct incorporation into substrate vesicles; and second, by stimulation of the activity of PLA₂ isoforms by up-regulating the rate of their synthesis at the transcriptional or translation level (Tran et al., 1996).

GM1 and GM3 gangliosides also inhibit cPLA₂ and PlsEtn-PLA₂ activities in a dose-dependent manner (Yang et al., 1994a,b). With PlsEtn-PLA₂ the IC₅₀ values for GM1 and GM3 gangliosides were 150.0 and 75.0 μg/ml, respectively. The IC₅₀ values for brain cPLA₂ for GM1 and GM3 were 250.0 and 100.0 μg/ml, respectively. The mechanism of inhibition by gangliosides remains unknown. However, the orientation of N-acetylneuraminic acid residues in glycoconjugates is important for inhibitory activity (Yang et al., 1994b). Gangliosides not only stabilize neural membranes but also regulate calcium influx and enzyme activities associated with signal transduction.

L. Cytidine 5-Diphosphoamines

CDP-amines are key intermediates in the biosynthesis of phosphatidylcholine and phosphatidylethanolamine. CDP-choline (citicoline) decreases cPLA₂ stimulation and hydroxyl radical generation after transient cerebral ischemia (Adibhatla and Hatcher, 2003). This process results in lowering of the concentration of free fatty acids in a dose- and time-dependent manner. CDP-choline protects neural membranes, not only by accelerating the re-synthesis of phospholipids but also by quenching free radicals generated by PLA₂ isozymes (Rao et al., 2001; Adibhatla et al., 2002). A mixture of CDP-ethanolamine and CDP-choline may be more effective than CDP-choline alone (Murphy and Horrocks, 1993).

M. Long-Chain Polyunsaturated Fatty Acids

Long-chain polyunsaturated fatty acids are normal constituents of neural membrane phospholipids and products of the PLA₂-catalyzed reaction. They include arachidonic acid (belonging to the n-6 class), eicosapentaenoic acid (EPA), and DHA (belonging to the n-3 class). Arachidonic acid is released by the action of cPLA₂, and EPA and DHA are released by the action of PlsEtn-PLA₂ on neural membrane phospholipids. In vitro, the addition of these fatty acids to the reaction mixture inhibits the PLA₂-catalyzed reaction in a dose- and time-dependent manner. This inhibition can be reversed by the addition of bovine serum albumin. The in vivo effects of these fatty acids on brain metabolism are quite complex. Arachidonic acid is metabolized to prostaglandins, leukotrienes, and thromboxanes by cyclooxygenases and lipoxygenases. These metabolites can cause vasoconstriction and hence compromise blood flow and oxygen delivery to brain tissue. EPA competes with arachidonic acid at the cyclooxygenase level to produce the 3-series prostaglandins (PGE₃, PGI₃, and TXA₃) or the 5-series leukotrienes (LTB₅, LTC₅, and LTD₅). These metabolites are less active than the corresponding arachidonic acid-derived compounds (Anderle et al., 2004). For example, TXA₃ is less active than TXA₂ in aggregating platelets and constricting blood vessels (James et al., 2000; Calder and Grimble, 2002). DHA is not a substrate for cyclooxygenase. It inhibits cyclooxygenase activity and is metabolized to docosanoids (Fig. 5). Docosanoids include 10,17S-docosatrienes and 17S-resolvins (Hong et al., 2003; Marcheselli et al., 2003; Serhan et al., 2004). They not only antagonize the effects of arachidonic acid-generated metabolites but also act potently on leukocyte trafficking as well as down-regulating the expression of cytokines in glial cells (Hong et al., 2003; Marcheselli et al., 2003; Mukherjee et al., 2004; Serhan et al., 2004). The specific receptors for these bioactive lipid metabolites occur in neural and non-neural tissues. These receptors include resolvin D receptors (ResoDR1), resolvin E receptors (resoER1), and neuroprotectin D receptors (NPDR). Characterization of these receptors in brain tissue is in progress. The generation of docosanoids may be an internal protective mechanism for preventing brain damage (Horrocks and Farooqui, 2004; Mukherjee et al., 2004; Serhan et al., 2004).

Fig. 5.

Chemical structures of docosahexaenoic acid and its metabolites. a, docosahexaenoic acid; b, eicosapentaenoic acid; c, 10,17S-docosatriene; d, 16,17S-docosatriene; e, 7,16,17S-resolvin; and f, 4,5,17S-resolvin. These metabolites retard the actions of arachidonic acid and its eicosanoid metabolites.

N. Phospholipase A₂ Antisense Oligonucleotides and Interfering RNA

Antisense oligonucleotides have been synthesized to inhibit isoforms of PLA₂ (Locati et al., 1996; Yoo et al., 2001; Laktionova et al., 2004). These antisense oligonucleotides efficiently inhibit the activity of various isoforms of PLA₂ and also block their expression. They may be used for the treatment of inflammation and oxidative stress in neurological disorders. It must be emphasized here that the in vivo effects of antisense oligonucleotides may not be predictable from in vitro studies, partly because of the potential for the activation of the immune system by nucleotides (Endres and von Schacky, 1996). Furthermore, for neurological disorders there may be additional problems, including the efficient delivery of antisense oligonucleotides to a specific brain region in vivo and the high cost in manufacturing large quantities of antisense oligonucleotides.

An important development for inhibiting the enzymic activity of PLA₂ isoforms has been the discovery of the RNA interference (RNAi) technique. This technology takes advantage of the evolutionary adaptation of neural cells to silence a gene whose corresponding double-stranded RNA molecule is present in the cell (Hannon, 2002). Introduction of a synthesized double-stranded RNA specific for a PLA₂ isoform gene may cause rapid and prolonged reduction of mRNA and protein expression of that PLA₂ isoform in brain tissue. RNAi has been developed for iPLA₂ in non-neural cells (Shinzawa and Tsujimoto, 2003). It inhibits protein expression and iPLA₂ activity in a dose- and time-dependent manner. In vivo injections of RNAi have not been made in intact animals, so the therapeutic importance of RNAi remains unknown.

V. Phospholipase A₂ Activity in Kainic Acid-Induced Neural Cell Injury

KA is a nondegradable analog of glutamate. It is 30- to 100-fold more potent than glutamate as a neuronal excitant. Systemic administration of KA in adult rats induces persistent seizures and seizure-mediated brain damage (Lerma, 1997; Ben-Ari and Cossart, 2000). KA produces selective degeneration of neurons, especially in striatal and hippocampal areas of brain after intraventricular and intracerebral injections (Ben-Ari and Cossart, 2000). Axons and nerve terminals are more resistant to the destructive effects of KA than the cell soma. The mechanisms underlying KA-induced neuronal damage are quite complex. These mechanisms not only include inhibition of mitochondrial function and increases in intracellular calcium ion, due to depolarization, but also free radical generation (Farooqui et al., 2001). Our nuclear microscopic studies have clearly indicated a steady increase in calcium ion at 1, 2, and 3 weeks after KA injection (Ong et al., 1999). This increase in calcium ion may be responsible for the stimulation of many calcium-dependent enzymes including isoforms of PLA₂ (Sandhya et al., 1998), calpain II (Ong et al., 1997), and endonucleases during KA-induced neurotoxicity.

Systemic administration of KA into adult rats markedly increases cPLA₂ immunoreactivity in neurons at 1 and 3 days after injection. The cPLA₂ immunoreactivity is also increased in astrocytes at 1, 2, 4, and 11 weeks after KA injection (Sandhya et al., 1998). Collective evidence suggests that an increase of cPLA₂, PlsEtn-PLA₂, and sPLA₂ activities in KA-induced toxicity may be involved in neurodegeneration, whereas the elevation of cPLA₂ activity in astrocytes may be associated with gliosis (Sandhya et al., 1998). We have also observed a decrease in 4-HNE and glutathione levels in KA-mediated toxicity.

Our immunocytochemical studies are supported by neurochemical studies on neuronal cell cultures (Kim et al., 1995; Thwin et al., 2003; Farooqui et al., 2003a,b). Treatment of neuron-enriched cultures with KA results in the stimulation of cPLA₂, PlsEtn-PLA₂, and sPLA₂ activities in a dose- and time-dependent manner (Fig. 6) (Farooqui et al., 2003a,b; Thwin et al., 2003). This stimulation of cPLA₂ activity in neuron-enriched cultures can be blocked by a nonspecific cPLA₂ inhibitor, quinacrine (Farooqui et al., 2003b), a PlsEtn-PLA₂ inhibitor, BEL (Farooqui et al., 2003a), a sPLA₂ inhibitor, 12-episclaradial (Thwin et al., 2003), or by a KA/AMPA receptor antagonist, 6-cyano-7-nitroquinoxaline-2,3-dione (Farooqui et al., 2003a). During KA neurotoxicity, the increased cPLA₂ immunoreactivity is accompanied by an increase in the 4-HNE immunoreactivity and a decrease in glutathione immunoreactivity (Ong et al., 2000) in hippocampus, indicating alterations in cellular redox. The reduction in glutathione levels may be due either to the formation of a 4-HNE-glutathione adduct or to decrease in cysteine uptake caused by KA-mediated neurotoxicity. Both processes increase the vulnerability of neurons to oxidative stress. All of these events, along with the decrease in ATP levels, are closely associated with cell death (Farooqui et al., 2004b).

Fig. 6.

Effect of kainic acid on cPLA₂ (□) and PlsEtn-PLA₂ (▪) activities of neuronal cultures. Data modified from Farooqui et al. (2003a,b) and Thwin et al. (2003).

The molecular mechanism(s) by which KA stimulates cPLA₂ activity are not fully understood. However, excessive stimulation of the KA receptors may produce a marked increase in the level of intracellular Ca²⁺ due to membrane depolarization. Overstimulation of KA receptors may also induce the release of proinflammatory cytokines. Ca²⁺ stimulates the enzymic activity through translocation to neural membranes, whereas cytokines may activate cPLA₂ activity through phosphorylation.

Like KA, intracerebroventricular injections of carrageenan, a high molecular weight sulfated polygalactose, and lipopolysaccharide, a major glycolipid component of Gram-negative bacterial outer membranes, also produce an increase in cPLA₂ activity and neuronal death in the hippocampus (Ong et al., 2003a; Rosenberger et al., 2004). Unlike KA, intracerebroventricular injections of carrageenan do not produce convulsions.

During KA-induced neurotoxicity, neuronal loss, as shown by a decrease in GluR1 staining, is visible in Nissl sections at 3 days after injection. In contrast, carrageenan injections do not produce a decrease in GluR1 staining until the 3rd day after injection, and cell death can be seen in Nissl sections only from 1 week after injection. Finally, during carrageenan neurotoxicity glial cell induction of cPLA₂ occurs earlier than KA-mediated neurotoxicity (Ong et al., 2003a). Like KA-mediated neurotoxicity, carrageenan injections induce the expression of cyclooxygenase immunoreactivity (Sandhya et al., 1998; Ibuki et al., 2003). This response appears at 3 h and becomes most prominent at 6 h after carrageenan injection. Intrathecal administration of a cyclooxygenase-2 inhibitor at 2 h after carrageenan injection produces a prominent therapeutic effect on hyperalgesia. These studies once again support the coupling between PLA₂ and cyclooxygenase enzymes. Similarly, intracerebroventricular injections of lipopolysaccharide produce elevations in cPLA₂ activity but not in sPLA₂ and iPLA₂ activities (Rosenberger et al., 2004).

The molecular mechanism of neuronal loss in carrageenan- and lipopolysaccharide-mediated toxicity is not fully understood. These agents may produce neuroinflammation by activating microglial cells and releasing proinflammatory and cytotoxic factors such as interleukin-1, tumor necrosis factor-α, and nitric oxide (Serhan et al., 2004; Wang et al., 2004a). All these factors are known to up-regulate cPLA₂ activity in a neurotoxin-mediated model of neurodegeneration and represent early steps in generation and maintenance of inflammatory processes and oxidative stress (Farooqui et al., 2002).

Our recent studies have indicated a significant increase in the number of 4-HNE-immunoreactive pyramidal neurons and in cPLA₂ activity in the hippocampus at 1 day, 1 week, and 2 weeks after a single intracerebroventricular injection of 1 μl of 10 mM ferrous ammonium citrate, an agent that produces severe oxidative stress (Ong et al., 2005). Intense 4-HNE labeling is observed at 1 day postinjection. 4-HNE immunoreactivity is markedly decreased after 2 weeks postinjection. A significant increase in cPLA₂ immunoreactivity is also observed in pyramidal neurons at 1 week postinjection. Despite the increased 4-HNE and cPLA₂ labeling, no loss of neurons is observed. Electron microscopic studies showed that 4-HNE- or cPLA₂-positive neurons have features of injured neurons, but they were still viable. The reduction of 4-HNE immunoreactivity in neurons at 2 weeks after oxidative injury, and the lack of cell loss at any of the time intervals, indicates that the hippocampal pyramidal neurons have a remarkable ability to recover from a single episode of severe oxidative injury (W.-Y. Ong et al., 2005, manuscript submitted for publication).

VI. Protection of Kainic Acid-Induced Neural Cell Injury by Phospholipase A₂ Inhibitors

In our studies on KA-induced toxicity in rat brain hippocampal slices and primary neuronal cells in culture, activities of PLA₂ isoforms and their immunoreactivities are markedly increased (Lu et al., 2001a,b; Farooqui et al., 2003a,b). Quinacrine and other inhibitors of cPLA₂ activity, such as AACOCF₃ and BEL, could block this increase in PLA₂ activities and immunoreactivity (Fig. 7). Detailed investigations on the effect of quinacrine indicate that this drug not only blocks the cPLA₂ enzymic activity but also inhibits the expression of its mRNA (Ong et al., 2003b). Thus, 3 days after KA injection into the right lateral ventricle of rats, cPLA₂ mRNA levels were up-regulated 6- to 13-fold in the injected right hippocampus and 5- to 9-fold in the noninjected contralateral hippocampus. cPLA₂ mRNA levels remained at the low basal level in phosphate-buffered saline-injected control rat hippocampus. One week later, cPLA₂ mRNA was up-regulated 3- to 6-fold in the injected right hippocampus and 3- to 8-fold in the noninjected contralateral side. Administration of quinacrine prevented the KA-mediated increases in cPLA₂ mRNA levels. In rat brain hippocampal slices, other antimalarial drugs, including chloroquine, hydroxychloroquine, and quinine, also produce a significant reduction of the increased cPLA₂ immunoreactivity. This suggests that the increased cPLA₂ immunoreactivity after KA-induced neuronal damage is regulated at the mRNA level and antimalarial drugs inhibit this increase (Ong et al., 2003b).

Similarly surfactin, a surfactant lipopeptide with antibiotic, antifungal, and anticoagulant properties, inhibits cPLA₂ activity in a dose-and time-dependent manner. Our studies on KA-induced neurotoxicity in rat hippocampal slice cultures indicate that surfactin significantly reduces neurodegeneration, up-regulation of cPLA₂ activity, and 4-HNE formation. This cPLA₂ inhibitor can be used to prevent KA-induced neurotoxicity (Farooqui et al., 2004b). Vitamin E and ganglioside, the nonspecific inhibitors of cPLA₂, protect neurons from KA-mediated neurotoxicity (Ortiz et al., 2001), supporting our proposal that PLA₂ inhibitors act as neuroprotective agents in KA-mediated neurotoxicity.

Fig. 7.

Histograms showing the effect of 100 μM kainate alone or 100 μM kainate followed 3 h later by a PLA₂ inhibitor. Slices were fixed and processed for immunocytochemistry 1 week after treatment. The y-axes indicate the percentage of a line traced along the stratum pyramidale of the CA fields of the hippocampus that contains immunoreactivity to the AMPA receptor subunit GluR1 (used here as a neuronal marker) (A) or cPLA₂ (B). The results were analyzed with Student's t test. Asterisks indicate statistically significant differences between the kainate-treated group and the other groups (P < 0.05). n = 6 to 12 slices in each group. A significantly greater number of GluR1-positive neurons remain in slices treated with kainate and quinacrine or AACOCF₃ than after kainate treatment alone (A). Treatment with kainate and quinacrine or AACOCF₃ also resulted in less induction of cPLA₂ immunoreactivity, compared with treatment with kainate alone (B). NORM, untreated slices; KA, kainate; KA + QUIN or AACOCF₃ or SURF or BEL, slices treated with kainate, followed by quinacrine, AACOCF₃, surfactin, or bromoenol lactone. Data modified from Lu et al. (2001b).

The molecular mechanism of action of PLA₂ inhibitors in KA-induced neurotoxicity may include the following possibilities:

PLA₂ inhibitors may inhibit cPLA₂ activity by binding to phospholipid substrates (Blackwell and Flower, 1983).
PLA₂ inhibitors may block cPLA₂ activity by interacting with the active site (Lu et al., 2001b).
PLA₂ inhibitors, such as quinacrine, may inhibit cPLA₂ by blocking the expression of the mRNA for cPLA₂ in kainic acid-induced neurotoxicity, as indicated by our northern blot studies (Ong et al., 2003b).
PLA₂ inhibitors might modulate KA receptors by controlling the levels of eicosanoids. The latter are known to be involved in the regulation of hippocampal glutamate receptors (Chabot et al., 1998). PLA₂ inhibitors can modulate the expression of cytokines, NF-κB, adhesion molecules, and brain proteases (Burgermeister et al., 1999). All these molecules are associated with the induction and maintenance of inflammatory processes after neuronal injury.
PLA₂ inhibitors may exert their neuroprotective effects by binding to an AP-1 site and suppressing or lowering transcription of genes for cPLA₂ isozymes. In addition to their effect on cPLA₂ activity and gene expression, PLA₂ inhibitors, such as quinacrine, have also been shown to have anesthetic and anti-inflammatory effects. These effects may be important in preventing neuronal degeneration after KA-induced neurotoxicity. Collective evidence strongly suggests that cPLA₂ inhibitors can be used as potential therapeutic agents for treatment of inflammation and oxidative stress in the KA-mediated model of neural cell injury.

VII. Phospholipase A₂ Activity in Neurological Disorders

It is now well established that activities of PLA₂ isoforms are up-regulated in acute neural trauma, ischemia, spinal cord injury, and head injury, and many neurodegenerative diseases (Fig. 8) with substantial inflammatory and oxidative components such as AD, PD, and MS (Kalyvas and David, 2004; Phillis and O'Regan, 2004; Sun et al., 2004). Many studies indicate that neuroinflammation in these neurological disorders is accompanied by the activation of astrocytes and microglia and the release of inflammatory cytokines. These cytokines propagate inflammation in turn by a number of mechanisms including the up-regulation of PLA₂ isoforms, generation of eicosanoids and platelet-activating factor, stimulation of nitric-oxide synthase, and calpain activation (Farooqui and Horrocks, 1991, 1994; Farooqui et al., 2000b). In this context, among the various approaches under investigation as therapies for neurotrauma and neurodegenerative diseases, there is growing support for strategies that prevent inflammatory reactions during neurodegeneration.

A. Ischemia

Ischemic injury produces the stimulation of cPLA₂ and PlsEtn-PLA₂ in brain tissue (Edgar et al., 1982; Rordorf et al., 1991; Clemens et al., 1996). The stimulation of these enzymes results in the massive release of free fatty acids in brain, the Bazan effect (Farooqui et al., 1994a). The formation of free fatty acids, depletion of ATP, and alterations in ion homeostasis induce membrane dysfunction that may lead to cellular injury (Farooqui and Horrocks, 1991, 1994). The stimulation of PlsEtn-PLA₂ may occupy a proximal position in the injury pathway, initiating neural cell injury, whereas cPLA₂ may participate by hydrolyzing PtdCho and amplifying the injury process (Sapirstein and Bonventre, 2000; Farooqui et al., 2003a,b). The mechanisms of stimulation of isoforms of PLA₂ in ischemic injury are not known. Covalent modification, such as phosphorylation, may be involved in the stimulation process (Edgar et al., 1982). An increased expression of cPLA₂ mRNA and sPLA₂ mRNA also occurs after transient forebrain ischemia (Lin et al., 2004; Sun et al., 2004). The role of cPLA₂ in neuronal damage is strongly supported by studies on cPLA₂ knockout mice (Bonventre et al., 1997; Sapirstein and Bonventre, 2000; Tabuchi et al., 2003). After transient middle cerebral artery occlusion, cPLA₂ knockout mice develop smaller infarcts, less brain edema, and less neurological deficits than control mice, indicating a reduced susceptibility of cPLA₂ knockout mice to ischemic neurodegeneration. Primary neural cell cultures prepared from cPLA₂-deficient mice generate significantly smaller amounts of prostaglandins and leukotrienes (Uozumi and Shimizu, 2002). This suggests that the cPLA₂ deletion contributes to a decrease in arachidonic acid supply to cyclooxygenase-2 and a resultant decrease in prostaglandins synthesis (Hong et al., 2001).

Fig. 8.

Involvement of PLA₂ isoforms in neurological disorders.

Fig. 9.

Activities of cPLA₂ (A) and PlsEtn-PLA₂ (B) in different regions of brains from normal subjects (□) and AD patients (▪). Specific activity is expressed as picomoles per minute per milligram of protein. FC, frontal cortex; PC, parietal cortex; OC, occipital cortex; NB, nucleus basalis; HP, hippocampus; CC, corpus callosum. Data modified from Farooqui et al. (2003a,b).

B. Alzheimer's Disease

Activities of cPLA₂ and PlsEtn-PLA₂ are markedly higher in nucleus basalis and hippocampal regions of AD brain compared with age-matched control brains (Fig. 9) (Stephenson et al., 1996, 1999; Farooqui et al., 1997a, 2003a,b). A similar elevation in COX-2 activity is also found in hippocampal neurons of AD patients compared with age-matched control subjects (Sugaya et al., 2000). In an earlier study, a significantly lower Ca²⁺-dependent PLA₂ activity was found in the parietal and frontal cortices in AD patients compared with age-matched, nondementia patients and control subjects (Gattaz et al., 1995). The method for determining enzymic activity is probably responsible for this discrepancy. Recent studies by this group (Gattaz et al., 2004) also indicate that iPLA₂ activity of platelets from AD patients is markedly lower than that from control subjects. This suggests that more studies are required on the determination of activities of PLA₂ isoforms not only in different regions of AD brain but also on various stages of AD (initial stage, moderately advanced stage, and advanced AD) in human populations. It should be kept in mind that the progress of neurodegeneration varies considerably during the development of AD. This process is strongly influenced by genetic factors. The level of the inflammatory response within the brain is a central factor influencing the neurodegenerative process through the release of inflammatory mediators that are supplied by PLA₂ and COX-2 catalyzed reactions.

The elevation of phospholipid degradation metabolites, phosphomonoesters and phosphodiesters, in AD brain supports our finding of increased cPLA₂ and PlsEtn-PLA₂ activities. The increase in phosphomonoester and phosphodiester correlates with pathological markers of AD, such as neurofibrillary tangles and senile plaques (Pettegrew, 1989). Changes in brain membrane phospholipid and high-energy phosphate metabolism occur before any clinical manifestation of AD (Pettegrew et al., 1995), suggesting that abnormal signal transduction due to disturbed phospholipid metabolism may be an important feature of AD. The aldehydic product of arachidonic acid metabolism, 4-HNE, colocalizes with intraneuronal neurofibrillary tangles and may contribute to the cytoskeletal derangement found in AD. Alterations in phospholipid metabolism may be closely associated with the loss of synapses and neurons and the formation of senile plaques and neurofibrillary tangles in AD (Pettegrew, 1989; Farooqui and Horrocks, 1994). We believe that the synapse loss in AD may be specifically related to lower levels of plasmalogens (phospholipids containing vinyl ether bonds) in autopsy brain samples (Wells et al., 1995; Ginsberg et al., 1998; Guan et al., 1999; Han et al., 2001; Pettegrew et al., 2001), which indicate that plasmalogen deficiency may be related to the stimulation of PlsEtn-PLA₂ (Farooqui et al., 1997a).

The exact cause of increased cPLA₂ and PlsEtn-PLA₂ activities in AD brain is not fully understood. However, there are several possibilities. Aβ, which accumulates in AD, activates cPLA₂ activity (Lehtonen et al., 1996; Kanfer et al., 1998). Treatment of cortical cultures with Aβ stimulates cPLA₂ activity. This stimulation is blocked not only by the cPLA₂ inhibitor MAFP but also by cPLA₂ antisense oligonucleotides (Kriem et al., 2005), strongly suggesting the involvement of cPLA₂ in the pathogenesis of AD (Kriem et al., 2005). The second possibility is that the activation of astrocytes and microglia in AD may result in expression of cytokines, TNF-α, IL-1β, and IL-6, that are known to stimulate cPLA₂ activity (Xu et al., 2003; Rosales-Corral et al., 2004). Finally, the Aβ-mediated influx of calcium ions promotes the activation and translocation of cPLA₂ from cytosol to neural membranes. This results in breakdown of the membranes and abnormal signal transduction in AD (Farooqui and Horrocks, 1994). β-Amyloid-mediated changes in calcium ion signaling underlie not only its action on long-term potentiation but also on many calcium-dependent enzymes (Farooqui and Horrocks, 1994), which may render neurons vulnerable to neurodegenerative process. At this stage it is not known whether elevation of cPLA₂ and PlsEtn-PLA₂ activities is the cause or the consequence of neurodegenerative process and whether changes in activities of PLA₂ isoforms are primary or secondary. Thus, more studies on the involvement of PLA₂ isoforms in pathogenesis of AD are required.

C. Experimental Model of Parkinson's Disease

PD is characterized by a selective degeneration of the dopaminergic neurons of the substantia nigra. Free radicals and lipid peroxides also play an important role in the pathogenesis of PD. They are generated by the action of PLA₂ isoforms and produce oxidative stress in dopaminergic neurons in the substantia nigra. Mice deficient in cPLA₂ activity are resistant to MPTP neurotoxicity. This resistance strongly suggests that cPLA₂ is closely associated with the pathophysiology of PD (Klivenyi et al., 1998). In brain, MPTP is converted to its toxic metabolite, 1-methyl-4-phenylpyridinium ion (MPP⁺), in the presence of monoamine oxidase B. MPP+ is actively taken up into nigrostriatal neurons where it inhibits mitochondrial oxidative phosphorylation, leading to neuronal cell death (Singer et al., 1987).

The involvement of cPLA₂ in PD pathogenesis is supported by MPP⁺-mediated toxicity in GH3 cell cultures (Yoshinaga et al., 2000). MPP⁺-mediated neurodegeneration is accompanied by the stimulation of PLA₂ and arachidonic acid release in GH3 cells. This release of arachidonic acid can be blocked by AACOCF₃, a specific inhibitor of cPLA₂. Once again, this finding suggests the involvement of cPLA₂ in MPP⁺-mediated neurodegeneration. It is interesting to note that in the MPTP-induced model of parkinsonism, quinacrine protects dopaminergic neurons from neurodegeneration (Tariq et al., 2001). In this system quinacrine may act not only as a PLA₂ inhibitor but also as a membrane stabilizer and antioxidant (Tariq et al., 2001; Turnbull et al., 2003).

D. Multiple Sclerosis and Experimental Autoimmune Encephalomyelitis

MS and EAE, an animal model for MS, are inflammatory demyelinating diseases of the brain and spinal cord that result in motor and sensory deficits. A marked increase in PLA₂ activity occurs in brain tissue from MS patients (Huterer et al., 1995). cPLA₂ is highly expressed in EAE lesions (Trigueros et al., 2003; Kalyvas and David, 2004; Phillis and O'Regan, 2004) and inhibition of this enzyme results in a remarkable reduction in the onset and progression of EAE. The reduction in EAE severity correlates with cPLA₂ activity and its downstream mediators such as COX-2, the LTB₄ receptor 2, and various chemokines and cytokines (Kalyvas and David, 2004). The induction and maintenance of neuroinflammation in MS patients may involve cPLA₂. sPLA₂ activity is markedly elevated in EAE and LPS-mediated neurotoxicity (Pinto et al., 2003). An extracellular sPLA₂ inhibitor, N-derivatized phosphatidylethanolamine linked to a polymeric carrier, blocks central nervous system inflammation under both in vivo and in vitro conditions. These interesting observations suggest that more studies are required on the involvement of PLA₂ isoforms in neurodegenerative processes in MS.

E. Prion Diseases

Prion diseases include scrapie, found in goats and sheep, bovine spongiform encephalopathy (mad cow disease) in cattle, and fetal familial insomnia, Creutzfeldt-Jakob disease (CJD), kuru, and Gerstmann-Sträussler-Scheinker syndrome in humans (Prusiner, 2001; Grossman et al., 2003). Neuronal loss, spongiform degeneration, and glial cell proliferation are the pathological hallmarks of prion diseases. Human prion protein (PrP^c) contains 209 amino acids, a disulfide bridge between residues 179 and 214, a glycosylphosphatidylinositol (GPI) anchor, and two sites of nonobligatory N-linked glycosylation at amino acids 181 and 197 (DeArmond and Prusiner, 2003). In prion diseases, the soluble PrP^c, which consists of an α-helix and random coil structures, is refolded into a β-pleated sheet, the insoluble protease resistant isoform, PrP^sc (DeArmond and Prusiner, 2003). The accumulation of PrP^sc, which occurs in the cytoplasm and in secondary lysosomes as well as in neuronal plasmalemma and synaptic regions, may be responsible for the loss of cognitive function in prion diseases (Lazarewicz et al., 1990; Jeffrey et al., 1992).

PrP^sc and PrP106-126, a neurotoxic prion peptide, are known to stimulate NMDA receptors. This stimulation is blocked by MK-801, memantine, and flupirtine (Muller et al., 1993; Perovic et al., 1995; Peyrin et al., 1999). PrP106-126 peptide-mediated stimulation of the NMDA receptor is accompanied with the release of arachidonic acid in cerebellar granule neurons, suggesting the association of PLA₂ isoforms in the pathogenesis of prion diseases (Stewart et al., 2001). The involvement of PLA₂ in the pathogenesis of prion diseases is also supported by recent neuronal cell culture studies (Bate and Williams, 2004). In this model of prion disease, neuronal PLA₂ is activated by GPI isolated from PrP^c or PrP^sc. The ability of GPI to activate PLA₂ is lost by either removal of the acyl chains or cleavage of the phosphatidylinositol-glycan linkage and inhibited by a monoclonal antibody that recognizes phosphatidylinositol (Bate and Williams, 2004). Furthermore, the treatment of neuronal cultures with inositol monophosphate or sialic acid provides resistance to the toxic effects of prion neurotoxic peptides. These observations strongly implicate PLA₂ in the pathogenesis of prion diseases. The involvement of PLA₂ in prion-mediated diseases may be a primary event or a secondary effect of an abnormal signal transduction process related to inflammation and oxidative stress in degenerating neurons. However, it is interesting to note that quinacrine, an acridine-based PLA₂ antagonist, inhibits PrP^sc formation (IC₅₀ 300 nM), and can be used for the treatment of the human prion disease, CJD (Doh-ura et al., 2000; Korth et al., 2001; Love, 2001; Follette, 2003; May et al., 2003). The molecular mechanism involved in the inhibition of PrP^sc formation by quinacrine remains unknown. However, it has been suggested that quinacrine blocks PrP106-126 formed channels (Farrelly et al., 2003). NMR spectroscopic studies indicate that the PLA₂ inhibitor, quinacrine, binds to human prion protein at the Tyr-225, Tyr-226, and Gln-227 residues of helix α3 (Vogtherr et al., 2003). Similarly, other antimalarial drugs, such as chloroquine and the phenothiazine derivatives acepromazine, chlorpromazine, and promazine, also bind to prion protein between residues 121 to 230, suggesting that Tyr-225, Tyr-226, and Gln-227 residues are necessary for the binding of antimalarial drugs and phenothiazine derivatives (Vogtherr et al., 2003) to PrP^c. It has also been reported that quinacrine acts an antioxidant and reduces the toxicity of PrP106-126 (Turnbull et al., 2003). This finding once again suggests that the release of arachidonic acid and the oxidative stress generated by altered arachidonic acid metabolism may play an important role in the pathogenesis of prion diseases (Guentchev et al., 2000; Milhavet et al., 2000).

F. Spinal Cord Injury

Spinal cord injury triggers a series of secondary neurochemical processes that result in apoptotic as well as necrotic cell death (Beattie et al., 2000). The neurochemical changes include a rise in glutamate and intracellular calcium, degradation of membrane phospholipids with generation of free fatty acids, diacylglycerols, eicosanoids, and lipid peroxides (Demediuk et al., 1985), and activation of phospholipases and lipases (Anderson et al., 1985; Taylor, 1988). During the 1st min of compression trauma to the spinal cord, 10% of the PlsEtn is lost with an overall loss of 18% found at 30 min after the compression injury (Horrocks et al., 1985). Similar results have been reported in another model of spinal cord injury in rabbits (Lukácová et al., 1996).

The loss of PlsEtn after compression and ischemic injuries can be explained by the stimulation of PlsEtn-PLA₂ due to shear stress (Taylor, 1988). Stimulation of the PlsEtn-PLA₂ may result in changes in membrane fluidity and permeability, resulting in increased calcium influx, impaired mitochondrial function, and the subsequent generation of ROS. Low levels of ROS act as second messengers and produce neurodegeneration by apoptosis whereas high levels of ROS produce irreversible damage to cellular components and cause cell death by necrosis (Denecker et al., 2001). Necrosis normally occurs at the core of the injury site, whereas neural cells, including oligodendroglia, undergo apoptosis several hours or days after injury in the surrounding area.

G. Head Injury

The neurochemical changes in head injury are accompanied by widespread neuronal depolarization, accumulation of glutamate in the extracellular space, and increased levels of arachidonic acid and eicosanoids as well as leukotrienes (McIntosh et al., 1998). The release of arachidonic acid and its metabolites is due to activation of cPLA₂ (Shohami et al., 1989), as well as the phospholipase C/diacylglycerol-lipase pathway (Wei et al., 1982). The pathological consequences of alterations in phospholipid metabolism in neural trauma and neurodegenerative diseases may include release of glutamate, energy failure, stimulation of PLA₂ and diacylglycerol lipase activities, free radical damage, and alteration of membrane fluidity and permeability. These changes may influence the pattern of membrane-bound enzymes, receptors, and ion channels (Farooqui and Horrocks, 1994).

Glutamate-mediated abnormal phospholipid metabolism may be a common mechanism involved in ischemia and neurodegenerative diseases such as AD. The acute neural trauma in ischemia is accompanied by a rapid release of glutamate and sustained calcium influx at the core of the injury site but not in the surrounding area. This process may result in necrotic cell death at the core of the injury, whereas penumbral region neurons may die by apoptosis. In contrast in AD, there is not an excessive release of glutamate. However, the number of NMDA and other glutamate receptors is decreased in neocortex and hippocampal regions compared with that in age-matched control subjects (Geddes et al., 1992). This decrease results in an alteration in calcium homeostasis and breakdown of membrane phospholipids due to the stimulation of cPLA₂ and PlsEtn-PLA₂ activities. In ischemic injury at the core site, the glutamate-mediated neurodegeneration may be rapid (days), because of the sudden lack of oxygen and a quick drop in ATP and alteration in ion homeostasis. In AD, oxygen, nutrients, and ATP are available to the nerve cell and ion homeostasis is maintained to a limited extent, so neural cells take a much longer time period (years) to die (Farooqui and Horrocks, 1994).

H. Epilepsy

Epileptic seizures are known to stimulate cPLA₂ activity and its expression with the accumulation of arachidonic acid (Visioli et al., 1994; Kajiwara et al., 1996). Studies on the pentylenetetrazol-induced model of epilepsy in rat brain indicate significant elevations in sPLA₂ activity in cortical, hippocampal, and cerebellar regions compared with the control group. The increase in sPLA₂ activity is more pronounced in hippocampal and cortical regions than in the cerebellar region (Yegin et al., 2002). At present, information on activities of PLA₂ isoforms is not available for different regions of epileptic human brain. More studies are needed on the involvement of PLA₂ isoforms in the pathogenesis of epilepsy.

I. Schizophrenia and Depressive Disorders

Marked elevations are found in iPLA₂ activity in brain tissue of schizophrenic patients (Hudson et al., 1996; Ross et al., 1997, 1999). This results in accelerated phospholipid metabolism in schizophrenia. Levels of phosphatidylcholine and phosphatidylethanolamine are decreased, whereas the levels of lysophosphatidylcholine are increased in brain, erythrocytes, platelets, and skin fibroblasts of patients with schizophrenia (Yao et al., 2000; Ross, 2003). The cause of the increased iPLA₂ activity is not known. However, abnormalities in dopamine and retinoid metabolism along with alterations in cytokines in schizophrenic patients may be responsible for the stimulation of PLA₂ isoforms (Laruelle et al., 1999; Farooqui et al., 2004a; Yao and Van Kammen, 2004). In contrast, cPLA₂ activity is markedly decreased in schizophrenic patients (Ross, 2003). Abnormalities in the promoter region of the gene encoding cPLA₂ may be responsible for the altered cPLA₂ activity in schizophrenic subjects (Hudson et al., 1996; Rybakowski et al., 2003). A dimorphic site within the first intron of cPLA₂ may also be responsible for abnormal PLA₂ activity (Ross, 2003). The wide range of phenotypic variability compounds the problem of analyzing and identifying vulnerable genes in schizophrenia. Some clinical or biochemical markers might be used to diminish this problem. Thus, more studies are needed to understand the involvement of PLA₂ polymorphism in the pathophysiology of schizophrenia (Junqueira et al., 2004). Cocaine users also have reduced cPLA₂ activity in their brain tissue (Ross and Turenne, 2002). As in schizophrenia, we suggest that dopaminergic hyperactivity in cocaine users may be responsible for the decreased cPLA₂ activity.

Studies on the association between cPLA₂ and mood disorders indicate a potential involvement of cPLA₂ polymorphism in mood disorders (Pae et al., 2004). It has been reported that genotyping and allele distributions in patients with major depressive disorders are significantly different from those of the control human subjects and a BanI polymorphism of the cPLA₂ gene may be related to the pathogenesis of major depressive disorder (Pae et al., 2004).

VIII. Use of Phospholipase A₂ Inhibitors for the Treatment of Neurological Disorders

In brain, quinacrine (Fig. 3) protects gerbil CA1 hippocampal pyramidal cells during 5 min of forebrain ischemia (Estevez and Phillis, 1997). After intravascular injections, quinacrine appears in monkey brain after 24 h (Dubin et al., 1982), indicating that this inhibitor is metabolically stable and can cross the blood-brain barrier. It is localized in neurons. It has also been administered (5 mg/kg) to rats that underwent 2 h of middle cerebral artery occlusion (Estevez and Phillis, 1997). The administration of quinacrine results in a marked reduction in neurological deficits after 24 h of reperfusion. Importantly, the effects of quinacrine persist even after 7 days. These findings are supported by biochemical and histopathological analysis that indicate a significant decrease in infarct size in quinacrine-treated rats compared with saline-treated controls. Based on these studies (Estevez and Phillis, 1997), it has been proposed that PLA₂ inhibitors have cerebroprotective effects in focal as well as global models of cerebral ischemia. In organotypic hippocampal cultures oxygen/glucose deprivation produces a 2-fold increase in PLA₂ activity with significant cell death. This increase in PLA₂ can be blocked by AACOCF₃ in a dose- and time-dependent manner (Arai et al., 2001). sPLA₂ and iPLA₂ inhibitors were ineffective in blocking cell death. In an attempt to evaluate the contribution of PLA₂ isoforms to the release of free fatty acids, rat cerebral cortex was superfused with inhibitors of PLA₂ activity. AACOCF₃ markedly inhibited the efflux of arachidonic, docosahexaenoic, linoleic, palmitic, and oleic acids from the ischemic/reperfused rat cerebral cortex (Phillis and O'Regan, 2004). Exposure to the sPLA₂ and iPLA₂ inhibitors has minimal effect on the efflux of free fatty acids. These observations strongly suggest that cPLA₂ plays an important role in ischemic injury and that PLA₂ inhibitors can be used for the treatment of ischemic injury.

In addition, quinacrine has been proposed as a therapeutic agent for prion diseases (Korth et al., 2001). Quinacrine blocks prion protein peptide (PrP106-126)-mediated caspase-3 activation, supporting the involvement of cPLA₂ in apoptotic cell death (Stewart et al., 2001). Quinacrine and a combination of quinacrine with chlorpromazine, a phenothiazine derivative, were used for the treatment of CJD using compassionate use as a justification (Love, 2001; Follette, 2003; Kobayashi et al., 2003). During quinacrine treatment, the initial responses of CJD patients have been positive, but within days of starting treatment, patients returned back to their previous states, indicating a transient recovery (Love, 2001; Follette, 2003; Kobayashi et al., 2003). The reason for the transient effect of quinacrine on CJD patients remains unknown. The transient effect may be due to the advanced stage of CJD. If quinacrine treatment could be started at the onset of CJD, patients would probably respond to this drug in a positive manner (Follette, 2003; Kobayashi et al., 2003). PLA₂ activities were not determined during these studies. Thus, no comments can be made about the levels of arachidonic acid and its metabolites, inflammatory reactions, and oxidative stress that occur in prion-mediated neurodegeneration in CJD. More studies are required on the involvement of PLA₂ isoforms and generation of proinflammatory mediators in the pathogenesis of prion diseases in animal and cell culture models.

Recent in vitro studies on prion-infected cell lines ScN2a, SMB, and ScGT1 also indicate that daily treatment of these cells with CDP, aristolochic acid, BEL, and AACOCF₃ causes a significant decrease in protease-resistant prion protein compared with untreated control cells. The treatment with PLA₂ inhibitors decreases protease-resistant prion protein but also reduces prostaglandin E₂ levels. This observation strongly suggests that PLA₂ activity may be closely related to the pathogenesis of prion diseases (Bate et al., 2004). Furthermore, corticosteroids that induce the formation of lipocortins (annexins), a family of PLA₂ inhibitory proteins (Kaetzel and Dedman, 1995), also reduce the content of protease-resistant prion protein in prion-infected cell lines. This finding again supports an involvement of PLA₂ in prion diseases (Bate et al., 2004). However, the use of glucocorticoids in prevention of prion diseases should be treated with caution because the chronic administration of glucocorticoids is known to produce neuronal atrophy (Abraham et al., 2001).

PAF, which is generated by the acetylation of lysophosphatidylcholine, another product of PLA₂-catalyzed reactions, increases the generation of protease-resistant prion protein, and PAF antagonists block it. The mechanism by which PAF antagonists inhibit the formation of protease-resistant prion protein remains unknown. However, PAF antagonists and PLA₂ inhibitors may act by altering intracellular trafficking of cellular prion protein. These observations suggest the pivotal role of PLA₂ and PAF in modulating formation of protease-resistant prion protein, an agent that is suggested to be the main cause of prion diseases (Bate et al., 2004).

Vitamin E protects from neuronal damage induced by cerebral ischemia by inhibiting apoptosis in hippocampal neurons (Tagami et al., 1999; Zhang et al., 2004). This finding suggests that vitamin E reacts with the free radicals and prevents neuronal apoptosis produced by cerebral ischemia and reperfusion. Vitamin E also protects neurons from a toxic concentration of sodium nitroprusside, a nitric oxide donor, in a dose-dependent manner indicating that this vitamin protects brain tissue by inhibiting free radical generation and oxidative stress. Double-blind human trials of vitamin E have been performed. It slows the progression of Alzheimer's disease (Sano et al., 1997) or has only symptomatic effects with no alteration of the progression of AD (Sano et al. 1997). In cat spinal cord, preloading with vitamin E and selenium promotes recovery after spinal cord injury (Anderson et al., 1985). Collective evidence suggests that vitamin E may be useful for the treatment of inflammation and oxidative stress in acute neural trauma and neurodegenerative diseases. Negative results in human trials are probably due to the lack of a range of redox inhibitors.

CDP-choline (citicoline) inhibits cPLA₂ activity and lowers the concentration of free fatty acids in a dose- and time-dependent manner (Adibhatla et al., 2002). This compound is an intermediate in PtdCho biosynthesis that has been used for the treatment of ischemic and head injuries (Andersen et al., 1999; Dempsey and Rao, 2003). It not only restores the concentration of PtdCho after ischemic injury by increasing PtdCho synthesis from diacylglycerol but also blocks the activation of cPLA₂ activity (Adibhatla et al., 2002). The decrease in cPLA₂ activity may lead to a reduction in levels of arachidonic acid and reactive oxygen species, with stabilization of neural membranes. CDP-choline also protects cerebellar granule neurons from glutamate-mediated neurotoxicity (Mir et al., 2003), suggesting that CDP-choline may protect neurons from excitotoxicity. CDP-choline has been used in phase III clinical trials for stroke and is being evaluated for the treatment of AD and PD. It also improves the verbal memory of aged human subjects. These observations suggest that this cPLA₂ inhibitor can be used for treating acute neural trauma as well as neurodegenerative diseases.

Neurotrophic effects of gangliosides have been demonstrated in AD, PD, spinal cord injury, and stroke (Geisler et al., 1991; Svennerholm, 1994). The mechanism underlying the ganglioside action is not fully understood. However, gangliosides are known to inhibit neurotransmitter release and cPLA₂ and PlsEtn-PLA₂ activities. Gangliosides also rescue neuronal cultures from death after neurotrophic factor deprivation (Ferrari et al., 1993). NMR studies indicate that GM1 ganglioside binds tightly with β-amyloid peptide and inhibits the α-helix to β-sheet conformational change in β-amyloid peptide (Mandal and Pettegrew, 2004). The interaction with GM1 ganglioside may release the inhibition of PLA₂ isoforms by GM1 and β-amyloid, resulting in delay of neurodegeneration in AD. In ischemic brain, gangliosides protect neural cells by scavenging free radicals generated during reperfusion (Fighera et al., 2004).

In the MPP⁺-mediated cell culture model of PD (Yoshinaga et al., 2000), neurodegeneration is accompanied by the stimulation of PLA₂ and arachidonic acid release in GH3 cells. This release of arachidonic acid can be blocked by arachidonyl trifluoromethyl ketone, a potent inhibitor of cPLA₂, suggesting the involvement of cPLA₂-mediated oxidative stress in MPP⁺-mediated neurodegeneration. Similarly in the MPTP-induced model of parkinsonism, quinacrine protects dopaminergic neurons from neurodegeneration (Tariq et al., 2001). In this system quinacrine may act not only as a PLA₂ inhibitor but also as a membrane stabilizer and antioxidant (Tariq et al., 2001; Turnbull et al., 2003).

Polyunsaturated fatty acids of the n-3 series have many beneficial effects in the central nervous system (Farooqui and Horrocks, 2004a). Thus, EPA prevents LPS-mediated TNF-α expression by preventing NF-κB activation and protects rat hippocampus from LPS-mediated neurotoxicity (Lonergan et al., 2004; Zhao et al., 2004). In C6 glioma cells, EPA modulates myelin proteolipid gene expression (Salvati et al., 2004). This fatty acid is used for the treatment of schizophrenia (Peet and Ryles, 2001; Horrobin, 2003).

Chronic preadministration of DHA prevents β-amyloid-induced impairment of an avoidance ability-related memory function in a rat model of AD (Hashimoto et al., 2002) and protects mice from synaptic loss and dendritic pathological changes in another model of AD (Calon et al., 2004). Thus, DHA is beneficial in preventing the learning deficiencies in these AD models. DHA also affects amyloid precursor protein processing by inhibiting α- and β-secretase activities (de Wilde et al., 2003; Walsh and Selkoe, 2004). Supplements of DHA produce a neuroprotective effect on β-amyloid deposition without significant toxic effects. DHA reverses the age-related impairment in LTP and depolarization-induced glutamate release. It also inhibits the production of TNF-α, interleukin-1, and interleukin-6. DHA protects the brain against ischemic and excitotoxic damage in rats (Gamoh et al., 1999; Terano et al., 1999). DHA may act as an antioxidant (Hossain et al., 1998). DHA induces antioxidant defenses by enhancing cerebral activities of catalase, glutathione peroxidase, and levels of glutathione (Hossain et al., 1999). Thus, EPA and DHA exert their neuroprotective effects by modulating cytokines, inflammation, and oxidative stress.

Treatment of Zellweger syndrome patients with purified DHA partially improves visual function, increases levels of plasmalogens, and reduces levels of saturated very long-chain fatty acids (Hossain et al., 1999). The level of DHA is also low in patients with multiple sclerosis. Fish oil supplements with vitamins improve the clinical outcome in MS patients (Nordvik et al., 2000). Collective evidence from many studies indicates that DHA supplementation restores signal transduction processes associated with behavioral deficits, learning activity in Alzheimer disease, schizophrenia, depression, hyperactivity, stroke, and peroxisomal disorders (Farooqui and Horrocks, 2004a).

All of the cPLA₂ inhibitors used in these studies are nonspecific. Thus, the design and synthesis of specific cPLA₂ inhibitors is urgently needed to make progress in this important area of research. The reaction catalyzed by cPLA₂ is a rate-limiting step for the generation of eicosanoids, lysophospholipids, and platelet-activating factor. High levels of these metabolites are responsible for oxidative stress, inflammation, and neuronal death at the injury site. Potent PLA₂ inhibitors can effectively block the above events associated with neurodegenerative processes and rescue neural cells from cell death. It is hoped that the synthesis of a new generation of cPLA₂ inhibitors would have regional specificity. The inhibitors should be able to reach the injury site where neural cells are under oxidative stress and where neurodegenerative processes are taking place.

IX. Prevention of Pain by Phospholipase A₂ Inhibitors

Proinflammatory cytokines released at the site of neural trauma and nerve injury may be involved in sensitization of nociceptors leading to hyperalgesia (Walters, 1994). Injections of carrageenan into the paw or face have been widely used as a model to induce pain sensitization (Ng and Ong, 2001). We have recently studied the effect of intracerebroventricular injections of a sPLA₂ inhibitor, 12-epi-scalaradial, a cPLA₂ inhibitor, AACOCF₃, and a iPLA₂ inhibitor, bromoenol lactone, on the development of allodynia after facial carrageenan injections in two strains of mice (Yeo et al., 2004) (Fig. 10). C57BL/6J (B6) mice show an increase in allodynia from 8 h to 3 days after facial carrageenan injection. On the other hand, the BALB/c strain did not show an increase in allodynia at any time point. In both B6 and BALB/c mice, all PLA₂ inhibitors significantly reduced responses to von Frey hair stimulation at 8 h and 1 day, but at 3 days only the sPLA₂ inhibitor had an effect. Because BALB/c mice do not show increases in allodynia after carrageenan injection, the reduction in responses seen with PLA₂ inhibitors actually means that these inhibitors produce a loss of normal sensitivity to von Frey hair stimulation. The effects of PLA₂ inhibitors are unlikely to be due simply to inhibition of arachidonic acid generation, because intracerebroventricular injection of arachidonic acid also had an antinociceptive effect (Yeo et al., 2004). It is proposed that lysophosphatidylcholine mediates pain transmission in the central nervous system. The pronounced and long-lasting antinociceptive effect of 12-epi-scalaradial is consistent with our recent finding that sPLA₂ induces exocytosis and neurotransmitter release in neurons and supports a key role of central nervous system sPLA₂ in synaptic and pain transmission. These results suggest that PLA₂ isoforms play an important role not only in pain transmission but also in nonpainful, touch, or pressure sensation. Our studies on the antinociceptive effect of PLA₂ inhibitors are supported by recent studies on intrathecal injections of MAFP and AACOCF₃ in rats. MAFP has a significant antinociceptive effect in the rat formalin test (Ates et al., 2003). Based on our studies, we suggest that PLA₂ inhibitors may reduce allodynia and hyperalgesia in inflammation-mediated central pain.

X. Perspective and Direction for Future Studies

PLA₂ isoforms along with cyclooxygenases have emerged as major players in modulating inflammation and oxidative stress in brain tissue. Elucidation of the mechanism of action of PLA₂ inhibitors in vivo is a critical area of research because of the potential pharmacological benefits of these compounds as therapeutic agents for the treatment of inflammation and oxidative stress in neurotrauma and neurodegenerative diseases (Farooqui et al., 1999). Although several inhibitors of PLA₂ activity have been reported in the literature (Farooqui et al., 1999; Cummings et al., 2000; Miele, 2003b), little information is available on the mechanism of their action. Different mechanisms of action are possible; e.g., an inhibitor can produce alterations in enzymic activity by perturbing the physicochemical properties of phospholipid bilayers. A PLA₂ inhibitor can directly interact with the active site of an isoform, as AACOCF₃, MAFP, and BEL, or it can act on an allosteric site on the enzyme molecule to bring about changes in enzymic activity. An inhibitor may also possess a detergent-like structure that can induce nonspecific changes in membrane properties in vivo through the interaction of its amphiphilic groups with other membrane components to produce changes in enzymic activity.

Fig. 10.

Total responses in mice treated with dimethyl sulfoxide (DMSO), PLA₂ inhibitors or arachidonic acid, and carrageenan at 8 h after injection. The y-axes indicate total scratching/withdrawal/attack/escape responses in mice that received intracerebroventricular injection of DMSO (5 μl, vehicle control), PLA₂ inhibitors (0.01 μmol in DMSO), or arachidonic acid (0.01 μmol in DMSO) and a facial injection of carrageenan, 8 h after injections. Data were analyzed by one-way analysis of variance with Bonferroni's multiple comparison post hoc test. *, statistically significant differences (P < 0.05). n = 4 mice in each group. Both B6 mice (A) and BALB/c mice (B) showed significantly fewer total responses to von Frey hair stimulation of the face after injection with inhibitors to each of the three isoforms of PLA₂ or arachidonic acid compared with DMSO. D+C, S+C, A+C, B+C, AA+C indicate DMSO, 12-epi-scalaradial, AACOCF₃, BEL, or arachidonic acid, plus carrageenan, respectively. Data modified from Yeo et al. (2004).

Inhibitors of cPLA₂ modulate the expression of cytokines, growth factors, NF-κB, and adhesion molecules and thus can block endogenous inflammatory reactions. Some nonspecific inhibitors of PLA₂ have been used for the treatment of ischemia, spinal cord injury, and AD in animal models and in humans. It is clear from the above discussion that novel, potent, and specific inhibitors of PLA₂ are now emerging as potential therapeutic agents for neuroinflammation and oxidative stress in cell culture systems, but they have not yet been used in animal models of neurological disorders.

In brain, PLA₂ occurs in multiple forms. Thus, specific PLA₂ inhibitors must be designed for individual PLA₂ isozymes to define their roles in brain metabolism. The design of PLA₂ inhibitors should be focused on our rapidly emerging understanding of the role of signal transduction pathways in neurological disorders. Because PLA₂-catalyzed reactions are the rate-limiting steps for the production of prostaglandins, leukotrienes, and thromboxanes, the identification of PLA₂-coupled receptors and their endogenous regulatory pathways that mediate proliferative, metabolic, and inflammatory signals can provide better targets for designing PLA₂ inhibitors. Specificity, selectivity, harmlessness, and the ability to cross the blood-brain barrier are important qualities of a PLA₂ inhibitor as a potential therapeutic agent for neurological disorders.

At this time, it is quite difficult to predict the potential side effects of the chronic use of cell-permeable, specific, or nonspecific inhibitors of PLA₂. Hence, studies on the availability of specific, nontoxic potent inhibitors with greater blood-brain barrier permeability in animal models of neurodegenerative diseases are urgently needed. Surely, PLA₂ isoforms from different sources will have different inhibitor sensitivities and reactivity in vivo. Nevertheless, pharmacological studies in animal models of acute trauma and neurodegenerative diseases will provide directions that should be taken to develop better PLA₂ inhibitors for targeting isoforms of brain PLA₂ activities.

In recent years advanced molecular biology procedures have been used in a number of studies to overcome some of the problems associated with the specificity of chemical inhibitors of PLA₂. For example, antisense oligonucleotides that inhibit specific cPLA₂ or iPLA₂ have been developed. Transgenic mice that are deficient in or overexpress cPLA₂ isoforms are now available (Bonventre et al., 1997). Overexpression of cPLA₂ allows one to study the effect of increased cPLA₂ activity, whereas a deficiency of cPLA₂ can be helpful in studying the consequences of reduced cPLA₂ activity on cellular metabolism in normal and diseased cells. RNAi for iPLA₂ has also been developed. Transfection studies with RNAi of iPLA₂ indicate that the levels of iPLA₂ protein and iPLA₂ activity are decreased in a dose-dependent manner in transfected non-neural cells (Shinzawa and Tsujimoto, 2003). Such studies are needed in neuronal cell cultures and animal models to understand the neurophysiological importance of the RNAi technique. We propose that a comparison of activities of PLA₂ isoforms and intensity of signal transduction process between normal and genetically manipulated mice may provide further insight into the role of PLA₂ isoforms, their ligands, and their lipid mediators in neurodegenerative processes.

Thus, the development of specific inhibitors for different PLA₂ isoforms should be an important goal for future research on brain PLA₂ activities. The chemical approach, together with molecular biological procedures such as RNAi and alterations in signal transduction processes in knockout mice, may provide the important information needed to develop specific PLA₂ inhibitors that can be used to retard oxidative stress and inflammatory reactions during neurodegeneration in neurological disorders.

Acknowledgments

We thank Dr. Tahira Farooqui, Department of Entomology, The Ohio State University, Columbus, OH, for useful discussion and Siraj A Farooqui for providing figures and help with the preparation of this manuscript.

Footnotes

↵1 Abbreviations: PLA₂, phospholipase A₂; PAF, platelet activating factor; AD, Alzheimer's disease; PD, Parkinson's disease; MS, multiple sclerosis; 4-HNE, 4-hydroxynonenal; sPLA₂, secretory phospholipase A₂; cPLA₂, cytosolic phospholipase A₂; PlsEtnPLA₂, plasmalogen-selective phospholipase A₂; iPLA₂, calcium-independent phospholipase A₂; PKC, protein kinase C; PtdCho, phosphatidylcholine; LTP, long-term potentiation; DHA, docosahexaenoic acid; IL, interleukin; TNF, tumor necrosis factor; AP-1, activator protein-1; NF-κB, nuclear factor-κB; ROS, reactive oxygen species; MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; PG, prostaglandin; NMR, nuclear magnetic resonance; AACOCF₃, arachidonyl trifluoromethyl ketone; Aβ, β-amyloid peptide; MeHg²⁺, methylmercury; MAPF, methyl arachidonyl fluorophosphonate; BEL, bromoenol lactone; AMPA, α-amino-3-hydroxy-5-methylisoxazole-4-propionate; LPS, lipopolysaccharide; KA, kainate; COX-2, cyclooxygenase-2; CBZ, carbamazepine; CDP, cytidine 5-diphospho; EPA, eicosapentaenoic acid; TX, thromboxane; LT, leukotriene; RNAi, RNA interference; MMP⁺, 1-methyl-4-phenylpyridinium ion; MS, multiple sclerosis; EAE, experimental autoimmune encephalomyelitis; CJD, Creutzfeldt-Jakob disease; PrP, prion disease protein; GPI, glycosylphosphatidylinositol; NMDA, N-methyl-d-aspartate; MK-801, 5H-dibenzo[a,d]cyclohepten-5,10-imine (dizocilpine maleate).
Article, publication date, and citation information can be found at http://pharmrev.aspetjournals.org.
doi:10.1124/pr.58.3.7.

The American Society for Pharmacology and Experimental Therapeutics

References

↵
Abraham IM, Harkany T, Horvath KM, and Luiten PG (2001) Action of glucocorticoids on survival of nerve cells: promoting neurodegeneration or neuroprotection? J Neuroendocrinol 13: 749-760.
OpenUrl CrossRef PubMed
↵
Ackermann EJ and Dennis EA (1995) Mammalian calcium-independent phospholipase A₂. Biochim Biophys Acta 1259: 125-136.
OpenUrl PubMed
↵
Adibhatla RM and Hatcher JF (2003) Citicoline decreases phospholipase A₂ stimulation and hydroxyl radical generation in transient cerebral ischemia. J Neurosci Res 73: 308-315.
OpenUrl CrossRef PubMed
↵
Adibhatla RM, Hatcher JF, and Dempsey RJ (2002) Citicoline: neuroprotective mechanisms in cerebral ischemia. J Neurochem 80: 12-23.
OpenUrl CrossRef PubMed
↵
Adibhatla RM, Hatcher JF, and Dempsey RJ (2003) Phospholipase A₂, hydroxyl radicals, and lipid peroxidation in transient cerebral ischemia. Antioxid Redox Signal 5: 647-654.
OpenUrl CrossRef PubMed
↵
Aitdafoun M, Mounier C, Heymans F, Binisti C, Bon C, and Godfroid JJ (1996) 4-Alkoxybenzamidines as new potent phospholipase A₂ inhibitors. Biochem Pharmacol 51: 737-742.
OpenUrl CrossRef PubMed
↵
Ajmone-Cat MA, Nicolini A, and Minghetti L (2003) Prolonged exposure of microglia to lipopolysaccharide modifies the intracellular signaling pathways and selectively promotes prostaglandin E-2 synthesis. J Neurochem 87: 1193-1203.
OpenUrl CrossRef PubMed
↵
Akiyama N, Hatori Y, Takashiro Y, Hirabayashi T, Saito T, and Murayama T (2004) Nerve growth factor-induced up-regulation of cytosolic phospholipase A₂α level in rat PC12 cells. Neurosci Lett 365: 218-222.
OpenUrl CrossRef PubMed
↵
Amandi-Burgermeister E, Tibes U, Kaiser BM, Friebe WG, and Scheuer WV (1997) Suppression of cytokine synthesis, integrin expression and chronic inflammation by inhibitors of cytosolic phospholipase A₂. Eur J Pharmacol 326: 237-250.
OpenUrl CrossRef PubMed
↵
Anderle P, Farmer P, Berger A, and Roberts MA (2004) Nutrigenomic approach to understanding the mechanisms by which dietary long-chain fatty acids induce gene signals and control mechanisms involved in carcinogenesis. Nutrition 20: 103-108.
OpenUrl CrossRef PubMed
↵
Andersen M, Overgaard K, Meden P, and Boysen G (1999) Effects of citicoline combined with thrombolytic therapy in a rat embolic stroke model. Stroke 30: 1464-1470.
OpenUrl Abstract/FREE Full Text
↵
Anderson DK, Saunders RD, Demediuk P, Dugan LL, Braughler JM, Hall ED, Means ED, and Horrocks LA (1985) Lipid hydrolysis and peroxidation in injured spinal cord: Partial protection with methylprednisolone or vitamin E and selenium. Cent Nerv Syst Trauma 2: 257-267.
OpenUrl PubMed
↵
Arai K, Ikegaya Y, Nakatani Y, Kudo I, Nishiyama N, and Matsuki N (2001) Phospholipase A₂ mediates ischemic injury in the hippocampus: a regional difference of neuronal vulnerability. Eur J Neurosci 13: 2319-2323.
OpenUrl CrossRef PubMed
↵
Asai K, Hirabayashi T, Houjou T, Uozumi N, Taguchi R, and Shimizu T (2003) Human group IVC phospholipase A₂ (cPLA₂γ)—roles in the membrane remodeling and activation induced by oxidative stress. J Biol Chem 278: 8809-8814.
OpenUrl Abstract/FREE Full Text
↵
Ates M, Hamza M, Seidel K, Kotalla CE, Ledent C, and Guhring H (2003) Intrathecally applied flurbiprofen produces an endocannabinoid-dependent antinociception in the rat formalin test. Eur J Neurosci 17: 597-604.
OpenUrl CrossRef PubMed
↵
Atsumi G, Murakami M, Kojima K, Hadano A, Tajima M, and Kudo I (2000) Distinct roles of two intracellular phospholipase A₂s in fatty acid release in the cell death pathway: proteolytic fragment of type IVA cytosolic phospholipase A_2α inhibits stimulus-induced arachidonate release, whereas that of type VI Ca²⁺-independent phospholipase A₂ augments spontaneous fatty acid release. J Biol Chem 275: 18248-18258.
OpenUrl Abstract/FREE Full Text
↵
Atsumi G, Tajima M, Hadano A, Nakatani Y, Murakami M, and Kudo I (1998) Fas-induced arachidonic acid release is mediated by Ca²⁺-independent phospholipase A₂ but not cytosolic phospholipase A₂ which undergoes proteolytic inactivation. J Biol Chem 273: 13870-13877.
OpenUrl Abstract/FREE Full Text
↵
Balboa MA, Varela-Nieto I, Lucas KK, and Dennis EA (2002) Expression and function of phospholipase A₂ in brain. FEBS Lett 531: 12-17.
OpenUrl CrossRef PubMed
↵
Basselin M, Chang L, Seemann R, Bell JM, and Rapoport SI (2003) Chronic lithium administration potentiates brain arachidonic acid signaling at rest and during cholinergic activation in awake rats. J Neurochem 85: 1553-1562.
OpenUrl CrossRef PubMed
↵
Bate C, Reid S, and Williams A (2004) Phospholipase A₂ inhibitors or platelet-activating factor antagonists prevent prion replication. J Biol Chem 279: 36405-36411.
OpenUrl Abstract/FREE Full Text
↵
Bate C and Williams A (2004) Role of glycosylphosphatidylinositols in the activation of phospholipase A₂ and the neurotoxicity of prions. J Gen Virol 85: 3797-3804.
OpenUrl Abstract/FREE Full Text
Bayón Y, Hernández M, Alonso A, Nunez L, Garcia-Sancho J, Leslie C, Crespo MS, and Nieto ML (1997) Cytosolic phospholipase A₂ is coupled to muscarinic receptors in the human astrocytoma cell line 1321N1: characterization of the transducing mechanism. Biochem J 323: 281-287.
OpenUrl Abstract/FREE Full Text
↵
Beattie MS, Farooqui AA, and Bresnahan JC (2000) Review of current evidence for apoptosis after spinal cord injury. J Neurotrauma 17: 915-925.
OpenUrl CrossRef PubMed
↵
Ben-Ari Y and Cossart R (2000) Kainate, a double agent that generates seizures: two decades of progress. Trends Neurosci 23: 580-587.
OpenUrl CrossRef PubMed
↵
Berlett BS and Stadtman ER (1997) Protein oxidation in aging, disease, and oxidative stress. J Biol Chem 272: 20313-20316.
OpenUrl FREE Full Text
↵
Blackwell GJ and Flower RJ (1983) Inhibition of phospholipase. Br Med Bull 39: 260-264.
OpenUrl FREE Full Text
↵
Boilard E, Bourgoin SG, Bernatchez C, Poubelle PE, and Surette ME (2003) Interaction of low molecular weight group IIA phospholipase A₂ with apoptotic human T cells: role of heparan sulfate proteoglycans. FASEB J 17: 1068-1080.
OpenUrl Abstract/FREE Full Text
↵
Bonventre JV, Huang ZH, Taheri MR, O'Leary E, Li E, Moskowitz MA, and Sapirstein A (1997) Reduced fertility and postischaemic brain injury in mice deficient in cytosolic phospholipase A₂. Nature (Lond) 390: 622-625.
OpenUrl CrossRef PubMed
↵
Bosetti F and Weerasinghe GR (2003) The expression of brain cyclooxygenase-2 is down-regulated in the cytosolic phospholipase A₂ knockout mouse. J Neurochem 87: 1471-1477.
OpenUrl CrossRef PubMed
↵
Brown WJ, Chambers K, and Doody A (2003) Phospholipase A₂ (PLA₂) enzymes in membrane trafficking: mediators of membrane shape and function. Traffic 4: 214-221.
OpenUrl CrossRef PubMed
↵
Burgermeister E, Tibes U, Stockinger H, and Scheuer WV (1999) Activation of nuclear factor-κB by lipopolysaccharide in mononuclear leukocytes is prevented by inhibitors of cytosolic phospholipase A₂. Eur J Pharmacol 369: 373-386.
OpenUrl CrossRef PubMed
↵
Burgess JR and Kuo CF (1996) Increased calcium-independent phospholipase A₂ activity in vitamin E and selenium-deficient rat lung, liver, and spleen cytosol is time-dependent and reversible. J Nutr Biochem 7: 366-374.
OpenUrl CrossRef
↵
Burke JR, Witmer MR, Tredup J, Micanovic R, Gregor KR, Lahiri J, Tramposch KM, and Villafranca JJ (1995) Cooperativity and binding in the mechanism of cytosolic phospholipase A₂. Biochemistry 34: 15165-15174.
OpenUrl CrossRef PubMed
↵
Burke JR, Witmer MR, Zusi FC, Gregor KR, Davern LB, Padmanabha R, Swann RT, Smith D, Tredup JA, Micanovic R, et al. (1999) Competitive, reversible inhibition of cytosolic phospholipase A₂ at the lipid-water interface by choline derivatives that partially partition into the phospholipid bilayer. J Biol Chem 274: 18864-18871.
OpenUrl Abstract/FREE Full Text
↵
Calder PC and Grimble RF (2002) Polyunsaturated fatty acids, inflammation and immunity. Eur J Clin Nutr 56: S14-S19.
OpenUrl CrossRef PubMed
↵
Calon F, Lim GP, Yang FS, Morihara T, Teter B, Ubeda O, Rostaing P, Triller A, Salem NJ, Ashe KH, et al. (2004) Docosahexaenoic acid protects from dendritic pathology in an Alzheimer's disease mouse model. Neuron 43: 633-645.
OpenUrl CrossRef PubMed
↵
Chabot C, Gagne J, Giguere C, Bernard J, Baudry M, and Massicotte G (1998) Bidirectional modulation of AMPA receptor properties by exogenous phospholipase A₂ in the hippocampus. Hippocampus 8: 299-309.
OpenUrl CrossRef PubMed
↵
Chakraborti S (2003) Phospholipase A₂ isoforms: a perspective. Cell Signal 15: 637-665.
OpenUrl CrossRef PubMed
↵
Chang MCJ and Jones CR (1998) Chronic lithium treatment decreases brain phospholipase A₂ activity. Neurochem Res 23: 887-892.
OpenUrl CrossRef PubMed
↵
Chiba H, Michibata H, Wakimoto K, Seishima M, Kawasaki S, Okubo K, Mitsui H, Torii H, and Imai Y (2004) Cloning of a gene for a novel epithelium-specific cytosolic phospholipase A₂, cPLA₂δ, induced in psoriatic skin. J Biol Chem 279: 12890-12897.
OpenUrl Abstract/FREE Full Text
↵
Clark JD and Tam S (2004) Potential therapeutic uses of phospholipase A₂ inhibitors. Expert Opin Ther Patents 14: 937-950.
OpenUrl CrossRef
↵
Clark MA, Conway TM, Shorr RGL, and Crooke ST (1987) Identification and isolation of a mammalian protein which is antigenically and functionally related to the phospholipase A₂ stimulatory peptide melittin. J Biol Chem 262: 4402-4406.
OpenUrl Abstract/FREE Full Text
↵
Clemens JA, Stephenson DT, Smalstig EB, Roberts EF, Johnstone EM, Sharp JD, Little SP, and Kramer RM (1996) Reactive glia express cytosolic phospholipase A₂ after transient global forebrain ischemia in the rat. Stroke 27: 527-535.
OpenUrl Abstract/FREE Full Text
↵
Connolly S, Bennion C, Botterell S, Croshaw PJ, Hallam C, Hardy K, Hartopp P, Jackson CG, King SJ, Lawrence L, et al. (2002) Design and synthesis of a novel and potent series of inhibitors of cytosolic phospholipase A₂ based on a 1,3-disubstituted propan-2-one skeleton. J Med Chem 45: 1348-1362.
OpenUrl CrossRef PubMed
↵
Corbella B and Vieta E (2003) Molecular targets of lithium action. Acta Neuropsychiatry 15: 316-340.
OpenUrl CrossRef
↵
Cummings BS, McHowat J, and Schnellmann RG (2000) Phospholipase A₂s in cell injury and death. J Pharmacol Exp Ther 294: 793-799.
OpenUrl Abstract/FREE Full Text
↵
de Wilde MC, Leenders I, Broersen LM, Kuipers AAM, van der Beek EM, and Kiliaan AJ (2003) The omega-3 fatty acid docosahexaenoic acid (DHA) inhibits the formation of beta amyloid in CHO7PA2 cells, in Society for Neuroscience 33rd Annual Meeting Abstracts; 2003 Nov 8-12; New Orleans, LA; Abstract nr 730.11.
↵
DeArmond SJ and Prusiner SB (2003) Perspectives on prion biology, prion disease pathogenesis, and pharmacologic approaches to treatment. Clin Lab Med 23: 1-41.
OpenUrl CrossRef PubMed
↵
DeCoster MA, Lambeau G, Lazdunski M, and Bazan NG (2002) Secreted phospholipase A₂ potentiates glutamate-induced calcium increase and cell death in primary neuronal cultures. J Neurosci Res 67: 634-645.
OpenUrl CrossRef PubMed
↵
Demediuk P, Saunders RD, Anderson DK, Means ED, and Horrocks LA (1985) Membrane lipid changes in laminectomized and traumatized cat spinal cord. Proc Natl Acad Sci USA 82: 7071-7075.
OpenUrl Abstract/FREE Full Text
↵
Dempsey RJ and Rao VLR (2003) Cytidinediphosphocholine treatment to decrease traumatic brain injury-induced hippocampal neuronal death, cortical contusion volume, and neurological dysfunction in rats. J Neurosurg 98: 867-873.
OpenUrl PubMed
↵
Denecker G, Vercammen D, Declercq W, and Vandenabeele P (2001) Apoptotic and necrotic cell death induced by death domain receptors. Cell Mol Life Sci 58: 356-370.
OpenUrl CrossRef PubMed
↵
Diaz-Arrastia R and Scott KS (1999) Expression of cPLA2-β and cPLA2-γ, novel paralogs of group IV cytosolic phospholipase A2 in mammalian brain. Soc Neurosci Abs 25: 2206.
OpenUrl
↵
Doh-ura K, Iwaki T, and Caughey B (2000) Lysosomotropic agents and cysteine protease inhibitors inhibit scrapie-associated prion protein accumulation. J Virol 74: 4894-4897.
OpenUrl Abstract/FREE Full Text
↵
Doug M, Guda K, Nambiar PR, Rezaie A, Belinsky GS, Lambeau G, Giardina C, and Rosenberg DW (2003) Inverse association between phospholipase A₂ and COX-2 expression during mouse colon tumorigenesis. Carcinogenesis 24: 307-315.
OpenUrl Abstract/FREE Full Text
↵
Douglas CE, Chan AC, and Choy PC (1986) Vitamin E inhibits platelet phospholipase A₂. Biochim Biophys Acta 876: 639-645.
OpenUrl PubMed
↵
Dubin NH, Blake DA, DiBlasi MC, Parmley TH, and King TM (1982) Pharmacokinetic studies on quinacrine following intrauterine administration to cynomolgus monkeys. Fertil Steril 38: 735-740.
OpenUrl PubMed
↵
Edgar AD, Strosznajder J, and Horrocks LA (1982) Activation of ethanolamine phospholipase A₂ in brain during ischemia. J Neurochem 39: 1111-1116.
OpenUrl PubMed
↵
Endres S and von Schacky C (1996) n-3 polyunsaturated fatty acids and human cytokine synthesis. Curr Opin Lipidol 7: 48-52.
OpenUrl CrossRef PubMed
↵
Estevez AY and Phillis JW (1997) The phospholipase A₂ inhibitor, quinacrine, reduces infarct size in rats after transient middle cerebral artery occlusion. Brain Res 752: 203-208.
OpenUrl CrossRef PubMed
↵
Farooqui AA, Antony P, Ong WY, Horrocks LA, and Freysz L (2004a) Retinoic acid-mediated phospholipase A₂ signaling in the nucleus. Brain Res Rev 45: 179-195.
OpenUrl CrossRef PubMed
↵
Farooqui AA, Haun SE, and Horrocks LA (1994a) Ischemia and hypoxia, in Basic Neurochemistry (Siegel GJ, Agranoff BW, Albers RW, and Molinoff PB eds) pp 867-883, Raven Press, New York.
↵
Farooqui AA and Horrocks LA (1991) Excitatory amino acid receptors, neural membrane phospholipid metabolism and neurological disorders. Brain Res Rev 16: 171-191.
OpenUrl CrossRef PubMed
↵
Farooqui AA and Horrocks LA (1994) Excitotoxicity and neurological disorders: involvement of membrane phospholipids. Int Rev Neurobiol 36: 267-323.
OpenUrl PubMed
↵
Farooqui AA and Horrocks LA (2001) Plasmalogens: workhorse lipids of membranes in normal and injured neurons and glia. Neuroscientist 7: 232-245.
OpenUrl Abstract/FREE Full Text
↵
Farooqui AA and Horrocks LA (2004a) Beneficial effects of docosahexaenoic acid on health of the human brain. Agro Food Ind Hi-Tech 15: 52-53.
OpenUrl
↵
Farooqui AA and Horrocks LA (2004b) Plasmalogens, platelet activating factor, and other ether lipids, in Bioactive Lipids (Nicolaou A and Kokotos G eds) pp 107-134, Oily Press, Bridgwater, UK.
↵
Farooqui AA, Horrocks LA, and Farooqui T (2000a) Deacylation and reacylation of neural membrane glycerophospholipids. J Mol Neurosci 14: 123-135.
OpenUrl CrossRef PubMed
↵
Farooqui AA, Litsky ML, Farooqui T, and Horrocks LA (1999) Inhibitors of intracellular phospholipase A₂ activity: their neurochemical effects and therapeutical importance for neurological disorders. Brain Res Bull 49: 139-153.
OpenUrl CrossRef PubMed
↵
Farooqui AA, Ong WY, and Horrocks LA (2003a) Plasmalogens, docosahexaenoic acid, and neurological disorders, in Peroxisomal Disorders and Regulation of Genes (Roels F, Baes M, and de Bies S eds) pp 335-354, Kluwer Academic/Plenum Publishers, London.
↵
Farooqui AA, Ong WY, and Horrocks LA (2003b) Stimulation of lipases and phospholipases in Alzheimer disease, in Nutrition and Biochemistry of Phospholipids (Szuhaj B and van Nieuwenhuyzen W eds) pp 14-29, AOCS Press, Champaign, IL.
↵
Farooqui AA, Ong WY, and Horrocks LA (2004b) Neuroprotection abilities of cytosolic phospholipase A₂ inhibitors in kainic acid-induced neurodegeneration. Curr Drug Targets Cardiovasc Haematol Disord 4: 85-96.
OpenUrl CrossRef PubMed
↵
Farooqui AA, Ong WY, Horrocks LA, and Farooqui T (2000b) Brain cytosolic phospholipase A₂: Localization, role, and involvement in neurological diseases. Neuroscientist 6: 169-180.
OpenUrl PubMed
↵
Farooqui AA, Ong WY, Lu XR, Halliwell B, and Horrocks LA (2001) Neurochemical consequences of kainate-induced toxicity in brain: involvement of arachidonic acid release and prevention of toxicity by phospholipase A₂ inhibitors. Brain Res Rev 38: 61-78.
OpenUrl CrossRef PubMed
↵
Farooqui AA, Ong WY, Lu XR, and Horrocks LA (2002) Cytosolic phospholipase A₂ inhibitors as therapeutic agents for neural cell injury. Curr Med Chem - Anti-Inflammatory & Anti-Allergy Agents 1: 193-204.
OpenUrl CrossRef
↵
Farooqui AA, Pendley CE II, Taylor WA, and Horrocks LA (1985) Studies on diacylglycerol lipases and lysophospholipases of bovine brain, in Phospholipids in the Nervous System, Vol. II: Physiological Role (Horrocks LA, Kanfer JN, and Porcellati G eds) pp 179-192, Raven Press, New York.
↵
Farooqui AA, Rapoport SI, and Horrocks LA (1997a) Membrane phospholipid alterations in Alzheimer disease: deficiency of ethanolamine plasmalogens. Neurochem Res 22: 523-527.
OpenUrl CrossRef PubMed
↵
Farooqui AA, Rosenberger TA, and Horrocks LA (1997b) Arachidonic acid, neurotrauma, and neurodegenerative diseases, in Handbook of Essential Fatty Acid Biology (Yehuda S and Mostofsky DI eds) pp 277-295, Humana Press, Totowa, NJ.
↵
Farooqui AA, Yang H-C, and Horrocks LA (1994b) Purification of lipases, phospholipases and kinases by heparin-Sepharose chromatography. J Chromatogr 673: 149-158.
OpenUrl CrossRef PubMed
↵
Farooqui AA, Yang H-C, and Horrocks LA (1995) Plasmalogens, phospholipases A₂, and signal transduction. Brain Res Rev 21: 152-161.
OpenUrl CrossRef PubMed
↵
Farooqui AA, Yang H-C, and Horrocks LA (1997c) Involvement of phospholipase A₂ in neurodegeneration. Neurochem Int 30: 517-522.
OpenUrl CrossRef PubMed
↵
Farooqui AA, Yang HC, Rosenberger TA, and Horrocks LA (1997d) Phospholipase A₂ and its role in brain tissue. J Neurochem 69: 889-901.
OpenUrl PubMed
↵
Farrelly PV, Kenna BL, Laohachai KL, Bahadi R, Salmona M, Forloni G, and Kourie JI (2003) Quinacrine blocks PrP (106-126)-formed channels. J Neurosci Res 74: 934-941.
OpenUrl CrossRef PubMed
↵
Fernando SR and Pertwee RG (1997) Evidence that methyl arachidonyl fluorophosphate is an irreversible cannabinoid receptor antagonist. Br J Pharmacol 121: 1716-1720.
OpenUrl CrossRef PubMed
↵
Ferrari G, Batistatou A, and Greene LA (1993) Gangliosides rescue neuronal cells from death after trophic factor deprivation. J Neurosci 13: 1879-1887.
OpenUrl Abstract
↵
Fighera MR, Bonini JS, Frussa R, Dutra CS, Hagen MEK, Rubin MA, and Mello CF (2004) Monosialoganglioside increases catalase activity in cerebral cortex of rats. Free Radic Res 38: 495-500.
OpenUrl CrossRef PubMed
↵
Fitzpatrick JS and Baudry M (1994) Blockade of long-term depression in neonatal hippocampal slices by a phospholipase A₂ inhibitor. Dev Brain Res 78: 81-86.
OpenUrl PubMed
↵
Follette P (2003) New perspectives for prion therapeutics meeting: prion disease treatment's early promise unravels. Science (Wash DC) 299: 191-192.
OpenUrl Abstract/FREE Full Text
↵
Friguet B, Stadtman ER, and Szweda LI (1994) Modification of glucose-6-phosphate dehydrogenase by 4-hydroxy-2-nonenal. J Biol Chem 269: 21639-21643.
OpenUrl Abstract/FREE Full Text
↵
Fuentes L, Pérez R, Nieto ML, Balsinde J, and Balboa MA (2003) Bromoenol lactone promotes cell death by a mechanism involving phosphatidate phosphohydrolase-1 rather than calcium-independent phospholipase A₂. J Biol Chem 278: 44683-44690.
OpenUrl Abstract/FREE Full Text
↵
Fujita S, Ikegaya Y, Nishikawa M, Nishiyama N, and Matsuki N (2001) Docosahexaenoic acid improves long-term potentiation attenuated by phospholipase A₂ inhibitor in rat hippocampal slices. Br J Pharmacol 132: 1417-1422.
OpenUrl CrossRef PubMed
↵
Fujita S, Ikegaya Y, Nishiyama N, and Matsuki N (2000) Ca²⁺-independent phospholipase A₂ inhibitor impairs spatial memory of mice. Jpn J Pharmacol 83: 277-278.
OpenUrl CrossRef PubMed
↵
Gamoh S, Hashimoto M, Sugioka K, Hossain MS, Hata N, Misawa Y, and Masumura S (1999) Chronic administration of docosahexaenoic acid improves reference memory-related learning ability in young rats. Neuroscience 93: 237-241.
OpenUrl CrossRef PubMed
↵
Gattaz WF, Maras A, Cairns NJ, Levy R, and Förstl H (1995) Decreased phospholipase A₂ activity in Alzheimer brains. Biol Psychiatry 37: 13-17.
OpenUrl CrossRef PubMed
↵
Gattaz WF, Forlenza OV, Talib LL, Barbosa NR, and Bottino CM (2004) Platelet phospholipase A₂ activity in Alzheimer's disease and mild cognitive impairment. J Neural Transm 111: 591-601.
OpenUrl CrossRef PubMed
↵
Geddes JW, Ulas J, Brunner LC, Choe W, and Cotman CW (1992) Hippocampal excitatory amino acid receptors in elderly, normal individuals and those with Alzheimer's disease: non-N-methyl-d-aspartate receptors. Neuroscience 50: 23-34.
OpenUrl CrossRef PubMed
↵
Geisler FH, Dorsey FC, and Coleman WP (1991) Recovery of motor function after spinal-cord injury—a randomized, placebo-controlled trial with GM-1 ganglioside. N Engl J Med 324: 1829-1887.
OpenUrl PubMed
↵
Ghelardoni S, Tomita YA, Bell JM, Rapoport SI, and Bosetti F (2004) Chronic carbamazepine selectively downregulates cytosolic phospholipase A₂ expression and cyclooxygenase activity in rat brain. Biol Psychiat 56: 248-254.
OpenUrl CrossRef PubMed
↵
Ghomashchi F, Stewart A, Hefner Y, Ramanadham S, Turk J, Leslie CC, and Gelb MH (2001) A pyrrolidine-based specific inhibitor of cytosolic phospholipase A_2α blocks arachidonic acid release in a variety of mammalian cells. Biochim Biophys Acta 1513: 160-166.
OpenUrl PubMed
↵
Ginsberg L, Xuereb JH, and Gershfeld NL (1998) Membrane instability, plasmalogen content, and Alzheimer's disease. J Neurochem 70: 2533-2538.
OpenUrl PubMed
↵
Gronich J, Konieczkowski M, Gelb MH, Nemenoff RA, and Sedor JR (1994) Interleukin 1α causes rapid activation of cytosolic phospholipase A₂ by phosphorylation in rat mesangial cells. J Clin Investig 93: 1224-1233.
OpenUrl CrossRef PubMed
↵
Grossman A, Zeiler B, and Sapirstein V (2003) Prion protein interactions with nucleic acid: possible models for prion disease and prion function. Neurochem Res 28: 955-963.
OpenUrl CrossRef PubMed
↵
Guan ZZ, Wang YA, Cairns NJ, Lantos PL, Dallner G, and Sindelar PJ (1999) Decrease and structural modifications of phosphatidylethanolamine plasmalogen in the brain with Alzheimer disease. J Neuropathol Exp Neurol 58: 740-747.
OpenUrl CrossRef PubMed
↵
Guentchev M, Voigtlander T, Haberler C, Groschup MH, and Budka H (2000) Evidence for oxidative stress in experimental prion disease. Neurobiol Dis 7: 270-273.
OpenUrl CrossRef PubMed
↵
Hamano H, Nabekura J, Nishikawa M, and Ogawa T (1996) Docosahexaenoic acid reduces GABA response in substantia nigra neuron of rat. J Neurophysiol 75: 1264-1270.
OpenUrl Abstract/FREE Full Text
↵
Han WK, Sapirstein A, Hung CC, Alessandrini A, and Bonventre JV (2003) Cross-talk between cytosolic phospholipase A₂α (cPLA_2α) and secretory phospholipase A₂ (sPLA₂) in hydrogen peroxide-induced arachidonic acid release in murine mesangial cells—sPLA₂ regulates cPLA_2α activity that is responsible for arachidonic acid release. J Biol Chem 278: 24153-24163.
OpenUrl Abstract/FREE Full Text
↵
Han XL, Holtzman DM, and McKeel DW Jr (2001) Plasmalogen deficiency in early Alzheimer's disease subjects and in animal models: molecular characterization using electrospray ionization mass spectrometry. J Neurochem 77: 1168-1180.
OpenUrl CrossRef PubMed
↵
Hanasaki K and Arita H (2002) Phospholipase A₂ receptor: a regulator of biological functions of secretory phospholipase A₂. Prostaglandins Other Lipid Mediat 68-69: 71-82.
OpenUrl CrossRef PubMed
↵
Hannon GJ (2002) RNA interference. Nature (Lond) 418: 244-251.
OpenUrl CrossRef PubMed
↵
Hashimoto M, Hossain S, Shimada T, Sugioka K, Yamasaki H, Fujii Y, Ishibashi Y, Oka JI, and Shido O (2002) Docosahexaenoic acid provides protection from impairment of learning ability in Alzheimer's disease model rats. J Neurochem 81: 1084-1091.
OpenUrl CrossRef PubMed
↵
Hazen SL and Gross RW (1993) The specific association of a phosphofructokinase isoform with myocardial calcium-independent phospholipase A₂: implications for the coordinated regulation of phospholipolysis and glycolysis. J Biol Chem 268: 9892-9900.
OpenUrl Abstract/FREE Full Text
↵
Hernandez M, Nieto ML, and Crespo MS (2000) Cytosolic phospholipase A₂ and the distinct transcriptional programs of astrocytoma cells. Trends Neurosci 23: 259-264.
OpenUrl CrossRef PubMed
↵
Hirabayashi T, Murayama T, and Shimizu T (2004) Regulatory mechanism and physiological role of cytosolic phospholipase A₂. Biol Pharm Bull 27: 1168-1173.
OpenUrl CrossRef PubMed
↵
Hirabayashi T and Shimizu T (2000) Localization and regulation of cytosolic phospholipase A₂. Biochim Biophys Acta 1488: 124-138.
OpenUrl PubMed
↵
Hirashima Y, Farooqui AA, Mills JS, and Horrocks LA (1992) Identification and purification of calcium-independent phospholipase A₂ from bovine brain cytosol. J Neurochem 59: 708-714.
OpenUrl CrossRef PubMed
↵
Hong KH, Bonventre JC, O'Leary E, Bonventre JV, and Lander ES (2001) Deletion of cytosolic phospholipase A₂ suppresses Apc^Min-induced tumorigenesis. Proc Natl Acad Sci USA 98: 3935-3939.
OpenUrl Abstract/FREE Full Text
↵
Hong S, Gronert K, Devchand PR, Moussignac RL, and Serhan CN (2003) Novel docosatrienes and 17S-resolvins generated from docosahexaenoic acid in murine brain, human blood, and glial cells—autacoids in anti-inflammation. J Biol Chem 278: 14677-14687.
OpenUrl Abstract/FREE Full Text
↵
Horrobin DF (2003) Eicosapentaenoic acid derivatives in the management of schizophrenia, in Phospholipid Spectrum Disorders in Psychiatry and Neurology (Peet M, Glen L, and Horrobin DF eds) pp 371-376, Marius Press, Carnforth, Lancashire, UK.
↵
Horrocks LA, Demediuk P, Saunders RD, Dugan L, Clendenon NR, Means ED, and Anderson DK (1985) The degradation of phospholipids, formation of metabolites of arachidonic acid, and demyelination following experimental spinal cord injury. Cent Nerv Syst Trauma 2: 115-120.
OpenUrl PubMed
↵
Horrocks LA and Farooqui AA (2004) Docosahexaenoic acid in the diet: its importance in maintenance and restoration of neural membrane function. Prostaglandins Leukotrienes Essent Fatty Acids 70: 361-372.
OpenUrl CrossRef PubMed
↵
Hossain MS, Hashimoto M, Gamoh S, and Masumura S (1999) Antioxidative effects of docosahexaenoic acid in the cerebrum versus cerebellum and brainstem of aged hypercholesterolemic rats. J Neurochem 72: 1133-1138.
OpenUrl CrossRef PubMed
↵
Hossain MS, Hashimoto M, and Masumura S (1998) Influence of docosahexaenoic acid on cerebral lipid peroxide level in aged rats with and without hypercholes-terolemia. Neurosci Lett 244: 157-160.
OpenUrl CrossRef PubMed
↵
Hudson CJ, Kennedy JL, Gotowiec A, Lin A, King N, Gojtan K, Macciardi F, Skorecki K, Meltzer HY, Warsh JJ, et al. (1996) Genetic variant near cytosolic phospholipase A₂ associated with schizophrenia. Schizophr Res 21: 111-116.
OpenUrl CrossRef PubMed
↵
Huterer SJ, Tourtellotte WW, and Wherrett JR (1995) Alterations in the activity of phospholipases A₂ in post-mortem white matter from patients with multiple sclerosis. Neurochem Res 20: 1335-1343.
OpenUrl CrossRef PubMed
↵
Ibuki T, Matsumura K, Yamazaki Y, Nozaki T, Tanaka Y, and Kobayashi S (2003) Cyclooxygenase-2 is induced in the endothelial cells throughout the central nervous system during carrageenan-induced hind paw inflammation; its possible role in hyperalgesia. J Neurochem 86: 318-328.
OpenUrl CrossRef PubMed
↵
James MJ, Gibson RA, and Cleland LG (2000) Dietary polyunsaturated fatty acids and inflammatory mediator production. Am J Clin Nutr 71: 343S-348S.
OpenUrl Abstract/FREE Full Text
↵
Jamme I, Petit E, Divoux D, Gerbi A, Maxient JM, and Nouvelot A (1995) Modulation of mouse cerebral Na⁺, K⁺-ATPase activity by oxygen free radicals. NeuroReport 7: 333-337.
OpenUrl PubMed
↵
Jeffrey M, Goodsir CM, Bruce ME, McBride PA, Scott JR, and Halliday WG (1992) Infection specific prion protein (PrP) accumulates on neuronal plasmalemma in scrapie infected mice. Neurosci Lett 147: 106-109.
OpenUrl CrossRef PubMed
↵
Junqueira R, Cordeiro Q, Meira-Lima I, Gattaz WF, and Vallada H (2004) Allelic association analysis of phospholipase A2 genes with schizophrenia. Psychiatr Genet 14: 157-160.
OpenUrl CrossRef PubMed
↵
Jupp OJ, Vandenabeele P, and MacEwan DJ (2003) Distinct regulation of cytosolic phospholipase A₂ phosphorylation, translocation, proteolysis and activation by tumour necrosis factor-receptor subtypes. Biochem J 374: 453-461.
OpenUrl CrossRef PubMed
↵
Kaetzel MA and Dedman JR (1995) Annexins: novel Ca²⁺-dependent regulators of membrane function. News Physiol Sci 10: 171-176.
OpenUrl Abstract/FREE Full Text
↵
Kajiwara K, Nagawawa H, Shimizu-Nishikawa S, Ookuri T, Kimura M, and Sugaya E (1996) Molecular characterization of seizure-related genes isolated by differential screening. Biochem Biophys Res Commun 219: 795-799.
OpenUrl CrossRef PubMed
↵
Kalyvas A and David S (2004) Cytosolic phospholipase A₂ plays a key role in the pathogenesis of multiple sclerosis-like disease. Neuron 41: 323-335.
OpenUrl CrossRef PubMed
↵
Kanfer JN, Sorrentino G, and Sitar DS (1998) Phospholipases as mediators of amyloid β-peptide neurotoxicity: an early event contributing to neurodegeneration characteristic of Alzheimer's disease. Neurosci Lett 257: 93-96.
OpenUrl CrossRef PubMed
↵
Katsuki H and Okuda S (1995) Arachidonic acid as a neurotoxic and neurotrophic substance. Prog Neurobiol 46: 607-636.
OpenUrl CrossRef PubMed
↵
Kim DK, Rordorf G, Nemenoff RA, Koroshetz WJ, and Bonventre JV (1995) Glutamate stably enhances the activity of two cytosolic forms of phospholipase A₂ in brain cortical cultures. Biochem J 310: 83-90.
OpenUrl Abstract/FREE Full Text
↵
Kishimoto K, Matsumura K, Kataoka Y, Morii H, and Watanabe Y (1999) Localization of cytosolic phospholipase A₂ messenger RNA mainly in neurons in the rat brain. Neuroscience 92: 1061-1077.
OpenUrl CrossRef PubMed
↵
Klivenyi P, Beal MF, Ferrante RJ, Andreassen OA, Wermer M, Chin MR, and Bonventre JV (1998) Mice deficient in group IV cytosolic phospholipase A₂ are resistant to MPTP neurotoxicity. J Neurochem 71: 2634-2637.
OpenUrl PubMed
↵
Kobayashi Y, Hirata K, Tanaka H, and Yamada T (2003) Quinacrine administration to a patient with Creutzfeldt-Jakob disease who received a cadaveric dura mater graft—an EEG evaluation. Rinsho Shinkeigaku 43: 403-408.
OpenUrl PubMed
↵
Kokotos G, Six DA, Loukas V, Smith T, Constantinou-Kokotou V, Hadjipavlou-Litina D, Kotsovolou S, Chiou A, Beltzner CC, and Dennis EA (2004) Inhibition of group IVA cytosolic phospholipase A₂ by novel 2-oxoamides in vitro, in cells, and in vivo. J Med Chem 47: 3615-3628.
OpenUrl CrossRef PubMed
Kolko M, DeCoster MA, Rodriguez de Turco EB, and Bazan NG (1996) Synergy by secretory phospholipase A₂ and glutamate on inducing cell death and sustained arachidonic acid metabolic changes in primary cortical neuronal cultures. J Biol Chem 271: 32722-32728.
OpenUrl Abstract/FREE Full Text
↵
Kolko M, Rodriguez de Turco EB, Diemer NH, and Bazan NG (2002) Secretory phospholipase A₂-mediated neuronal cell death involves glutamate ionotropic receptors. NeuroReport 13: 1963-1966.
OpenUrl CrossRef PubMed
↵
Korth C, May BC, Cohen FE, and Prusiner SB (2001) Acridine and phenothiazine derivatives as pharmacotherapeutics for prion disease. Proc Natl Acad Sci USA 98: 9836-9841.
OpenUrl Abstract/FREE Full Text
↵
Kramer BC, Yabut JA, Cheong J, Jnobaptiste R, Robakis T, Olanow CW, and Mytilineou C (2004) Toxicity of glutathione depletion in mesencephalic cultures: a role for arachidonic acid and its lipoxygenase metabolites. Eur J Neurosci 19: 280-286.
OpenUrl CrossRef PubMed
↵
Kriem B, Sponne I, Fifre A, Malaplate-Armand C, Lozac'h-Pillot K, Koziel V, Yen-Potin FT, Bihain B, Oster T, Olivier JL, et al. (2005) Cytosolic phospholipase A₂ mediates neuronal apoptosis induced by soluble oligomers of the amyloid-β peptide. FASEB J 19: 85-87.
OpenUrl Abstract/FREE Full Text
↵
Kuroiwa N, Nakamura M, Tagaya M, and Takatsuki A (2001) Arachidonyltrifluoromethyl ketone, a phospholipase A₂ antagonist, induces dispersal of both Golgi stack- and trans Golgi network-resident proteins throughout the cytoplasm. Biochem Biophys Res Commun 281: 582-588.
OpenUrl CrossRef PubMed
Kurrasch-Orbaugh DM, Parrish JC, Watts VJ, and Nichols DE (2003) A complex signaling cascade links the serotonin_2A receptor to phospholipase A₂ activation: the involvement of MAP kinases. J Neurochem 86: 980-991.
OpenUrl CrossRef PubMed
↵
Laktionova P, Rykova E, Toni M, Spisni E, Griffoni C, Bryksin A, Volodko N, Vlassov V, and Tomasi V (2004) Knock down of cytosolic phospholipase A₂: an antisense oligonucleotide having a nuclear localization binds a C-terminal motif of glyceraldehyde-3-phosphate dehydrogenase. Biochim Biophys Acta 1636: 129-135.
OpenUrl PubMed
↵
Larsson PKA, Claesson HE, and Kennedy BP (1998) Multiple splice variants of the human calcium-independent phospholipase A₂ and their effect on enzyme activity. J Biol Chem 273: 207-214.
OpenUrl Abstract/FREE Full Text
↵
Laruelle M, Abi-Dargham A, Gil R, Kegeles L, and Innis R (1999) Increased dopamine transmission in schizophrenia: relationship to illness phases. Biol Psychiatry 46: 56-72.
OpenUrl CrossRef PubMed
↵
Latorre E, Collado MP, Fernández I, Aragonés MD, and Catalán RE (2003) Signaling events mediating activation of brain ethanolamine plasmalogen hydrolysis by ceramide. Eur J Biochem 270: 36-46.
OpenUrl PubMed
↵
Lazarewicz JW, Wroblewski JT, and Costa E (1990) N-Methyl-d-aspartate-sensitive glutamate receptors induce calcium-mediated arachidonic acid release in primary cultures of cerebellar granule cells. J Neurochem 55: 1875-1881.
OpenUrl CrossRef PubMed
↵
Lehr M (1996) 3-(3,5-Dimethyl-4-octadecanoylpyrrol-2-yl)propionic acids as inhibitors of 85 kDa cytosolic phospholipase A₂. Arch Pharm (Weinheim) 329: 483-488.
OpenUrl PubMed
↵
Lehr M (1997a) Structure-activity relationship studies on (4-acylpyrrol-2-yl)alkanoic acids as inhibitors of the cytosolic phospholipase A₂: variation of the alkanoic acid substituent, the acyl chain and the position of the pyrrole nitrogen. Eur J Med Chem 32: 805-814.
OpenUrl CrossRef
↵
Lehr M (1997b) Synthesis, biological evaluation, and structure-activity relationships of 3-acylindole-2-carboxylic acids as inhibitors of the cytosolic phospholipase A₂. J Med Chem 40: 2694-2705.
OpenUrl CrossRef PubMed
↵
Lehtonen JYA, Holopainen JM, and Kinnunen PKJ (1996) Activation of phospholipase A₂ by amyloid β-peptides in vitro. Biochemistry 35: 9407-9414.
OpenUrl CrossRef PubMed
↵
Lerma J (1997) Kainate reveals its targets. Neuron 19: 1155-1158.
OpenUrl CrossRef PubMed
↵
Leslie CC (2004) Regulation of arachidonic acid availability for eicosanoid production. Biochem Cell Biol 82: 1-17.
OpenUrl CrossRef PubMed
↵
Lin TN, Wang Q, Simonyi A, Chen JJ, Cheung WM, He YY, Xu J, Sun AY, Hsu CY, and Sun GY (2004) Induction of secretory phospholipase A₂ in reactive astrocytes in response to transient focal cerebral ischemia in the rat brain. J Neurochem 90: 637-645.
OpenUrl CrossRef PubMed
↵
Locati M, Lamorte G, Luini W, Introna M, Bernasconi S, Mantovani A, and Sozzani S (1996) Inhibition of monocyte chemotaxis to C-C chemokines by antisense oligonucleotide for cytosolic phospholipase A₂. J Biol Chem 271: 6010-6016.
OpenUrl Abstract/FREE Full Text
↵
Lonergan PE, Martin DSD, Horrobin DF, and Lynch MA (2004) Neuroprotective actions of eicosapentaenoic acid on lipopolysaccharide-induced dysfunction in rat hippocampus. J Neurochem 91: 20-29.
OpenUrl CrossRef PubMed
↵
Love R (2001) Old drugs to treat new variant Creutzfeldt-Jakob disease. Lancet 358: 563.
OpenUrl CrossRef PubMed
↵
Lu XR, Ong WY, and Halliwell B (2001a) The phospholipase A₂ inhibitor quinacrine prevents increased immunoreactivity to cytoplasmic phospholipase A₂ (cPLA₂) and hydroxynonenal (HNE) in neurons of the lateral septum following fimbria-fornix transection. Exp Brain Res 138: 500-508.
OpenUrl CrossRef PubMed
↵
Lu XR, Ong WY, Halliwell B, Horrocks LA, and Farooqui AA (2001b) Differential effects of calcium-dependent and calcium-independent phospholipase A₂ inhibitors on kainate-induced neuronal injury in rat hippocampal slices. Free Radic Biol Med 30: 1263-1273.
OpenUrl CrossRef PubMed
↵
Lukácová N, Halát G, Chavko M, and Marsala J (1996) Ischemia-reperfusion injury in the spinal cord of rabbits strongly enhances lipid peroxidation and modifies phospholipid profiles. Neurochem Res 21: 869-873.
OpenUrl PubMed
↵
Macchioni L, Corazzi L, Nardicchi V, Mannucci R, Arcuri C, Porcellati S, Sposini T, Donato R, and Goracci G (2004) Rat brain cortex mitochondria release group II secretory phospholipase A₂ under reduced membrane potential. J Biol Chem 279: 37860-37869.
OpenUrl Abstract/FREE Full Text
↵
Mandal PK and Pettegrew JW (2004) Alzheimer's disease: NMR studies of asialo (GM1) and trisialo (GT1b) ganglioside interactions with A β(1-40) peptide in a membrane mimic environment. Neurochem Res 29: 447-453.
OpenUrl CrossRef PubMed
↵
Marcheselli VL, Hong S, Lukiw WJ, Tian XH, Gronert K, Musto A, Hardy M, Gimenez JM, Chiang N, Serhan CN, et al. (2003) Novel docosanoids inhibit brain ischemia-reperfusion-mediated leukocyte infiltration and pro-inflammatory gene expression. J Biol Chem 278: 43807-43817.
OpenUrl Abstract/FREE Full Text
↵
Matsuzawa A, Murakami M, Atsumi G, Imai K, Prados P, Inoue K, and Kudo I (1996) Release of secretory phospholipase A₂ from rat neuronal cells and its possible function in the regulation of catecholamine secretion. Biochem J 318: 701-709.
OpenUrl Abstract/FREE Full Text
↵
May BCH, Fafarman AT, Hong SB, Rogers M, Deady LW, Prusiner SB, and Cohen FE (2003) Potent inhibition of scrapie prion replication in cultured cells by bisacridines. Proc Natl Acad Sci USA 100: 3416-3421.
OpenUrl Abstract/FREE Full Text
↵
Mazière C, Conte MA, Degonville J, Ali D, and Mazière JC (1999) Cellular enrichment with polyunsaturated fatty acids induces an oxidative stress and activates the transcription factors AP1 and NFκB. Biochem Biophys Res Commun 265: 116-122.
OpenUrl CrossRef PubMed
↵
McIntosh TK, Saatman KE, Raghupathi R, Graham DI, Smith DH, Lee VM, and Trojanowski JQ (1998) The molecular and cellular sequelae of experimental traumatic brain injury: pathogenetic mechanisms. Neuropathol Appl Neurobiol 24: 251-267.
OpenUrl CrossRef PubMed
↵
Miele L (2003a) New weapons against inflammation: dual inhibitors of phospholipase A₂ and transglutaminase. J Clin Investig 111: 19-21.
OpenUrl CrossRef PubMed
↵
Miele L (2003b) New weapons against inflammation: dual inhibitors of phospholipase A₂ and transglutaminase. J Clin Investig 111: 19-21.
OpenUrl CrossRef PubMed
↵
Milhavet O, McMahon HE, Rachidi W, Nishida N, Katamine S, Mange A, Arlotto M, Casanova D, Riondel J, Favier A, et al. (2000) Prion infection impairs the cellular response to oxidative stress. Proc Natl Acad Sci USA 97: 13937-13942.
OpenUrl Abstract/FREE Full Text
↵
Mir C, Clotet J, Aledo R, Durany N, Argemi J, Lozano R, Cervos-Navarro J, and Casals N (2003) CDP-choline prevents glutamate-mediated cell death in cerebellar granule neurons. J Mol Neurosci 20: 53-59.
OpenUrl CrossRef PubMed
↵
Molloy GY, Rattray M, and Williams RJ (1998) Genes encoding multiple forms of phospholipase A₂ are expressed in rat brain. Neurosci Lett 258: 139-142.
OpenUrl CrossRef PubMed
↵
Mosior M, Six DA, and Dennis EA (1998a) Group IV cytosolic phospholipase A₂ binds with high affinity and specificity to phosphatidylinositol 4,5-bisphosphate resulting in dramatic increases in activity. J Biol Chem 273: 2184-2191.
OpenUrl Abstract/FREE Full Text
↵
Moskowitz N, Puszkin S, and Schook W (1983) Characterization of brain synaptic vesicle phospholipase A₂ activity and its modulation by calmodulin, prostaglandin E₂, prostaglandin F_2α, cyclic AMP and ATP. J Neurochem 41: 1576-1586.
OpenUrl PubMed
↵
Mukherjee PK, Marcheselli VL, Serhan CN, and Bazan NG (2004) Neuroprotectin D1: a docosahexaenoic acid-derived docosatriene protects human retinal pigment epithelial cells from oxidative stress. Proc Natl Acad Sci USA 101: 8491-8496.
OpenUrl Abstract/FREE Full Text
↵
Muller WEG, Ushijima H, Schroder HC, Forrest JMS, Schatton WFH, Rytik PG, and Heffner-Lauc M (1993) Cytoprotective effect of NMDA receptor antagonists on prion protein (PrionSc)-induced toxicity in rat cortical cell cultures. Eur J Pharmacol 246: 261-267.
OpenUrl CrossRef PubMed
↵
Murakami M, Nakatani Y, Atsumi G, Inoue K, and Kudo I (1997) Regulatory functions of phospholipase A₂. Crit Rev Immunol 17: 225-283.
OpenUrl CrossRef PubMed
↵
Murphy EJ and Horrocks LA (1993) CDPcholine, CDPethanolamine, lipid metabolism and disorders of the central nervous system, in Phospholipids and Signal Transmission (Massarelli R, Horrocks L, Kanfer JN, and Löffelholz K eds) pp 353-372, Springer-Verlag GmbH, Heidelberg.
↵
Nakashima S, Ikeno Y, Yokoyama T, Kuwana M, Bolchi A, Ottonello S, Kitamoto K, and Arioka M (2003) Secretory phospholipases A₂ induce neurite outgrowth in PC12 cells. Biochem J 376: 655-666.
OpenUrl CrossRef PubMed
↵
Ng CH and Ong WY (2001) Increased expression of γ-aminobutyric acid transporters GAT-1 and GAT-3 in the spinal trigeminal nucleus after facial carrageenan injections. Pain 92: 29-40.
OpenUrl CrossRef PubMed
↵
Nordvik I, Myhr KM, Nyland H, and Bjerve KS (2000) Effect of dietary advice and n-3 supplementation in newly diagnosed MS patients. Acta Neurol Scand 102: 143-149.
OpenUrl CrossRef PubMed
↵
Obata T, Sakurai Y, Kase Y, Tanifuji Y, Horiguchi T, Haq S, Kilter H, Michael A, Tao J, O'Leary E, et al. (2003) Simultaneous determination of endocannabinoids (arachidonylethanolamide and 2-arachidonylglycerol) and isoprostane (8-epiprostaglandin F_2α) by gas chromatography-mass spectrometry-selected ion monitoring for medical samples. J Chromatogr B 792: 131-140.
OpenUrl CrossRef
↵
Oinuma H, Takamura T, Hasegawa T, Nomoto KI, Naitoh T, Daiku Y, Hamano S, Kakisawa H, and Minami N (1991) Synthesis and biological evaluation of substituted benzenesulfonamides as novel potent membrane-bound phospholipase A₂ inhibitors. J Med Chem 34: 2260-2267.
OpenUrl CrossRef PubMed
↵
Ong WY, He Y, Suresh S, and Patel S (1997) Differential expression of apoD and apoE in the kainate lesioned rat hippocampus. Neuroscience 79: 359-367.
OpenUrl CrossRef PubMed
↵
Ong WY, Hu CY, Hjelle OP, Ottersen OP, and Halliwell B (2000) Changes in glutathione in the hippocampus of rats injected with kainate: depletion in neurons and upregulation in glia. Exp Brain Res 132: 510-516.
OpenUrl CrossRef PubMed
↵
Ong WY, Ling SF, Yeo JF, Chiueh CC, and Farooqui AA (2005) Injury and recovery of pyramidal neurons in the rat hippocampus after a single episode of oxidative stress induced by intracerebroventricular injection of ferrous ammonium citrate. Reprod Nutr Dev 45: 647-662.
OpenUrl CrossRef PubMed
↵
Ong WY, Lu XR, Horrocks LA, Farooqui AA, and Garey LJ (2003a) Induction of astrocytic cytoplasmic phospholipase A₂ and neuronal death after intracerebroventricular carrageenan injection, and neuroprotective effects of quinacrine. Exp Neurol 183: 449-457.
OpenUrl CrossRef PubMed
↵
Ong WY, Lu XR, Ong BKC, Horrocks LA, Farooqui AA, and Lim SK (2003b) Quinacrine abolishes increases in cytoplasmic phospholipase A₂ mRNA levels in the rat hippocampus after kainate-induced neuronal injury. Exp Brain Res 148: 521-524.
OpenUrl PubMed
↵
Ong WY, Ren MQ, Makjanic J, Lim TM, and Watt F (1999) A nuclear microscopic study of elemental changes in the rat hippocampus after kainate-induced neuronal injury. J Neurochem 72: 1574-1579.
OpenUrl CrossRef PubMed
↵
Ono T, Yamada K, Chikazawa Y, Ueno M, Nakamoto S, Okuno T, and Seno K (2002) Characterization of a novel inhibitor of cytosolic phospholipase A₂α, pyrrophenone. Biochem J 363: 727-735.
OpenUrl CrossRef PubMed
↵
Ortiz GG, Sánchez-Ruiz MY, Tan DX, Reiter RJ, Benítez-King G, and Beas-Zárate C (2001) Melatonin, vitamin E, and estrogen reduce damage induced by kainic acid in the hippocampus: potassium-stimulated GABA release. J Pineal Res 31: 62-67.
OpenUrl CrossRef PubMed
↵
Ouyang Y and Kaminski NE (1999) Phospholipase A₂ inhibitors p-bromophenacyl bromide and arachidonyl trifluoromethyl ketone suppressed interleukin-2 (IL-2) expression in murine primary splenocytes. Arch Toxicol 73: 1-6.
OpenUrl CrossRef PubMed
↵
Pae CU, Yu HS, Kim JJ, Lee CU, Lee SJ, Lee KU, Jun TY, Paik IH, Serretti A, and Lee C (2004) BanI polymorphism of the cytosolic phospholipase A₂ gene and mood disorders in the Korean population. Neuropsychobiology 49: 185-188.
OpenUrl CrossRef PubMed
↵
Palomba L, Bianchi M, Persichini T, Magnani M, Colasanti M, and Cantoni O (2004) Downregulation of nitric oxide formation by cytosolic phospholipase A₂-released arachidonic acid. Free Radic Biol Med 36: 319-329.
OpenUrl CrossRef PubMed
↵
Pardue S, Rapoport SI, and Bosetti F (2003) Co-localization of cytosolic phospholipase A₂ and cyclooxygenase-2 in rhesus monkey cerebellum. Mol Brain Res 116: 106-114.
OpenUrl CrossRef PubMed
↵
Peet M and Ryles S (2001) Eicosapentaenoic acid—a potential new treatment for schizophrenia?, in Fatty Acids: Physiological and Behavioral Functions (Mostofsky DI, Yehuda S, and Salem N eds) pp 345-356, Humana Press Inc, Totowa, NJ.
↵
Pentland AP, Morrison AR, Jacobs SC, Hruza LL, Hebert JS, and Packer L (1992) Tocopherol analogs suppress arachidonic acid metabolism via phospholipase inhibition. J Biol Chem 267: 15578-15584.
OpenUrl Abstract/FREE Full Text
↵
Pérez R, Melero R, Balboa MA, and Balsinde J (2004) Role of group VIA calcium-independent phospholipase A₂ in arachidonic acid release, phospholipid fatty acid incorporation, and apoptosis in U937 cells responding to hydrogen peroxide. J Biol Chem 279: 40385-40391.
OpenUrl Abstract/FREE Full Text
↵
Perovic S, Pergande G, Ushijima H, Kelve M, Forrest J, and Muller WEG (1995) Flupirtine partially prevents neuronal injury induced by prion protein fragment and lead acetate. Neurodegeneration 4: 369-374.
OpenUrl CrossRef PubMed
↵
Pettegrew JW (1989) Molecular insights into Alzheimer disease. Ann NY Acad Sci 568: 5-28.
OpenUrl PubMed
↵
Pettegrew JW, Klunk WE, Kanal E, Panchalingam K, and McClure RJ (1995) Changes in brain membrane phospholipid and high-energy phosphate metabolism precede dementia. Neurobiol Aging 16: 973-975.
OpenUrl CrossRef PubMed
↵
Pettegrew JW, Panchalingam K, Hamilton RL, and McClure RJ (2001) Brain membrane phospholipid alterations in Alzheimer's disease. Neurochem Res 26: 771-782.
OpenUrl CrossRef PubMed
↵
Pettus BJ, Bielawska A, Subramanian P, Wijesinghe DS, Maceyka M, Leslie CC, Evans JH, Freiberg J, Roddy P, Hannun YA, et al. (2004) Ceramide 1-phosphate is a direct activator of cytosolic phospholipase A₂. J Biol Chem 279: 11320-11326.
OpenUrl Abstract/FREE Full Text
↵
Peyrin JM, Lasmezas CI, Haik S, Tagliavini F, Salmona M, Williams A, Richie D, Deslys JP, and Dormont D (1999) Microglial cells respond to amyloidogenic PrP peptide by the production of inflammatory cytokines. NeuroReport 10: 723-729.
OpenUrl CrossRef PubMed
↵
Phillis JW and O'Regan MH (2004) A potentially critical role of phospholipases in central nervous system ischemic, traumatic, and neurodegenerative disorders. Brain Res Rev 44: 13-47.
OpenUrl CrossRef PubMed
↵
Pickard RT, Strifler BA, Kramer RM, and Sharp JD (1999) Molecular cloning of two new human paralogs of 85-kDa cytosolic phospholipase A₂. J Biol Chem 274: 8823-8831.
OpenUrl Abstract/FREE Full Text
↵
Pinto F, Brenner T, Dan P, Krimsky M, and Yedgar S (2003) Extracellular phospholipase A₂ inhibitors suppress central nervous system inflammation. Glia 44: 275-282.
OpenUrl CrossRef PubMed
↵
Pirianov G, Danielsson C, Carlberg C, James SY, and Colston KW (1999) Potentiation by vitamin D analogs of TNFα and ceramide-induced apoptosis in MCF-7 cells is associated with activation of cytosolic phospholipase A₂. Cell Death Differ 6: 890-901.
OpenUrl CrossRef PubMed
↵
Portilla D and Dai G (1996) Purification of a novel calcium-independent phospholipase A₂ from rabbit kidney. J Biol Chem 271: 15451-15457.
OpenUrl Abstract/FREE Full Text
↵
Prusiner SB (2001) Shattuck lecture—Neurodegenerative diseases and prions. N Engl J Med 344: 1516-1526.
OpenUrl CrossRef PubMed
Qu Y, Chang L, Klaff J, Seeman R, Balbo A, and Rapoport SI (2003a) Imaging of brain serotonergic neurotransmission involving phospholipase A₂ activation and arachidonic acid release in unanesthetized rats. Brain Res Brain Res Protoc 12: 16-25.
OpenUrl CrossRef PubMed
Qu Y, Chang L, Klaff J, Seemann R, and Rapoport SI (2003b) Imaging brain phospholipase A₂-mediated signal transduction in response to acute fluoxetine administration in unanesthetized rats. Neuropsychopharmacology 28: 1219-1226.
OpenUrl PubMed
↵
Rao AM, Hatcher JF, and Dempsey RJ (2001) Does CDP-choline modulate phospholipase activities after transient forebrain ischemia? Brain Res 893: 268-272.
OpenUrl CrossRef PubMed
↵
Rapoport SI (1999) In vivo fatty acid incorporation into brain phospholipids in relation to signal transduction and membrane remodeling. Neurochem Res 24: 1403-1415.
OpenUrl CrossRef PubMed
↵
Ray P, Ray R, Broomfield CA, and Berman JD (1994) Inhibition of bioenergetics alters intracellular calcium, membrane composition, and fluidity in a neuronal cell line. Neurochem Res 19: 57-63.
OpenUrl CrossRef PubMed
↵
Riendeau D, Guay J, Weech PK, Laliberté F, Yergey J, Li C, Desmarais S, Perrier H, Liu S, Nicoll-Griffith D, et al. (1994) Arachidonyl trifluoromethyl ketone, a potent inhibitor of 85-kDa phospholipase A₂, blocks production of arachidonate and 12-hydroxyeicosatetraenoic acid by calcium ionophore-challenged platelets. J Biochem 269: 15619-15624.
OpenUrl
↵
Rintala J, Seemann R, Chandrasekaran K, Rosenberger TA, Chang L, Contreras MA, Rapoport SI, and Chang MCJ (1999) 85 kDa cytosolic phospholipase A₂ is a target for chronic lithium in rat brain. NeuroReport 10: 3887-3890.
OpenUrl CrossRef PubMed
↵
Rordorf G, Uemura Y, and Bonventre JV (1991) Characterization of phospholipase A₂ (PLA₂) activity in gerbil brain: enhanced activities of cytosolic, mitochondrial, and microsomal forms after ischemia and reperfusion. J Neurosci 11: 1829-1836.
OpenUrl Abstract
↵
Rosales-Corral S, Tan DX, Reiter RJ, Valdivia-Velázquez M, Acosta-Martiínez JP, and Ortiz GG (2004) Kinetics of the neuroinflammation-oxidative stress correlation in rat brain following the injection of fibrillar amyloid-β onto the hippocampus in vivo. J Neuroimmunol 150: 20-28.
OpenUrl CrossRef PubMed
↵
Rosenberger TA, Villacreses NE, Contreras MA, Bonventre JV, and Rapoport SI (2003) Brain lipid metabolism in the cPLA₂ knockout mouse. J Lipid Res 44: 109-117.
OpenUrl Abstract/FREE Full Text
↵
Rosenberger TA, Villacreses NE, Hovda JT, Bosetti F, Weerasinghe G, Wine RN, Harry GJ, and Rapoport SI (2004) Rat brain arachidonic acid metabolism is increased by a 6-day intracerebral ventricular infusion of bacterial lipopolysaccharide. J Neurochem 88: 1168-1178.
OpenUrl CrossRef PubMed
↵
Ross BM (2003) Phospholipase A₂-associated processes in the human brain and their role in neuropathology and psychopathology, in Phospholipid Spectrum Disorders in Psychiatry and Neurology (Peet M, Glen L, and Horrobin DF eds) pp 163-182, Marius Press, Carnforth, Lancashire, UK.
↵
Ross BM, Hudson C, Erlich J, Warsh JJ, and Kish SJ (1997) Increased phospholipid breakdown in schizophrenia— evidence for the involvement of a calcium-independent phospholipase A₂. Arch Gen Psychiatry 54: 487-494.
OpenUrl CrossRef PubMed
↵
Ross BM, Kim DK, Bonventre JV, and Kish SJ (1995) Characterization of a novel phospholipase A₂ activity in human brain. J Neurochem 64: 2213-2221.
OpenUrl PubMed
↵
Ross BM and Turenne SD (2002) Chronic cocaine administration reduces phospholipase A₂ activity in rat brain striatum. Prostaglandins Leukotrienes Essent Fatty Acids 66: 479-483.
OpenUrl CrossRef PubMed
↵
Ross BM, Turenne S, Moszczynska A, Warsh JJ, and Kish SJ (1999) Differential alteration of phospholipase A₂ activities in brain of patients with schizophrenia. Brain Res 821: 407-413.
OpenUrl CrossRef PubMed
↵
Rybakowski JK, Borkowska A, Czerski PM, Dmitrzak-Weglarz M, and Hauser J (2003) The study of cytosolic phospholipase A₂ gene polymorphism in schizophrenia using eye movement disturbances as an endophenotypic marker. Neuropsychobiology 47: 115-119.
OpenUrl CrossRef PubMed
↵
Salvati S, Natali F, Attorri L, Raggi C, Di Biase A, and Sanchez M (2004) Stimulation of myelin proteolipid protein gene expression by eicosapentaenoic acid in C6 glioma cells. Neurochem Int 44: 331-338.
OpenUrl CrossRef PubMed
↵
Sandhya TL, Ong WY, Horrocks LA, and Farooqui AA (1998) A light and electron microscopic study of cytoplasmic phospholipase A₂ and cyclooxygenase-2 in the hippocampus after kainate lesions. Brain Res 788: 223-231.
OpenUrl CrossRef PubMed
↵
Sano M, Ernesto C, Thomas RG, Klauber MR, Schafer K, Grundman M, Woodbury P, Growdon J, Cotman DW, Pfeiffer E, et al. (1997) A controlled trial of selegiline, α-tocopherol, or both as treatment for Alzheimer's disease. N Engl J Med 336: 1216-1222.
OpenUrl CrossRef PubMed
↵
Sapirstein A and Bonventre JV (2000) Phospholipases A₂ in ischemic and toxic brain injury. Neurochem Res 25: 745-753.
OpenUrl CrossRef PubMed
↵
Schapira AH (1996) Oxidative stress and mitochondrial dysfunction in neurodegeneration. Curr Opin Neurol 9: 260-264.
OpenUrl CrossRef PubMed
↵
Scott KF, Graham GG, and Bryant KJ (2003) Secreted phospholipase A₂ enzymes as therapeutic targets. Expert Opin Ther Targets 7: 427-440.
OpenUrl CrossRef PubMed
↵
Seashols SJ, del Castillo Olivares A, Gil G, and Barbour SE (2004) Regulation of group VIA phospholipase A₂ expression by sterol availability. Biochim Biophys Acta 1684: 29-37.
OpenUrl PubMed
↵
Seno K, Okuno T, Nishi K, Murakami Y, Watanabe F, Matsuura T, Wada M, Fujii Y, Yamada M, Ogawa T, et al. (2000) Pyrrolidine inhibitors of human cytosolic phospholipase A₂. J Med Chem 43: 1041-1044.
OpenUrl CrossRef PubMed
↵
Serhan CN, Gotlinger K, Hong S, and Arita M (2004) Resolvins, docosatrienes, and neuroprotectins, novel ω-3-derived mediators, and their aspirin-triggered endogenous epimers: an overview of their protective roles in catabasis. Prostaglandins Other Lipid Mediat 73: 155-172.
OpenUrl CrossRef PubMed
↵
Shanker G and Aschner M (2003) Methylmercury-induced reactive oxygen species formation in neonatal cerebral astrocytic cultures is attenuated by antioxidants. Mol Brain Res 110: 85-91.
OpenUrl PubMed
↵
Shanker G, Hampson RE, and Aschner M (2004) Methylmercury stimulates arachidonic acid release and cytosolic phospholipase A₂ expression in primary neuronal cultures. Neurotoxicology 25: 399-406.
OpenUrl CrossRef PubMed
↵
Shin EJ, Jhoo JH, Kim WK, Jhoo WK, Lee C, Jung BD, and Kim HC (2004) Protection against kainate neurotoxicity by pyrrolidine dithiocarbamate. Clin Exp Pharmacol Physiol 31: 320-326.
OpenUrl CrossRef PubMed
↵
Shinzawa K and Tsujimoto Y (2003) PLA₂ activity is required for nuclear shrinkage in caspase-independent cell death. J Cell Biol 163: 1219-1230.
OpenUrl Abstract/FREE Full Text
↵
Shirai Y and Ito M (2004) Specific differential expression of phospholipase A₂ subtypes in rat cerebellum. J Neurocytol 33: 297-307.
OpenUrl CrossRef PubMed
↵
Shohami E, Shapira Y, Yadid G, Reisfeld N, and Yedgar S (1989) Brain phospholipase A₂ is activated after experimental closed head injury in the rat. J Neurochem 53: 1541-1546.
OpenUrl CrossRef PubMed
↵
Singer TP, Castagnoli N Jr, Ramsay RR, and Trevor AJ (1987) Biochemical events in the development of parkinsonism induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. J Neurochem 49: 1-8.
OpenUrl PubMed
↵
Smalheiser NR, Dissanayake S, and Kapil A (1996) Rapid regulation of neurite outgrowth and retraction by phospholipase A₂-derived arachidonic acid and its metabolites. Brain Res 721: 39-48.
OpenUrl CrossRef PubMed
↵
Song C, Chang XJ, Bean KM, Proia MS, Knopf JL, and Kriz RW (1999) Molecular characterization of cytosolic phospholipase A_2-β. J Biol Chem 274: 17063-17067.
OpenUrl Abstract/FREE Full Text
↵
St-Gelais F, Ménard C, Congar P, Trudeau LE, and Massicotte G (2004) Postsynaptic injection of calcium-independent phospholipase A₂ inhibitors selectively increases AMPA receptor-mediated synaptic transmission. Hippocampus 14: 319-325.
OpenUrl CrossRef PubMed
↵
Stephenson DT, Lemere CA, Selkoe DJ, and Clemens JA (1996) Cytosolic phospholipase A₂ (cPLA₂) immunoreactivity is elevated in Alzheimer's disease brain. Neurobiol Dis 3: 51-63.
OpenUrl CrossRef PubMed
↵
Stephenson D, Rash K, Smalstig B, Roberts E, Johnstone E, Sharp J, Panetta J, Little S, Kramer R, and Clemens J (1999) Cytosolic phospholipase A₂ is induced in reactive glia following different forms of neurodegeneration. Glia 27: 110-128.
OpenUrl CrossRef PubMed
↵
Stewart LR, White AR, Jobling MF, Needham BE, Maher F, Thyer J, Beyreuther K, Masters CL, Collins SJ, and Cappai R (2001) Involvement of the 5-lipoxygenase pathway in the neurotoxicity of the prion peptide PrP106-126. J Neurosci Res 65: 565-572.
OpenUrl CrossRef PubMed
Stone SJ, Cui Z, and Vance JE (1998) Cloning and expression of mouse liver phosphatidylserine synthase-1 cDNA— overexpression in rat hepatoma cells inhibits the CDP-ethanolamine pathway for phosphatidylethanolamine biosynthesis. J Biol Chem 273: 7293-7302.
OpenUrl Abstract/FREE Full Text
↵
Street IP, Lin HK, Laliberté F, Ghomashchi F, Wang Z, Perrier H, Tremblay NM, Huang Z, Weech PK, and Gelb MH (1993) Slow- and tight-binding inhibitors of the 85-kDa human phospholipase A₂. Biochemistry 32: 5935-5940.
OpenUrl CrossRef PubMed
↵
Strokin M, Sergeeva M, and Reiser G (2003) Docosahexaenoic acid and arachidonic acid release in rat brain astrocytes is mediated by two separate isoforms of phospholipase A₂ and is differently regulated by cyclic AMP and Ca²⁺. Br J Pharmacol 139: 1014-1022.
OpenUrl CrossRef PubMed
↵
Sugaya K, Uz T, Kumar V, and Manev H (2000) New anti-inflammatory treatment strategy in Alzheimer's disease. Jpn J Pharmacol 82: 85-94.
OpenUrl CrossRef PubMed
↵
Sun GY, Xu JF, Jensen MD, and Simonyi A (2004) Phospholipase A₂ in the central nervous system: implications for neurodegenerative diseases. J Lipid Res 45: 205-213.
OpenUrl Abstract/FREE Full Text
↵
Svennerholm L (1994) Gangliosides-a new therapeutic agent against stroke and Alzheimer's disease. Life Sci 55: 2125-2134.
OpenUrl CrossRef PubMed
↵
Tabuchi S, Uozumi N, Ishii S, Shimizu Y, Watanabe T, and Shimizu T (2003) Mice deficient in cytosolic phospholipase A₂ are less susceptible to cerebral ischemia/reperfusion injury, in Brain Edema XII (Kuroiwa T, Baethmann A, Czernicki Z, Hoff JT, Ito U, Katayama Y, Mararou A, Mendelow AD, and Reulen HJ eds) pp 169-172, Springer-Verlag Wien, Vienna.
↵
Tagami M, Ikeda K, Yamagata K, Nara Y, Fujino H, Kubota A, Numano F, and Yamori Y (1999) Vitamin E prevents apoptosis in hippocampal neurons caused by cerebral ischemia and reperfusion in stroke-prone spontaneously hypertensive rats. Lab Invest 79: 609-615.
OpenUrl PubMed
↵
Tariq M, Khan HA, Al Moutaery K, and Al Deeb S (2001) Protective effect of quinacrine on striatal dopamine levels in 6-OHDA and MPTP models of Parkinsonism in rodents. Brain Res Bull 54: 77-82.
OpenUrl CrossRef PubMed
↵
Taylor WA (1988) Effects of Impact Injury of Rat Spinal Cord on Activities of Some Enzymes of Lipid Hydrolysis. Doctoral Dissertation, The Ohio State University, Columbus, OH.
↵
Terano T, Fujishiro S, Ban T, Yamamoto K, Tanaka T, Noguchi Y, Tamura Y, Yazawa K, and Hirayama T (1999) Docosahexaenoic acid supplementation improves the moderately severe dementia from thrombotic cerebrovascular diseases. Lipids 34 (Suppl): S345-S346.
OpenUrl CrossRef PubMed
↵
Thwin MM, Ong WY, Fong CW, Sato K, Kodama K, Farooqui AA, and Gopalakrishnakone P (2003) Secretory phospholipase A₂ activity in the normal and kainate injected rat brain, and inhibition by a peptide derived from python serum. Exp Brain Res 150: 427-433.
OpenUrl PubMed
↵
Tong W, Shah D, Xu JF, Diehl JA, Hans A, Hannink M, and Sun GY (1999) Involvement of lipid mediators on cytokine signaling and induction of secretory phospholipase A₂ in immortalized astrocytes (DITNC). J Mol Neurosci 12: 89-99.
OpenUrl PubMed
↵
Tran K, Wong JT, Lee E, Chan AC, and Choy PC (1996) Vitamin E potentiates arachidonate release and phospholipase A₂ activity in rat heart myoblastic cells. Biochem J 319: 385-391.
OpenUrl Abstract/FREE Full Text
Trevisi L, Bova S, Cargnelli G, Ceolotto G, and Luciani S (2002) Endothelin-1-induced arachidonic acid release by cytosolic phospholipase A₂ activation in rat vascular smooth muscle via extracellular signal-regulated kinases pathway. Biochem Pharmacol 64: 425-431.
OpenUrl CrossRef PubMed
↵
Trigueros SDA, Kalyvas A, and David S (2003) Phospholipase A₂ plays an important role in myelin breakdown and phagocytosis during Wallerian degeneration. Mol Cell Neurosci 24: 753-765.
OpenUrl CrossRef PubMed
↵
Trimble LA, Street IP, Perrier H, Tremblay NM, Weech PK, and Bernstein MA (1993) NMR structural studies of the tight complex between a trifluoromethyl ketone inhibitor and the 85-kDa human phospholipase A₂. Biochemistry 32: 12560-12565.
OpenUrl CrossRef PubMed
↵
Turnbull S, Tabner BJ, Brown DR, and Allsop D (2003) Quinacrine acts as an antioxidant and reduces the toxicity of the prion peptide PrP106-126. NeuroReport 14: 1743-1745.
OpenUrl CrossRef PubMed
↵
Uozumi N and Shimizu T (2002) Roles for cytosolic phospholipase A₂α as revealed by gene-targeted mice. Prostaglandins Other Lipid Mediat 68-69: 59-69.
OpenUrl CrossRef PubMed
↵
Vanags DM, Larsson P, Feltenmark S, Jakobsson PJ, Orrenius S, Claesson HE, and Aguilar-Santelises M (1997) Inhibitors of arachidonic acid metabolism reduce DNA and nuclear fragmentation induced by TNF plus cycloheximide in U937 cells. Cell Death Differ 4: 479-486.
OpenUrl CrossRef PubMed
↵
Visioli F, Rodriguez de Turco EB, Kreisman NR, and Bazan NG (1994) Membrane lipid degradation is related to interictal cortical activity in a series of seizures. Metab Brain Dis 9: 161-170.
OpenUrl CrossRef PubMed
↵
Vogtherr M, Grimme S, Elshorst B, Jacobs DM, Fiebig K, Griesinger C, and Zahn R (2003) Antimalarial drug quinacrine binds to C-terminal helix of cellular prion protein. J Med Chem 46: 3563-3564.
OpenUrl CrossRef PubMed
↵
Walsh DM and Selkoe DJ (2004) Deciphering the molecular basis of memory failure in Alzheimer's disease. Neuron 44: 181-193.
OpenUrl CrossRef PubMed
↵
Walters ET (1994) Injury-related behavior and neuronal plasticity: an evolutionary perspective on sensitization, hyperalgesia, and analgesia. Int Rev Neurobiol 36: 325-427.
OpenUrl PubMed
↵
Wang TG, Qin L, Liu B, Liu YX, Wilson B, Eling TE, Langenbach R, Taniura S, and Hong JS (2004a) Role of reactive oxygen species in LPS-induced production of prostaglandin E-2 in microglia. J Neurochem 88: 939-947.
OpenUrl CrossRef PubMed
↵
Wang XH, Yan GT, Wang LH, Hao XH, Zhang K, and Xue H (2004b) The mediating role of cPLA₂ in IL-1β and IL-6 release in LPS-induced HeLa cells. Cell Biochem Funct 22: 41-44.
OpenUrl CrossRef PubMed
↵
Wang ZG (2003) Role of redox state in modulation of ion channel function by fatty acids and phospholipids. Br J Pharmacol 139: 681-683.
OpenUrl CrossRef PubMed
↵
Weerasinghe GR, Rapoport SI, and Bosetti F (2004) The effect of chronic lithium on arachidonic acid release and metabolism in rat brain does not involve secretory phospholipase A₂ or lipoxygenase/cytochrome P450 pathways. Brain Res Bull 63: 485-489.
OpenUrl CrossRef PubMed
↵
Wei EP, Lamb RG, and Kontos HA (1982) Increased phospholipase C activity after experimental brain injury. J Neurosurg 56: 695-698.
OpenUrl PubMed
↵
Wei S, Ong WY, Thwin MM, Fong CW, Farooqui AA, Gopalakrishnakone P, and Hong WJ (2003) Differential activities of secretory phospholipase A₂ (sPLA₂)inrat brain and effects of sPLA₂ on neurotransmitter release. Neuroscience 121: 891-898.
OpenUrl CrossRef PubMed
↵
Wells K, Farooqui AA, Liss L, and Horrocks LA (1995) Neural membrane phospholipids in Alzheimer disease. Neurochem Res 20: 1329-1333.
OpenUrl CrossRef PubMed
↵
Wolf MJ, Izumi Y, Zorumski CF, and Gross RW (1995) Long-term potentiation requires activation of calcium-independent phospholipase A₂. FEBS Lett 377: 358-362.
OpenUrl CrossRef PubMed
Xing M, Wilkins PL, McConnell BK, and Mattera R (1994) Regulation of phospholipase A₂ activity in undifferentiated and neutrophil-like HL60 cells: linkage between impaired responses to agonists and absence of protein kinase C-dependent phosphorylation of cytosolic phospholipase A₂. J Biol Chem 269: 3117-3124.
OpenUrl Abstract/FREE Full Text
↵
Xu JF, Yu S, Sun AY, and Sun GY (2003) Oxidant-mediated AA release from astrocytes involves cPLA₂ and iPLA₂. Free Radic Biol Med 34: 1531-1543.
OpenUrl CrossRef PubMed
↵
Yagi K, Shirai Y, Hirai M, Sakai N, and Saito N (2004) Phospholipase A₂ products retain a neuron specific γ isoform of PKC on the plasma membrane through the C1 domain—a molecular mechanism for sustained enzyme activity. Neurochem Int 45: 39-47.
OpenUrl CrossRef PubMed
↵
Yang H-C, Farooqui AA, and Horrocks LA (1994a) Effects of glycosaminoglycans and glycosphingolipids on cytosolic phospholipases A₂ from bovine brain. Biochem J 299: 91-95.
OpenUrl Abstract/FREE Full Text
↵
Yang H-C, Farooqui AA, and Horrocks LA (1994b) Effects of sialic acid and sialoglycoconjugates on cytosolic phospholipases A₂ from bovine brain. Biochem Biophys Res Commun 199: 1158-1166.
OpenUrl CrossRef PubMed
↵
Yang HC, Mosior M, Ni B, and Dennis EA (1999) Regional distribution, ontogeny, purification, and characterization of the Ca²⁺-independent phospholipase A₂ from rat brain. J Neurochem 73: 1278-1287.
OpenUrl CrossRef PubMed
↵
Yao JK and Van Kammen DP (2004) Membrane phospholipids and cytokine interaction in schizophrenia, in Disorders of Synaptic Plasticity and Schizophrenia (Smythies J ed) pp 297-326, Academic Press, San Diego, CA.
↵
Yao JK, Leonard S, and Reddy RD (2000) Membrane phospholipid abnormalities in postmortem brains from schizophrenic patients. Schizophr Res 42: 7-17.
OpenUrl CrossRef PubMed
↵
Yegin A, Akbas SH, Ozben T, and Korgun DK (2002) Secretory phospholipase A₂ and phospholipids in neural membranes in an experimental epilepsy model. Acta Neurol Scand 106: 258-262.
OpenUrl CrossRef PubMed
↵
Yeo JF, Ong WY, Ling SF, and Farooqui AA (2004) Intracerebroventricular injection of phospholipases A₂ inhibitors modulates allodynia after facial carrageenan injection in mice. Pain 112: 148-155.
OpenUrl CrossRef PubMed
↵
Yoo MH, Woo CH, You HJ, Cho SH, Kim BC, Choi JE, Chun JS, Jhun BH, Kim TS, and Kim JH (2001) Role of the cytosolic phospholipase A₂-linked cascade in signaling by an oncogenic, constitutively active Ha-Ras isoform. J Biol Chem 276: 24645-24653.
OpenUrl Abstract/FREE Full Text
↵
Yoshihara Y and Watanabe Y (1990) Translocation of phospholipase A₂ from cytosol to membranes in rat brain induced by calcium ions. Biochem Biophys Res Commun 170: 484-490.
OpenUrl CrossRef PubMed
↵
Yoshihara Y, Yamaji M, Kawasaki M, and Watanabe Y (1992) Ontogeny of cytosolic phospholipase A₂ activity in rat brain. Biochem Biophys Res Commun 185: 350-355.
OpenUrl CrossRef PubMed
↵
Yoshinaga N, Yasuda Y, Murayama T, and Nomura Y (2000) Possible involvement of cytosolic phospholipase A₂ in cell death induced by 1-methyl-4-phenylpyridinium ion, a dopaminergic neurotoxin, in GH3 cells. Brain Res 855: 244-251.
OpenUrl CrossRef PubMed
↵
Zanassi P, Paolillo M, and Schinelli S (1998) Coexpression of phospholipase A₂ isoforms in rat striatal astrocytes. Neurosci Lett 247: 83-86.
OpenUrl CrossRef PubMed
↵
Zhang B, Tanaka J, Yang L, Yang L, Sakanaka M, Hata R, Maeda N, and Mitsuda N (2004) Protective effect of vitamin E against focal brain ischemia and neuronal death through induction of target genes of hypoxia-inducible factor-1. Neuroscience 126: 433-440.
OpenUrl CrossRef PubMed
↵
Zhao Y, Joshi-Barve S, Barve S, and Chen LH (2004) Eicosapentaenoic acid prevents LPS-induced TNF-α expression by preventing NF-κB activation. J Am Coll Nutr 23: 71-78.
OpenUrl CrossRef PubMed

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[1] ↵
Abraham IM, Harkany T, Horvath KM, and Luiten PG (2001) Action of glucocorticoids on survival of nerve cells: promoting neurodegeneration or neuroprotection? J Neuroendocrinol 13: 749-760.
OpenUrl CrossRef PubMed

[2] ↵
Ackermann EJ and Dennis EA (1995) Mammalian calcium-independent phospholipase A₂. Biochim Biophys Acta 1259: 125-136.
OpenUrl PubMed

[3] ↵
Adibhatla RM and Hatcher JF (2003) Citicoline decreases phospholipase A₂ stimulation and hydroxyl radical generation in transient cerebral ischemia. J Neurosci Res 73: 308-315.
OpenUrl CrossRef PubMed

[4] ↵
Adibhatla RM, Hatcher JF, and Dempsey RJ (2002) Citicoline: neuroprotective mechanisms in cerebral ischemia. J Neurochem 80: 12-23.
OpenUrl CrossRef PubMed

[5] ↵
Adibhatla RM, Hatcher JF, and Dempsey RJ (2003) Phospholipase A₂, hydroxyl radicals, and lipid peroxidation in transient cerebral ischemia. Antioxid Redox Signal 5: 647-654.
OpenUrl CrossRef PubMed

[6] ↵
Aitdafoun M, Mounier C, Heymans F, Binisti C, Bon C, and Godfroid JJ (1996) 4-Alkoxybenzamidines as new potent phospholipase A₂ inhibitors. Biochem Pharmacol 51: 737-742.
OpenUrl CrossRef PubMed

[7] ↵
Ajmone-Cat MA, Nicolini A, and Minghetti L (2003) Prolonged exposure of microglia to lipopolysaccharide modifies the intracellular signaling pathways and selectively promotes prostaglandin E-2 synthesis. J Neurochem 87: 1193-1203.
OpenUrl CrossRef PubMed

[8] ↵
Akiyama N, Hatori Y, Takashiro Y, Hirabayashi T, Saito T, and Murayama T (2004) Nerve growth factor-induced up-regulation of cytosolic phospholipase A₂α level in rat PC12 cells. Neurosci Lett 365: 218-222.
OpenUrl CrossRef PubMed

[9] ↵
Amandi-Burgermeister E, Tibes U, Kaiser BM, Friebe WG, and Scheuer WV (1997) Suppression of cytokine synthesis, integrin expression and chronic inflammation by inhibitors of cytosolic phospholipase A₂. Eur J Pharmacol 326: 237-250.
OpenUrl CrossRef PubMed

[10] ↵
Anderle P, Farmer P, Berger A, and Roberts MA (2004) Nutrigenomic approach to understanding the mechanisms by which dietary long-chain fatty acids induce gene signals and control mechanisms involved in carcinogenesis. Nutrition 20: 103-108.
OpenUrl CrossRef PubMed

[11] ↵
Andersen M, Overgaard K, Meden P, and Boysen G (1999) Effects of citicoline combined with thrombolytic therapy in a rat embolic stroke model. Stroke 30: 1464-1470.
OpenUrl Abstract/FREE Full Text

[12] ↵
Anderson DK, Saunders RD, Demediuk P, Dugan LL, Braughler JM, Hall ED, Means ED, and Horrocks LA (1985) Lipid hydrolysis and peroxidation in injured spinal cord: Partial protection with methylprednisolone or vitamin E and selenium. Cent Nerv Syst Trauma 2: 257-267.
OpenUrl PubMed

[13] ↵
Arai K, Ikegaya Y, Nakatani Y, Kudo I, Nishiyama N, and Matsuki N (2001) Phospholipase A₂ mediates ischemic injury in the hippocampus: a regional difference of neuronal vulnerability. Eur J Neurosci 13: 2319-2323.
OpenUrl CrossRef PubMed

[14] ↵
Asai K, Hirabayashi T, Houjou T, Uozumi N, Taguchi R, and Shimizu T (2003) Human group IVC phospholipase A₂ (cPLA₂γ)—roles in the membrane remodeling and activation induced by oxidative stress. J Biol Chem 278: 8809-8814.
OpenUrl Abstract/FREE Full Text

[15] ↵
Ates M, Hamza M, Seidel K, Kotalla CE, Ledent C, and Guhring H (2003) Intrathecally applied flurbiprofen produces an endocannabinoid-dependent antinociception in the rat formalin test. Eur J Neurosci 17: 597-604.
OpenUrl CrossRef PubMed

[16] ↵
Atsumi G, Murakami M, Kojima K, Hadano A, Tajima M, and Kudo I (2000) Distinct roles of two intracellular phospholipase A₂s in fatty acid release in the cell death pathway: proteolytic fragment of type IVA cytosolic phospholipase A_2α inhibits stimulus-induced arachidonate release, whereas that of type VI Ca²⁺-independent phospholipase A₂ augments spontaneous fatty acid release. J Biol Chem 275: 18248-18258.
OpenUrl Abstract/FREE Full Text

[17] ↵
Atsumi G, Tajima M, Hadano A, Nakatani Y, Murakami M, and Kudo I (1998) Fas-induced arachidonic acid release is mediated by Ca²⁺-independent phospholipase A₂ but not cytosolic phospholipase A₂ which undergoes proteolytic inactivation. J Biol Chem 273: 13870-13877.
OpenUrl Abstract/FREE Full Text

[18] ↵
Balboa MA, Varela-Nieto I, Lucas KK, and Dennis EA (2002) Expression and function of phospholipase A₂ in brain. FEBS Lett 531: 12-17.
OpenUrl CrossRef PubMed

[19] ↵
Basselin M, Chang L, Seemann R, Bell JM, and Rapoport SI (2003) Chronic lithium administration potentiates brain arachidonic acid signaling at rest and during cholinergic activation in awake rats. J Neurochem 85: 1553-1562.
OpenUrl CrossRef PubMed

[20] ↵
Bate C, Reid S, and Williams A (2004) Phospholipase A₂ inhibitors or platelet-activating factor antagonists prevent prion replication. J Biol Chem 279: 36405-36411.
OpenUrl Abstract/FREE Full Text

[21] ↵
Bate C and Williams A (2004) Role of glycosylphosphatidylinositols in the activation of phospholipase A₂ and the neurotoxicity of prions. J Gen Virol 85: 3797-3804.
OpenUrl Abstract/FREE Full Text

[22] Bayón Y, Hernández M, Alonso A, Nunez L, Garcia-Sancho J, Leslie C, Crespo MS, and Nieto ML (1997) Cytosolic phospholipase A₂ is coupled to muscarinic receptors in the human astrocytoma cell line 1321N1: characterization of the transducing mechanism. Biochem J 323: 281-287.
OpenUrl Abstract/FREE Full Text

[23] ↵
Beattie MS, Farooqui AA, and Bresnahan JC (2000) Review of current evidence for apoptosis after spinal cord injury. J Neurotrauma 17: 915-925.
OpenUrl CrossRef PubMed

[24] ↵
Ben-Ari Y and Cossart R (2000) Kainate, a double agent that generates seizures: two decades of progress. Trends Neurosci 23: 580-587.
OpenUrl CrossRef PubMed

[25] ↵
Berlett BS and Stadtman ER (1997) Protein oxidation in aging, disease, and oxidative stress. J Biol Chem 272: 20313-20316.
OpenUrl FREE Full Text

[26] ↵
Blackwell GJ and Flower RJ (1983) Inhibition of phospholipase. Br Med Bull 39: 260-264.
OpenUrl FREE Full Text

[27] ↵
Boilard E, Bourgoin SG, Bernatchez C, Poubelle PE, and Surette ME (2003) Interaction of low molecular weight group IIA phospholipase A₂ with apoptotic human T cells: role of heparan sulfate proteoglycans. FASEB J 17: 1068-1080.
OpenUrl Abstract/FREE Full Text

[28] ↵
Bonventre JV, Huang ZH, Taheri MR, O'Leary E, Li E, Moskowitz MA, and Sapirstein A (1997) Reduced fertility and postischaemic brain injury in mice deficient in cytosolic phospholipase A₂. Nature (Lond) 390: 622-625.
OpenUrl CrossRef PubMed

[29] ↵
Bosetti F and Weerasinghe GR (2003) The expression of brain cyclooxygenase-2 is down-regulated in the cytosolic phospholipase A₂ knockout mouse. J Neurochem 87: 1471-1477.
OpenUrl CrossRef PubMed

[30] ↵
Brown WJ, Chambers K, and Doody A (2003) Phospholipase A₂ (PLA₂) enzymes in membrane trafficking: mediators of membrane shape and function. Traffic 4: 214-221.
OpenUrl CrossRef PubMed

[31] ↵
Burgermeister E, Tibes U, Stockinger H, and Scheuer WV (1999) Activation of nuclear factor-κB by lipopolysaccharide in mononuclear leukocytes is prevented by inhibitors of cytosolic phospholipase A₂. Eur J Pharmacol 369: 373-386.
OpenUrl CrossRef PubMed

[32] ↵
Burgess JR and Kuo CF (1996) Increased calcium-independent phospholipase A₂ activity in vitamin E and selenium-deficient rat lung, liver, and spleen cytosol is time-dependent and reversible. J Nutr Biochem 7: 366-374.
OpenUrl CrossRef

[33] ↵
Burke JR, Witmer MR, Tredup J, Micanovic R, Gregor KR, Lahiri J, Tramposch KM, and Villafranca JJ (1995) Cooperativity and binding in the mechanism of cytosolic phospholipase A₂. Biochemistry 34: 15165-15174.
OpenUrl CrossRef PubMed

[34] ↵
Burke JR, Witmer MR, Zusi FC, Gregor KR, Davern LB, Padmanabha R, Swann RT, Smith D, Tredup JA, Micanovic R, et al. (1999) Competitive, reversible inhibition of cytosolic phospholipase A₂ at the lipid-water interface by choline derivatives that partially partition into the phospholipid bilayer. J Biol Chem 274: 18864-18871.
OpenUrl Abstract/FREE Full Text

[35] ↵
Calder PC and Grimble RF (2002) Polyunsaturated fatty acids, inflammation and immunity. Eur J Clin Nutr 56: S14-S19.
OpenUrl CrossRef PubMed

[36] ↵
Calon F, Lim GP, Yang FS, Morihara T, Teter B, Ubeda O, Rostaing P, Triller A, Salem NJ, Ashe KH, et al. (2004) Docosahexaenoic acid protects from dendritic pathology in an Alzheimer's disease mouse model. Neuron 43: 633-645.
OpenUrl CrossRef PubMed

[37] ↵
Chabot C, Gagne J, Giguere C, Bernard J, Baudry M, and Massicotte G (1998) Bidirectional modulation of AMPA receptor properties by exogenous phospholipase A₂ in the hippocampus. Hippocampus 8: 299-309.
OpenUrl CrossRef PubMed

[38] ↵
Chakraborti S (2003) Phospholipase A₂ isoforms: a perspective. Cell Signal 15: 637-665.
OpenUrl CrossRef PubMed

[39] ↵
Chang MCJ and Jones CR (1998) Chronic lithium treatment decreases brain phospholipase A₂ activity. Neurochem Res 23: 887-892.
OpenUrl CrossRef PubMed

[40] ↵
Chiba H, Michibata H, Wakimoto K, Seishima M, Kawasaki S, Okubo K, Mitsui H, Torii H, and Imai Y (2004) Cloning of a gene for a novel epithelium-specific cytosolic phospholipase A₂, cPLA₂δ, induced in psoriatic skin. J Biol Chem 279: 12890-12897.
OpenUrl Abstract/FREE Full Text

[41] ↵
Clark JD and Tam S (2004) Potential therapeutic uses of phospholipase A₂ inhibitors. Expert Opin Ther Patents 14: 937-950.
OpenUrl CrossRef

[42] ↵
Clark MA, Conway TM, Shorr RGL, and Crooke ST (1987) Identification and isolation of a mammalian protein which is antigenically and functionally related to the phospholipase A₂ stimulatory peptide melittin. J Biol Chem 262: 4402-4406.
OpenUrl Abstract/FREE Full Text

[43] ↵
Clemens JA, Stephenson DT, Smalstig EB, Roberts EF, Johnstone EM, Sharp JD, Little SP, and Kramer RM (1996) Reactive glia express cytosolic phospholipase A₂ after transient global forebrain ischemia in the rat. Stroke 27: 527-535.
OpenUrl Abstract/FREE Full Text

[44] ↵
Connolly S, Bennion C, Botterell S, Croshaw PJ, Hallam C, Hardy K, Hartopp P, Jackson CG, King SJ, Lawrence L, et al. (2002) Design and synthesis of a novel and potent series of inhibitors of cytosolic phospholipase A₂ based on a 1,3-disubstituted propan-2-one skeleton. J Med Chem 45: 1348-1362.
OpenUrl CrossRef PubMed

[45] ↵
Corbella B and Vieta E (2003) Molecular targets of lithium action. Acta Neuropsychiatry 15: 316-340.
OpenUrl CrossRef

[46] ↵
Cummings BS, McHowat J, and Schnellmann RG (2000) Phospholipase A₂s in cell injury and death. J Pharmacol Exp Ther 294: 793-799.
OpenUrl Abstract/FREE Full Text

[47] ↵
de Wilde MC, Leenders I, Broersen LM, Kuipers AAM, van der Beek EM, and Kiliaan AJ (2003) The omega-3 fatty acid docosahexaenoic acid (DHA) inhibits the formation of beta amyloid in CHO7PA2 cells, in Society for Neuroscience 33rd Annual Meeting Abstracts; 2003 Nov 8-12; New Orleans, LA; Abstract nr 730.11.

[48] ↵
DeArmond SJ and Prusiner SB (2003) Perspectives on prion biology, prion disease pathogenesis, and pharmacologic approaches to treatment. Clin Lab Med 23: 1-41.
OpenUrl CrossRef PubMed

[49] ↵
DeCoster MA, Lambeau G, Lazdunski M, and Bazan NG (2002) Secreted phospholipase A₂ potentiates glutamate-induced calcium increase and cell death in primary neuronal cultures. J Neurosci Res 67: 634-645.
OpenUrl CrossRef PubMed

[50] ↵
Demediuk P, Saunders RD, Anderson DK, Means ED, and Horrocks LA (1985) Membrane lipid changes in laminectomized and traumatized cat spinal cord. Proc Natl Acad Sci USA 82: 7071-7075.
OpenUrl Abstract/FREE Full Text

[51] ↵
Dempsey RJ and Rao VLR (2003) Cytidinediphosphocholine treatment to decrease traumatic brain injury-induced hippocampal neuronal death, cortical contusion volume, and neurological dysfunction in rats. J Neurosurg 98: 867-873.
OpenUrl PubMed

[52] ↵
Denecker G, Vercammen D, Declercq W, and Vandenabeele P (2001) Apoptotic and necrotic cell death induced by death domain receptors. Cell Mol Life Sci 58: 356-370.
OpenUrl CrossRef PubMed

[53] ↵
Diaz-Arrastia R and Scott KS (1999) Expression of cPLA2-β and cPLA2-γ, novel paralogs of group IV cytosolic phospholipase A2 in mammalian brain. Soc Neurosci Abs 25: 2206.
OpenUrl

[54] ↵
Doh-ura K, Iwaki T, and Caughey B (2000) Lysosomotropic agents and cysteine protease inhibitors inhibit scrapie-associated prion protein accumulation. J Virol 74: 4894-4897.
OpenUrl Abstract/FREE Full Text

[55] ↵
Doug M, Guda K, Nambiar PR, Rezaie A, Belinsky GS, Lambeau G, Giardina C, and Rosenberg DW (2003) Inverse association between phospholipase A₂ and COX-2 expression during mouse colon tumorigenesis. Carcinogenesis 24: 307-315.
OpenUrl Abstract/FREE Full Text

[56] ↵
Douglas CE, Chan AC, and Choy PC (1986) Vitamin E inhibits platelet phospholipase A₂. Biochim Biophys Acta 876: 639-645.
OpenUrl PubMed

[57] ↵
Dubin NH, Blake DA, DiBlasi MC, Parmley TH, and King TM (1982) Pharmacokinetic studies on quinacrine following intrauterine administration to cynomolgus monkeys. Fertil Steril 38: 735-740.
OpenUrl PubMed

[58] ↵
Edgar AD, Strosznajder J, and Horrocks LA (1982) Activation of ethanolamine phospholipase A₂ in brain during ischemia. J Neurochem 39: 1111-1116.
OpenUrl PubMed

[59] ↵
Endres S and von Schacky C (1996) n-3 polyunsaturated fatty acids and human cytokine synthesis. Curr Opin Lipidol 7: 48-52.
OpenUrl CrossRef PubMed

[60] ↵
Estevez AY and Phillis JW (1997) The phospholipase A₂ inhibitor, quinacrine, reduces infarct size in rats after transient middle cerebral artery occlusion. Brain Res 752: 203-208.
OpenUrl CrossRef PubMed

[61] ↵
Farooqui AA, Antony P, Ong WY, Horrocks LA, and Freysz L (2004a) Retinoic acid-mediated phospholipase A₂ signaling in the nucleus. Brain Res Rev 45: 179-195.
OpenUrl CrossRef PubMed

[62] ↵
Farooqui AA, Haun SE, and Horrocks LA (1994a) Ischemia and hypoxia, in Basic Neurochemistry (Siegel GJ, Agranoff BW, Albers RW, and Molinoff PB eds) pp 867-883, Raven Press, New York.

[63] ↵
Farooqui AA and Horrocks LA (1991) Excitatory amino acid receptors, neural membrane phospholipid metabolism and neurological disorders. Brain Res Rev 16: 171-191.
OpenUrl CrossRef PubMed

[64] ↵
Farooqui AA and Horrocks LA (1994) Excitotoxicity and neurological disorders: involvement of membrane phospholipids. Int Rev Neurobiol 36: 267-323.
OpenUrl PubMed

[65] ↵
Farooqui AA and Horrocks LA (2001) Plasmalogens: workhorse lipids of membranes in normal and injured neurons and glia. Neuroscientist 7: 232-245.
OpenUrl Abstract/FREE Full Text

[66] ↵
Farooqui AA and Horrocks LA (2004a) Beneficial effects of docosahexaenoic acid on health of the human brain. Agro Food Ind Hi-Tech 15: 52-53.
OpenUrl

[67] ↵
Farooqui AA and Horrocks LA (2004b) Plasmalogens, platelet activating factor, and other ether lipids, in Bioactive Lipids (Nicolaou A and Kokotos G eds) pp 107-134, Oily Press, Bridgwater, UK.

[68] ↵
Farooqui AA, Horrocks LA, and Farooqui T (2000a) Deacylation and reacylation of neural membrane glycerophospholipids. J Mol Neurosci 14: 123-135.
OpenUrl CrossRef PubMed

[69] ↵
Farooqui AA, Litsky ML, Farooqui T, and Horrocks LA (1999) Inhibitors of intracellular phospholipase A₂ activity: their neurochemical effects and therapeutical importance for neurological disorders. Brain Res Bull 49: 139-153.
OpenUrl CrossRef PubMed

[70] ↵
Farooqui AA, Ong WY, and Horrocks LA (2003a) Plasmalogens, docosahexaenoic acid, and neurological disorders, in Peroxisomal Disorders and Regulation of Genes (Roels F, Baes M, and de Bies S eds) pp 335-354, Kluwer Academic/Plenum Publishers, London.

[71] ↵
Farooqui AA, Ong WY, and Horrocks LA (2003b) Stimulation of lipases and phospholipases in Alzheimer disease, in Nutrition and Biochemistry of Phospholipids (Szuhaj B and van Nieuwenhuyzen W eds) pp 14-29, AOCS Press, Champaign, IL.

[72] ↵
Farooqui AA, Ong WY, and Horrocks LA (2004b) Neuroprotection abilities of cytosolic phospholipase A₂ inhibitors in kainic acid-induced neurodegeneration. Curr Drug Targets Cardiovasc Haematol Disord 4: 85-96.
OpenUrl CrossRef PubMed

[73] ↵
Farooqui AA, Ong WY, Horrocks LA, and Farooqui T (2000b) Brain cytosolic phospholipase A₂: Localization, role, and involvement in neurological diseases. Neuroscientist 6: 169-180.
OpenUrl PubMed

[74] ↵
Farooqui AA, Ong WY, Lu XR, Halliwell B, and Horrocks LA (2001) Neurochemical consequences of kainate-induced toxicity in brain: involvement of arachidonic acid release and prevention of toxicity by phospholipase A₂ inhibitors. Brain Res Rev 38: 61-78.
OpenUrl CrossRef PubMed

[75] ↵
Farooqui AA, Ong WY, Lu XR, and Horrocks LA (2002) Cytosolic phospholipase A₂ inhibitors as therapeutic agents for neural cell injury. Curr Med Chem - Anti-Inflammatory & Anti-Allergy Agents 1: 193-204.
OpenUrl CrossRef

[76] ↵
Farooqui AA, Pendley CE II, Taylor WA, and Horrocks LA (1985) Studies on diacylglycerol lipases and lysophospholipases of bovine brain, in Phospholipids in the Nervous System, Vol. II: Physiological Role (Horrocks LA, Kanfer JN, and Porcellati G eds) pp 179-192, Raven Press, New York.

[77] ↵
Farooqui AA, Rapoport SI, and Horrocks LA (1997a) Membrane phospholipid alterations in Alzheimer disease: deficiency of ethanolamine plasmalogens. Neurochem Res 22: 523-527.
OpenUrl CrossRef PubMed

[78] ↵
Farooqui AA, Rosenberger TA, and Horrocks LA (1997b) Arachidonic acid, neurotrauma, and neurodegenerative diseases, in Handbook of Essential Fatty Acid Biology (Yehuda S and Mostofsky DI eds) pp 277-295, Humana Press, Totowa, NJ.

[79] ↵
Farooqui AA, Yang H-C, and Horrocks LA (1994b) Purification of lipases, phospholipases and kinases by heparin-Sepharose chromatography. J Chromatogr 673: 149-158.
OpenUrl CrossRef PubMed

[80] ↵
Farooqui AA, Yang H-C, and Horrocks LA (1995) Plasmalogens, phospholipases A₂, and signal transduction. Brain Res Rev 21: 152-161.
OpenUrl CrossRef PubMed

[81] ↵
Farooqui AA, Yang H-C, and Horrocks LA (1997c) Involvement of phospholipase A₂ in neurodegeneration. Neurochem Int 30: 517-522.
OpenUrl CrossRef PubMed

[82] ↵
Farooqui AA, Yang HC, Rosenberger TA, and Horrocks LA (1997d) Phospholipase A₂ and its role in brain tissue. J Neurochem 69: 889-901.
OpenUrl PubMed

[83] ↵
Farrelly PV, Kenna BL, Laohachai KL, Bahadi R, Salmona M, Forloni G, and Kourie JI (2003) Quinacrine blocks PrP (106-126)-formed channels. J Neurosci Res 74: 934-941.
OpenUrl CrossRef PubMed

[84] ↵
Fernando SR and Pertwee RG (1997) Evidence that methyl arachidonyl fluorophosphate is an irreversible cannabinoid receptor antagonist. Br J Pharmacol 121: 1716-1720.
OpenUrl CrossRef PubMed

[85] ↵
Ferrari G, Batistatou A, and Greene LA (1993) Gangliosides rescue neuronal cells from death after trophic factor deprivation. J Neurosci 13: 1879-1887.
OpenUrl Abstract

[86] ↵
Fighera MR, Bonini JS, Frussa R, Dutra CS, Hagen MEK, Rubin MA, and Mello CF (2004) Monosialoganglioside increases catalase activity in cerebral cortex of rats. Free Radic Res 38: 495-500.
OpenUrl CrossRef PubMed

[87] ↵
Fitzpatrick JS and Baudry M (1994) Blockade of long-term depression in neonatal hippocampal slices by a phospholipase A₂ inhibitor. Dev Brain Res 78: 81-86.
OpenUrl PubMed

[88] ↵
Follette P (2003) New perspectives for prion therapeutics meeting: prion disease treatment's early promise unravels. Science (Wash DC) 299: 191-192.
OpenUrl Abstract/FREE Full Text

[89] ↵
Friguet B, Stadtman ER, and Szweda LI (1994) Modification of glucose-6-phosphate dehydrogenase by 4-hydroxy-2-nonenal. J Biol Chem 269: 21639-21643.
OpenUrl Abstract/FREE Full Text

[90] ↵
Fuentes L, Pérez R, Nieto ML, Balsinde J, and Balboa MA (2003) Bromoenol lactone promotes cell death by a mechanism involving phosphatidate phosphohydrolase-1 rather than calcium-independent phospholipase A₂. J Biol Chem 278: 44683-44690.
OpenUrl Abstract/FREE Full Text

[91] ↵
Fujita S, Ikegaya Y, Nishikawa M, Nishiyama N, and Matsuki N (2001) Docosahexaenoic acid improves long-term potentiation attenuated by phospholipase A₂ inhibitor in rat hippocampal slices. Br J Pharmacol 132: 1417-1422.
OpenUrl CrossRef PubMed

[92] ↵
Fujita S, Ikegaya Y, Nishiyama N, and Matsuki N (2000) Ca²⁺-independent phospholipase A₂ inhibitor impairs spatial memory of mice. Jpn J Pharmacol 83: 277-278.
OpenUrl CrossRef PubMed

[93] ↵
Gamoh S, Hashimoto M, Sugioka K, Hossain MS, Hata N, Misawa Y, and Masumura S (1999) Chronic administration of docosahexaenoic acid improves reference memory-related learning ability in young rats. Neuroscience 93: 237-241.
OpenUrl CrossRef PubMed

[94] ↵
Gattaz WF, Maras A, Cairns NJ, Levy R, and Förstl H (1995) Decreased phospholipase A₂ activity in Alzheimer brains. Biol Psychiatry 37: 13-17.
OpenUrl CrossRef PubMed

[95] ↵
Gattaz WF, Forlenza OV, Talib LL, Barbosa NR, and Bottino CM (2004) Platelet phospholipase A₂ activity in Alzheimer's disease and mild cognitive impairment. J Neural Transm 111: 591-601.
OpenUrl CrossRef PubMed

[96] ↵
Geddes JW, Ulas J, Brunner LC, Choe W, and Cotman CW (1992) Hippocampal excitatory amino acid receptors in elderly, normal individuals and those with Alzheimer's disease: non-N-methyl-d-aspartate receptors. Neuroscience 50: 23-34.
OpenUrl CrossRef PubMed

[97] ↵
Geisler FH, Dorsey FC, and Coleman WP (1991) Recovery of motor function after spinal-cord injury—a randomized, placebo-controlled trial with GM-1 ganglioside. N Engl J Med 324: 1829-1887.
OpenUrl PubMed

[98] ↵
Ghelardoni S, Tomita YA, Bell JM, Rapoport SI, and Bosetti F (2004) Chronic carbamazepine selectively downregulates cytosolic phospholipase A₂ expression and cyclooxygenase activity in rat brain. Biol Psychiat 56: 248-254.
OpenUrl CrossRef PubMed

[99] ↵
Ghomashchi F, Stewart A, Hefner Y, Ramanadham S, Turk J, Leslie CC, and Gelb MH (2001) A pyrrolidine-based specific inhibitor of cytosolic phospholipase A_2α blocks arachidonic acid release in a variety of mammalian cells. Biochim Biophys Acta 1513: 160-166.
OpenUrl PubMed

[100] ↵
Ginsberg L, Xuereb JH, and Gershfeld NL (1998) Membrane instability, plasmalogen content, and Alzheimer's disease. J Neurochem 70: 2533-2538.
OpenUrl PubMed

[101] ↵
Gronich J, Konieczkowski M, Gelb MH, Nemenoff RA, and Sedor JR (1994) Interleukin 1α causes rapid activation of cytosolic phospholipase A₂ by phosphorylation in rat mesangial cells. J Clin Investig 93: 1224-1233.
OpenUrl CrossRef PubMed

[102] ↵
Grossman A, Zeiler B, and Sapirstein V (2003) Prion protein interactions with nucleic acid: possible models for prion disease and prion function. Neurochem Res 28: 955-963.
OpenUrl CrossRef PubMed

[103] ↵
Guan ZZ, Wang YA, Cairns NJ, Lantos PL, Dallner G, and Sindelar PJ (1999) Decrease and structural modifications of phosphatidylethanolamine plasmalogen in the brain with Alzheimer disease. J Neuropathol Exp Neurol 58: 740-747.
OpenUrl CrossRef PubMed

[104] ↵
Guentchev M, Voigtlander T, Haberler C, Groschup MH, and Budka H (2000) Evidence for oxidative stress in experimental prion disease. Neurobiol Dis 7: 270-273.
OpenUrl CrossRef PubMed

[105] ↵
Hamano H, Nabekura J, Nishikawa M, and Ogawa T (1996) Docosahexaenoic acid reduces GABA response in substantia nigra neuron of rat. J Neurophysiol 75: 1264-1270.
OpenUrl Abstract/FREE Full Text

[106] ↵
Han WK, Sapirstein A, Hung CC, Alessandrini A, and Bonventre JV (2003) Cross-talk between cytosolic phospholipase A₂α (cPLA_2α) and secretory phospholipase A₂ (sPLA₂) in hydrogen peroxide-induced arachidonic acid release in murine mesangial cells—sPLA₂ regulates cPLA_2α activity that is responsible for arachidonic acid release. J Biol Chem 278: 24153-24163.
OpenUrl Abstract/FREE Full Text

[107] ↵
Han XL, Holtzman DM, and McKeel DW Jr (2001) Plasmalogen deficiency in early Alzheimer's disease subjects and in animal models: molecular characterization using electrospray ionization mass spectrometry. J Neurochem 77: 1168-1180.
OpenUrl CrossRef PubMed

[108] ↵
Hanasaki K and Arita H (2002) Phospholipase A₂ receptor: a regulator of biological functions of secretory phospholipase A₂. Prostaglandins Other Lipid Mediat 68-69: 71-82.
OpenUrl CrossRef PubMed

[109] ↵
Hannon GJ (2002) RNA interference. Nature (Lond) 418: 244-251.
OpenUrl CrossRef PubMed

[110] ↵
Hashimoto M, Hossain S, Shimada T, Sugioka K, Yamasaki H, Fujii Y, Ishibashi Y, Oka JI, and Shido O (2002) Docosahexaenoic acid provides protection from impairment of learning ability in Alzheimer's disease model rats. J Neurochem 81: 1084-1091.
OpenUrl CrossRef PubMed

[111] ↵
Hazen SL and Gross RW (1993) The specific association of a phosphofructokinase isoform with myocardial calcium-independent phospholipase A₂: implications for the coordinated regulation of phospholipolysis and glycolysis. J Biol Chem 268: 9892-9900.
OpenUrl Abstract/FREE Full Text

[112] ↵
Hernandez M, Nieto ML, and Crespo MS (2000) Cytosolic phospholipase A₂ and the distinct transcriptional programs of astrocytoma cells. Trends Neurosci 23: 259-264.
OpenUrl CrossRef PubMed

[113] ↵
Hirabayashi T, Murayama T, and Shimizu T (2004) Regulatory mechanism and physiological role of cytosolic phospholipase A₂. Biol Pharm Bull 27: 1168-1173.
OpenUrl CrossRef PubMed

[114] ↵
Hirabayashi T and Shimizu T (2000) Localization and regulation of cytosolic phospholipase A₂. Biochim Biophys Acta 1488: 124-138.
OpenUrl PubMed

[115] ↵
Hirashima Y, Farooqui AA, Mills JS, and Horrocks LA (1992) Identification and purification of calcium-independent phospholipase A₂ from bovine brain cytosol. J Neurochem 59: 708-714.
OpenUrl CrossRef PubMed

[116] ↵
Hong KH, Bonventre JC, O'Leary E, Bonventre JV, and Lander ES (2001) Deletion of cytosolic phospholipase A₂ suppresses Apc^Min-induced tumorigenesis. Proc Natl Acad Sci USA 98: 3935-3939.
OpenUrl Abstract/FREE Full Text

[117] ↵
Hong S, Gronert K, Devchand PR, Moussignac RL, and Serhan CN (2003) Novel docosatrienes and 17S-resolvins generated from docosahexaenoic acid in murine brain, human blood, and glial cells—autacoids in anti-inflammation. J Biol Chem 278: 14677-14687.
OpenUrl Abstract/FREE Full Text

[118] ↵
Horrobin DF (2003) Eicosapentaenoic acid derivatives in the management of schizophrenia, in Phospholipid Spectrum Disorders in Psychiatry and Neurology (Peet M, Glen L, and Horrobin DF eds) pp 371-376, Marius Press, Carnforth, Lancashire, UK.

[119] ↵
Horrocks LA, Demediuk P, Saunders RD, Dugan L, Clendenon NR, Means ED, and Anderson DK (1985) The degradation of phospholipids, formation of metabolites of arachidonic acid, and demyelination following experimental spinal cord injury. Cent Nerv Syst Trauma 2: 115-120.
OpenUrl PubMed

[120] ↵
Horrocks LA and Farooqui AA (2004) Docosahexaenoic acid in the diet: its importance in maintenance and restoration of neural membrane function. Prostaglandins Leukotrienes Essent Fatty Acids 70: 361-372.
OpenUrl CrossRef PubMed

[121] ↵
Hossain MS, Hashimoto M, Gamoh S, and Masumura S (1999) Antioxidative effects of docosahexaenoic acid in the cerebrum versus cerebellum and brainstem of aged hypercholesterolemic rats. J Neurochem 72: 1133-1138.
OpenUrl CrossRef PubMed

[122] ↵
Hossain MS, Hashimoto M, and Masumura S (1998) Influence of docosahexaenoic acid on cerebral lipid peroxide level in aged rats with and without hypercholes-terolemia. Neurosci Lett 244: 157-160.
OpenUrl CrossRef PubMed

[123] ↵
Hudson CJ, Kennedy JL, Gotowiec A, Lin A, King N, Gojtan K, Macciardi F, Skorecki K, Meltzer HY, Warsh JJ, et al. (1996) Genetic variant near cytosolic phospholipase A₂ associated with schizophrenia. Schizophr Res 21: 111-116.
OpenUrl CrossRef PubMed

[124] ↵
Huterer SJ, Tourtellotte WW, and Wherrett JR (1995) Alterations in the activity of phospholipases A₂ in post-mortem white matter from patients with multiple sclerosis. Neurochem Res 20: 1335-1343.
OpenUrl CrossRef PubMed

[125] ↵
Ibuki T, Matsumura K, Yamazaki Y, Nozaki T, Tanaka Y, and Kobayashi S (2003) Cyclooxygenase-2 is induced in the endothelial cells throughout the central nervous system during carrageenan-induced hind paw inflammation; its possible role in hyperalgesia. J Neurochem 86: 318-328.
OpenUrl CrossRef PubMed

[126] ↵
James MJ, Gibson RA, and Cleland LG (2000) Dietary polyunsaturated fatty acids and inflammatory mediator production. Am J Clin Nutr 71: 343S-348S.
OpenUrl Abstract/FREE Full Text

[127] ↵
Jamme I, Petit E, Divoux D, Gerbi A, Maxient JM, and Nouvelot A (1995) Modulation of mouse cerebral Na⁺, K⁺-ATPase activity by oxygen free radicals. NeuroReport 7: 333-337.
OpenUrl PubMed

[128] ↵
Jeffrey M, Goodsir CM, Bruce ME, McBride PA, Scott JR, and Halliday WG (1992) Infection specific prion protein (PrP) accumulates on neuronal plasmalemma in scrapie infected mice. Neurosci Lett 147: 106-109.
OpenUrl CrossRef PubMed

[129] ↵
Junqueira R, Cordeiro Q, Meira-Lima I, Gattaz WF, and Vallada H (2004) Allelic association analysis of phospholipase A2 genes with schizophrenia. Psychiatr Genet 14: 157-160.
OpenUrl CrossRef PubMed

[130] ↵
Jupp OJ, Vandenabeele P, and MacEwan DJ (2003) Distinct regulation of cytosolic phospholipase A₂ phosphorylation, translocation, proteolysis and activation by tumour necrosis factor-receptor subtypes. Biochem J 374: 453-461.
OpenUrl CrossRef PubMed

[131] ↵
Kaetzel MA and Dedman JR (1995) Annexins: novel Ca²⁺-dependent regulators of membrane function. News Physiol Sci 10: 171-176.
OpenUrl Abstract/FREE Full Text

[132] ↵
Kajiwara K, Nagawawa H, Shimizu-Nishikawa S, Ookuri T, Kimura M, and Sugaya E (1996) Molecular characterization of seizure-related genes isolated by differential screening. Biochem Biophys Res Commun 219: 795-799.
OpenUrl CrossRef PubMed

[133] ↵
Kalyvas A and David S (2004) Cytosolic phospholipase A₂ plays a key role in the pathogenesis of multiple sclerosis-like disease. Neuron 41: 323-335.
OpenUrl CrossRef PubMed

[134] ↵
Kanfer JN, Sorrentino G, and Sitar DS (1998) Phospholipases as mediators of amyloid β-peptide neurotoxicity: an early event contributing to neurodegeneration characteristic of Alzheimer's disease. Neurosci Lett 257: 93-96.
OpenUrl CrossRef PubMed

[135] ↵
Katsuki H and Okuda S (1995) Arachidonic acid as a neurotoxic and neurotrophic substance. Prog Neurobiol 46: 607-636.
OpenUrl CrossRef PubMed

[136] ↵
Kim DK, Rordorf G, Nemenoff RA, Koroshetz WJ, and Bonventre JV (1995) Glutamate stably enhances the activity of two cytosolic forms of phospholipase A₂ in brain cortical cultures. Biochem J 310: 83-90.
OpenUrl Abstract/FREE Full Text

[137] ↵
Kishimoto K, Matsumura K, Kataoka Y, Morii H, and Watanabe Y (1999) Localization of cytosolic phospholipase A₂ messenger RNA mainly in neurons in the rat brain. Neuroscience 92: 1061-1077.
OpenUrl CrossRef PubMed

[138] ↵
Klivenyi P, Beal MF, Ferrante RJ, Andreassen OA, Wermer M, Chin MR, and Bonventre JV (1998) Mice deficient in group IV cytosolic phospholipase A₂ are resistant to MPTP neurotoxicity. J Neurochem 71: 2634-2637.
OpenUrl PubMed

[139] ↵
Kobayashi Y, Hirata K, Tanaka H, and Yamada T (2003) Quinacrine administration to a patient with Creutzfeldt-Jakob disease who received a cadaveric dura mater graft—an EEG evaluation. Rinsho Shinkeigaku 43: 403-408.
OpenUrl PubMed

[140] ↵
Kokotos G, Six DA, Loukas V, Smith T, Constantinou-Kokotou V, Hadjipavlou-Litina D, Kotsovolou S, Chiou A, Beltzner CC, and Dennis EA (2004) Inhibition of group IVA cytosolic phospholipase A₂ by novel 2-oxoamides in vitro, in cells, and in vivo. J Med Chem 47: 3615-3628.
OpenUrl CrossRef PubMed

[141] Kolko M, DeCoster MA, Rodriguez de Turco EB, and Bazan NG (1996) Synergy by secretory phospholipase A₂ and glutamate on inducing cell death and sustained arachidonic acid metabolic changes in primary cortical neuronal cultures. J Biol Chem 271: 32722-32728.
OpenUrl Abstract/FREE Full Text

[142] ↵
Kolko M, Rodriguez de Turco EB, Diemer NH, and Bazan NG (2002) Secretory phospholipase A₂-mediated neuronal cell death involves glutamate ionotropic receptors. NeuroReport 13: 1963-1966.
OpenUrl CrossRef PubMed

[143] ↵
Korth C, May BC, Cohen FE, and Prusiner SB (2001) Acridine and phenothiazine derivatives as pharmacotherapeutics for prion disease. Proc Natl Acad Sci USA 98: 9836-9841.
OpenUrl Abstract/FREE Full Text

[144] ↵
Kramer BC, Yabut JA, Cheong J, Jnobaptiste R, Robakis T, Olanow CW, and Mytilineou C (2004) Toxicity of glutathione depletion in mesencephalic cultures: a role for arachidonic acid and its lipoxygenase metabolites. Eur J Neurosci 19: 280-286.
OpenUrl CrossRef PubMed

[145] ↵
Kriem B, Sponne I, Fifre A, Malaplate-Armand C, Lozac'h-Pillot K, Koziel V, Yen-Potin FT, Bihain B, Oster T, Olivier JL, et al. (2005) Cytosolic phospholipase A₂ mediates neuronal apoptosis induced by soluble oligomers of the amyloid-β peptide. FASEB J 19: 85-87.
OpenUrl Abstract/FREE Full Text

[146] ↵
Kuroiwa N, Nakamura M, Tagaya M, and Takatsuki A (2001) Arachidonyltrifluoromethyl ketone, a phospholipase A₂ antagonist, induces dispersal of both Golgi stack- and trans Golgi network-resident proteins throughout the cytoplasm. Biochem Biophys Res Commun 281: 582-588.
OpenUrl CrossRef PubMed

[147] Kurrasch-Orbaugh DM, Parrish JC, Watts VJ, and Nichols DE (2003) A complex signaling cascade links the serotonin_2A receptor to phospholipase A₂ activation: the involvement of MAP kinases. J Neurochem 86: 980-991.
OpenUrl CrossRef PubMed

[148] ↵
Laktionova P, Rykova E, Toni M, Spisni E, Griffoni C, Bryksin A, Volodko N, Vlassov V, and Tomasi V (2004) Knock down of cytosolic phospholipase A₂: an antisense oligonucleotide having a nuclear localization binds a C-terminal motif of glyceraldehyde-3-phosphate dehydrogenase. Biochim Biophys Acta 1636: 129-135.
OpenUrl PubMed

[149] ↵
Larsson PKA, Claesson HE, and Kennedy BP (1998) Multiple splice variants of the human calcium-independent phospholipase A₂ and their effect on enzyme activity. J Biol Chem 273: 207-214.
OpenUrl Abstract/FREE Full Text

[150] ↵
Laruelle M, Abi-Dargham A, Gil R, Kegeles L, and Innis R (1999) Increased dopamine transmission in schizophrenia: relationship to illness phases. Biol Psychiatry 46: 56-72.
OpenUrl CrossRef PubMed

[151] ↵
Latorre E, Collado MP, Fernández I, Aragonés MD, and Catalán RE (2003) Signaling events mediating activation of brain ethanolamine plasmalogen hydrolysis by ceramide. Eur J Biochem 270: 36-46.
OpenUrl PubMed

[152] ↵
Lazarewicz JW, Wroblewski JT, and Costa E (1990) N-Methyl-d-aspartate-sensitive glutamate receptors induce calcium-mediated arachidonic acid release in primary cultures of cerebellar granule cells. J Neurochem 55: 1875-1881.
OpenUrl CrossRef PubMed

[153] ↵
Lehr M (1996) 3-(3,5-Dimethyl-4-octadecanoylpyrrol-2-yl)propionic acids as inhibitors of 85 kDa cytosolic phospholipase A₂. Arch Pharm (Weinheim) 329: 483-488.
OpenUrl PubMed

[154] ↵
Lehr M (1997a) Structure-activity relationship studies on (4-acylpyrrol-2-yl)alkanoic acids as inhibitors of the cytosolic phospholipase A₂: variation of the alkanoic acid substituent, the acyl chain and the position of the pyrrole nitrogen. Eur J Med Chem 32: 805-814.
OpenUrl CrossRef

[155] ↵
Lehr M (1997b) Synthesis, biological evaluation, and structure-activity relationships of 3-acylindole-2-carboxylic acids as inhibitors of the cytosolic phospholipase A₂. J Med Chem 40: 2694-2705.
OpenUrl CrossRef PubMed

[156] ↵
Lehtonen JYA, Holopainen JM, and Kinnunen PKJ (1996) Activation of phospholipase A₂ by amyloid β-peptides in vitro. Biochemistry 35: 9407-9414.
OpenUrl CrossRef PubMed

[157] ↵
Lerma J (1997) Kainate reveals its targets. Neuron 19: 1155-1158.
OpenUrl CrossRef PubMed

[158] ↵
Leslie CC (2004) Regulation of arachidonic acid availability for eicosanoid production. Biochem Cell Biol 82: 1-17.
OpenUrl CrossRef PubMed

[159] ↵
Lin TN, Wang Q, Simonyi A, Chen JJ, Cheung WM, He YY, Xu J, Sun AY, Hsu CY, and Sun GY (2004) Induction of secretory phospholipase A₂ in reactive astrocytes in response to transient focal cerebral ischemia in the rat brain. J Neurochem 90: 637-645.
OpenUrl CrossRef PubMed

[160] ↵
Locati M, Lamorte G, Luini W, Introna M, Bernasconi S, Mantovani A, and Sozzani S (1996) Inhibition of monocyte chemotaxis to C-C chemokines by antisense oligonucleotide for cytosolic phospholipase A₂. J Biol Chem 271: 6010-6016.
OpenUrl Abstract/FREE Full Text

[161] ↵
Lonergan PE, Martin DSD, Horrobin DF, and Lynch MA (2004) Neuroprotective actions of eicosapentaenoic acid on lipopolysaccharide-induced dysfunction in rat hippocampus. J Neurochem 91: 20-29.
OpenUrl CrossRef PubMed

[162] ↵
Love R (2001) Old drugs to treat new variant Creutzfeldt-Jakob disease. Lancet 358: 563.
OpenUrl CrossRef PubMed

[163] ↵
Lu XR, Ong WY, and Halliwell B (2001a) The phospholipase A₂ inhibitor quinacrine prevents increased immunoreactivity to cytoplasmic phospholipase A₂ (cPLA₂) and hydroxynonenal (HNE) in neurons of the lateral septum following fimbria-fornix transection. Exp Brain Res 138: 500-508.
OpenUrl CrossRef PubMed

[164] ↵
Lu XR, Ong WY, Halliwell B, Horrocks LA, and Farooqui AA (2001b) Differential effects of calcium-dependent and calcium-independent phospholipase A₂ inhibitors on kainate-induced neuronal injury in rat hippocampal slices. Free Radic Biol Med 30: 1263-1273.
OpenUrl CrossRef PubMed

[165] ↵
Lukácová N, Halát G, Chavko M, and Marsala J (1996) Ischemia-reperfusion injury in the spinal cord of rabbits strongly enhances lipid peroxidation and modifies phospholipid profiles. Neurochem Res 21: 869-873.
OpenUrl PubMed

[166] ↵
Macchioni L, Corazzi L, Nardicchi V, Mannucci R, Arcuri C, Porcellati S, Sposini T, Donato R, and Goracci G (2004) Rat brain cortex mitochondria release group II secretory phospholipase A₂ under reduced membrane potential. J Biol Chem 279: 37860-37869.
OpenUrl Abstract/FREE Full Text

[167] ↵
Mandal PK and Pettegrew JW (2004) Alzheimer's disease: NMR studies of asialo (GM1) and trisialo (GT1b) ganglioside interactions with A β(1-40) peptide in a membrane mimic environment. Neurochem Res 29: 447-453.
OpenUrl CrossRef PubMed

[168] ↵
Marcheselli VL, Hong S, Lukiw WJ, Tian XH, Gronert K, Musto A, Hardy M, Gimenez JM, Chiang N, Serhan CN, et al. (2003) Novel docosanoids inhibit brain ischemia-reperfusion-mediated leukocyte infiltration and pro-inflammatory gene expression. J Biol Chem 278: 43807-43817.
OpenUrl Abstract/FREE Full Text

[169] ↵
Matsuzawa A, Murakami M, Atsumi G, Imai K, Prados P, Inoue K, and Kudo I (1996) Release of secretory phospholipase A₂ from rat neuronal cells and its possible function in the regulation of catecholamine secretion. Biochem J 318: 701-709.
OpenUrl Abstract/FREE Full Text

[170] ↵
May BCH, Fafarman AT, Hong SB, Rogers M, Deady LW, Prusiner SB, and Cohen FE (2003) Potent inhibition of scrapie prion replication in cultured cells by bisacridines. Proc Natl Acad Sci USA 100: 3416-3421.
OpenUrl Abstract/FREE Full Text

[171] ↵
Mazière C, Conte MA, Degonville J, Ali D, and Mazière JC (1999) Cellular enrichment with polyunsaturated fatty acids induces an oxidative stress and activates the transcription factors AP1 and NFκB. Biochem Biophys Res Commun 265: 116-122.
OpenUrl CrossRef PubMed

[172] ↵
McIntosh TK, Saatman KE, Raghupathi R, Graham DI, Smith DH, Lee VM, and Trojanowski JQ (1998) The molecular and cellular sequelae of experimental traumatic brain injury: pathogenetic mechanisms. Neuropathol Appl Neurobiol 24: 251-267.
OpenUrl CrossRef PubMed

[173] ↵
Miele L (2003a) New weapons against inflammation: dual inhibitors of phospholipase A₂ and transglutaminase. J Clin Investig 111: 19-21.
OpenUrl CrossRef PubMed

[174] ↵
Miele L (2003b) New weapons against inflammation: dual inhibitors of phospholipase A₂ and transglutaminase. J Clin Investig 111: 19-21.
OpenUrl CrossRef PubMed

[175] ↵
Milhavet O, McMahon HE, Rachidi W, Nishida N, Katamine S, Mange A, Arlotto M, Casanova D, Riondel J, Favier A, et al. (2000) Prion infection impairs the cellular response to oxidative stress. Proc Natl Acad Sci USA 97: 13937-13942.
OpenUrl Abstract/FREE Full Text

[176] ↵
Mir C, Clotet J, Aledo R, Durany N, Argemi J, Lozano R, Cervos-Navarro J, and Casals N (2003) CDP-choline prevents glutamate-mediated cell death in cerebellar granule neurons. J Mol Neurosci 20: 53-59.
OpenUrl CrossRef PubMed

[177] ↵
Molloy GY, Rattray M, and Williams RJ (1998) Genes encoding multiple forms of phospholipase A₂ are expressed in rat brain. Neurosci Lett 258: 139-142.
OpenUrl CrossRef PubMed

[178] ↵
Mosior M, Six DA, and Dennis EA (1998a) Group IV cytosolic phospholipase A₂ binds with high affinity and specificity to phosphatidylinositol 4,5-bisphosphate resulting in dramatic increases in activity. J Biol Chem 273: 2184-2191.
OpenUrl Abstract/FREE Full Text

[179] ↵
Moskowitz N, Puszkin S, and Schook W (1983) Characterization of brain synaptic vesicle phospholipase A₂ activity and its modulation by calmodulin, prostaglandin E₂, prostaglandin F_2α, cyclic AMP and ATP. J Neurochem 41: 1576-1586.
OpenUrl PubMed

[180] ↵
Mukherjee PK, Marcheselli VL, Serhan CN, and Bazan NG (2004) Neuroprotectin D1: a docosahexaenoic acid-derived docosatriene protects human retinal pigment epithelial cells from oxidative stress. Proc Natl Acad Sci USA 101: 8491-8496.
OpenUrl Abstract/FREE Full Text

[181] ↵
Muller WEG, Ushijima H, Schroder HC, Forrest JMS, Schatton WFH, Rytik PG, and Heffner-Lauc M (1993) Cytoprotective effect of NMDA receptor antagonists on prion protein (PrionSc)-induced toxicity in rat cortical cell cultures. Eur J Pharmacol 246: 261-267.
OpenUrl CrossRef PubMed

[182] ↵
Murakami M, Nakatani Y, Atsumi G, Inoue K, and Kudo I (1997) Regulatory functions of phospholipase A₂. Crit Rev Immunol 17: 225-283.
OpenUrl CrossRef PubMed

[183] ↵
Murphy EJ and Horrocks LA (1993) CDPcholine, CDPethanolamine, lipid metabolism and disorders of the central nervous system, in Phospholipids and Signal Transmission (Massarelli R, Horrocks L, Kanfer JN, and Löffelholz K eds) pp 353-372, Springer-Verlag GmbH, Heidelberg.

[184] ↵
Nakashima S, Ikeno Y, Yokoyama T, Kuwana M, Bolchi A, Ottonello S, Kitamoto K, and Arioka M (2003) Secretory phospholipases A₂ induce neurite outgrowth in PC12 cells. Biochem J 376: 655-666.
OpenUrl CrossRef PubMed

[185] ↵
Ng CH and Ong WY (2001) Increased expression of γ-aminobutyric acid transporters GAT-1 and GAT-3 in the spinal trigeminal nucleus after facial carrageenan injections. Pain 92: 29-40.
OpenUrl CrossRef PubMed

[186] ↵
Nordvik I, Myhr KM, Nyland H, and Bjerve KS (2000) Effect of dietary advice and n-3 supplementation in newly diagnosed MS patients. Acta Neurol Scand 102: 143-149.
OpenUrl CrossRef PubMed

[187] ↵
Obata T, Sakurai Y, Kase Y, Tanifuji Y, Horiguchi T, Haq S, Kilter H, Michael A, Tao J, O'Leary E, et al. (2003) Simultaneous determination of endocannabinoids (arachidonylethanolamide and 2-arachidonylglycerol) and isoprostane (8-epiprostaglandin F_2α) by gas chromatography-mass spectrometry-selected ion monitoring for medical samples. J Chromatogr B 792: 131-140.
OpenUrl CrossRef

[188] ↵
Oinuma H, Takamura T, Hasegawa T, Nomoto KI, Naitoh T, Daiku Y, Hamano S, Kakisawa H, and Minami N (1991) Synthesis and biological evaluation of substituted benzenesulfonamides as novel potent membrane-bound phospholipase A₂ inhibitors. J Med Chem 34: 2260-2267.
OpenUrl CrossRef PubMed

[189] ↵
Ong WY, He Y, Suresh S, and Patel S (1997) Differential expression of apoD and apoE in the kainate lesioned rat hippocampus. Neuroscience 79: 359-367.
OpenUrl CrossRef PubMed

[190] ↵
Ong WY, Hu CY, Hjelle OP, Ottersen OP, and Halliwell B (2000) Changes in glutathione in the hippocampus of rats injected with kainate: depletion in neurons and upregulation in glia. Exp Brain Res 132: 510-516.
OpenUrl CrossRef PubMed

[191] ↵
Ong WY, Ling SF, Yeo JF, Chiueh CC, and Farooqui AA (2005) Injury and recovery of pyramidal neurons in the rat hippocampus after a single episode of oxidative stress induced by intracerebroventricular injection of ferrous ammonium citrate. Reprod Nutr Dev 45: 647-662.
OpenUrl CrossRef PubMed

[192] ↵
Ong WY, Lu XR, Horrocks LA, Farooqui AA, and Garey LJ (2003a) Induction of astrocytic cytoplasmic phospholipase A₂ and neuronal death after intracerebroventricular carrageenan injection, and neuroprotective effects of quinacrine. Exp Neurol 183: 449-457.
OpenUrl CrossRef PubMed

[193] ↵
Ong WY, Lu XR, Ong BKC, Horrocks LA, Farooqui AA, and Lim SK (2003b) Quinacrine abolishes increases in cytoplasmic phospholipase A₂ mRNA levels in the rat hippocampus after kainate-induced neuronal injury. Exp Brain Res 148: 521-524.
OpenUrl PubMed

[194] ↵
Ong WY, Ren MQ, Makjanic J, Lim TM, and Watt F (1999) A nuclear microscopic study of elemental changes in the rat hippocampus after kainate-induced neuronal injury. J Neurochem 72: 1574-1579.
OpenUrl CrossRef PubMed

[195] ↵
Ono T, Yamada K, Chikazawa Y, Ueno M, Nakamoto S, Okuno T, and Seno K (2002) Characterization of a novel inhibitor of cytosolic phospholipase A₂α, pyrrophenone. Biochem J 363: 727-735.
OpenUrl CrossRef PubMed

[196] ↵
Ortiz GG, Sánchez-Ruiz MY, Tan DX, Reiter RJ, Benítez-King G, and Beas-Zárate C (2001) Melatonin, vitamin E, and estrogen reduce damage induced by kainic acid in the hippocampus: potassium-stimulated GABA release. J Pineal Res 31: 62-67.
OpenUrl CrossRef PubMed

[197] ↵
Ouyang Y and Kaminski NE (1999) Phospholipase A₂ inhibitors p-bromophenacyl bromide and arachidonyl trifluoromethyl ketone suppressed interleukin-2 (IL-2) expression in murine primary splenocytes. Arch Toxicol 73: 1-6.
OpenUrl CrossRef PubMed

[198] ↵
Pae CU, Yu HS, Kim JJ, Lee CU, Lee SJ, Lee KU, Jun TY, Paik IH, Serretti A, and Lee C (2004) BanI polymorphism of the cytosolic phospholipase A₂ gene and mood disorders in the Korean population. Neuropsychobiology 49: 185-188.
OpenUrl CrossRef PubMed

[199] ↵
Palomba L, Bianchi M, Persichini T, Magnani M, Colasanti M, and Cantoni O (2004) Downregulation of nitric oxide formation by cytosolic phospholipase A₂-released arachidonic acid. Free Radic Biol Med 36: 319-329.
OpenUrl CrossRef PubMed

[200] ↵
Pardue S, Rapoport SI, and Bosetti F (2003) Co-localization of cytosolic phospholipase A₂ and cyclooxygenase-2 in rhesus monkey cerebellum. Mol Brain Res 116: 106-114.
OpenUrl CrossRef PubMed

[201] ↵
Peet M and Ryles S (2001) Eicosapentaenoic acid—a potential new treatment for schizophrenia?, in Fatty Acids: Physiological and Behavioral Functions (Mostofsky DI, Yehuda S, and Salem N eds) pp 345-356, Humana Press Inc, Totowa, NJ.

[202] ↵
Pentland AP, Morrison AR, Jacobs SC, Hruza LL, Hebert JS, and Packer L (1992) Tocopherol analogs suppress arachidonic acid metabolism via phospholipase inhibition. J Biol Chem 267: 15578-15584.
OpenUrl Abstract/FREE Full Text

[203] ↵
Pérez R, Melero R, Balboa MA, and Balsinde J (2004) Role of group VIA calcium-independent phospholipase A₂ in arachidonic acid release, phospholipid fatty acid incorporation, and apoptosis in U937 cells responding to hydrogen peroxide. J Biol Chem 279: 40385-40391.
OpenUrl Abstract/FREE Full Text

[204] ↵
Perovic S, Pergande G, Ushijima H, Kelve M, Forrest J, and Muller WEG (1995) Flupirtine partially prevents neuronal injury induced by prion protein fragment and lead acetate. Neurodegeneration 4: 369-374.
OpenUrl CrossRef PubMed

[205] ↵
Pettegrew JW (1989) Molecular insights into Alzheimer disease. Ann NY Acad Sci 568: 5-28.
OpenUrl PubMed

[206] ↵
Pettegrew JW, Klunk WE, Kanal E, Panchalingam K, and McClure RJ (1995) Changes in brain membrane phospholipid and high-energy phosphate metabolism precede dementia. Neurobiol Aging 16: 973-975.
OpenUrl CrossRef PubMed

[207] ↵
Pettegrew JW, Panchalingam K, Hamilton RL, and McClure RJ (2001) Brain membrane phospholipid alterations in Alzheimer's disease. Neurochem Res 26: 771-782.
OpenUrl CrossRef PubMed

[208] ↵
Pettus BJ, Bielawska A, Subramanian P, Wijesinghe DS, Maceyka M, Leslie CC, Evans JH, Freiberg J, Roddy P, Hannun YA, et al. (2004) Ceramide 1-phosphate is a direct activator of cytosolic phospholipase A₂. J Biol Chem 279: 11320-11326.
OpenUrl Abstract/FREE Full Text

[209] ↵
Peyrin JM, Lasmezas CI, Haik S, Tagliavini F, Salmona M, Williams A, Richie D, Deslys JP, and Dormont D (1999) Microglial cells respond to amyloidogenic PrP peptide by the production of inflammatory cytokines. NeuroReport 10: 723-729.
OpenUrl CrossRef PubMed

[210] ↵
Phillis JW and O'Regan MH (2004) A potentially critical role of phospholipases in central nervous system ischemic, traumatic, and neurodegenerative disorders. Brain Res Rev 44: 13-47.
OpenUrl CrossRef PubMed

[211] ↵
Pickard RT, Strifler BA, Kramer RM, and Sharp JD (1999) Molecular cloning of two new human paralogs of 85-kDa cytosolic phospholipase A₂. J Biol Chem 274: 8823-8831.
OpenUrl Abstract/FREE Full Text

[212] ↵
Pinto F, Brenner T, Dan P, Krimsky M, and Yedgar S (2003) Extracellular phospholipase A₂ inhibitors suppress central nervous system inflammation. Glia 44: 275-282.
OpenUrl CrossRef PubMed

[213] ↵
Pirianov G, Danielsson C, Carlberg C, James SY, and Colston KW (1999) Potentiation by vitamin D analogs of TNFα and ceramide-induced apoptosis in MCF-7 cells is associated with activation of cytosolic phospholipase A₂. Cell Death Differ 6: 890-901.
OpenUrl CrossRef PubMed

[214] ↵
Portilla D and Dai G (1996) Purification of a novel calcium-independent phospholipase A₂ from rabbit kidney. J Biol Chem 271: 15451-15457.
OpenUrl Abstract/FREE Full Text

[215] ↵
Prusiner SB (2001) Shattuck lecture—Neurodegenerative diseases and prions. N Engl J Med 344: 1516-1526.
OpenUrl CrossRef PubMed

[216] Qu Y, Chang L, Klaff J, Seeman R, Balbo A, and Rapoport SI (2003a) Imaging of brain serotonergic neurotransmission involving phospholipase A₂ activation and arachidonic acid release in unanesthetized rats. Brain Res Brain Res Protoc 12: 16-25.
OpenUrl CrossRef PubMed

[217] Qu Y, Chang L, Klaff J, Seemann R, and Rapoport SI (2003b) Imaging brain phospholipase A₂-mediated signal transduction in response to acute fluoxetine administration in unanesthetized rats. Neuropsychopharmacology 28: 1219-1226.
OpenUrl PubMed

[218] ↵
Rao AM, Hatcher JF, and Dempsey RJ (2001) Does CDP-choline modulate phospholipase activities after transient forebrain ischemia? Brain Res 893: 268-272.
OpenUrl CrossRef PubMed

[219] ↵
Rapoport SI (1999) In vivo fatty acid incorporation into brain phospholipids in relation to signal transduction and membrane remodeling. Neurochem Res 24: 1403-1415.
OpenUrl CrossRef PubMed

[220] ↵
Ray P, Ray R, Broomfield CA, and Berman JD (1994) Inhibition of bioenergetics alters intracellular calcium, membrane composition, and fluidity in a neuronal cell line. Neurochem Res 19: 57-63.
OpenUrl CrossRef PubMed

[221] ↵
Riendeau D, Guay J, Weech PK, Laliberté F, Yergey J, Li C, Desmarais S, Perrier H, Liu S, Nicoll-Griffith D, et al. (1994) Arachidonyl trifluoromethyl ketone, a potent inhibitor of 85-kDa phospholipase A₂, blocks production of arachidonate and 12-hydroxyeicosatetraenoic acid by calcium ionophore-challenged platelets. J Biochem 269: 15619-15624.
OpenUrl

[222] ↵
Rintala J, Seemann R, Chandrasekaran K, Rosenberger TA, Chang L, Contreras MA, Rapoport SI, and Chang MCJ (1999) 85 kDa cytosolic phospholipase A₂ is a target for chronic lithium in rat brain. NeuroReport 10: 3887-3890.
OpenUrl CrossRef PubMed

[223] ↵
Rordorf G, Uemura Y, and Bonventre JV (1991) Characterization of phospholipase A₂ (PLA₂) activity in gerbil brain: enhanced activities of cytosolic, mitochondrial, and microsomal forms after ischemia and reperfusion. J Neurosci 11: 1829-1836.
OpenUrl Abstract

[224] ↵
Rosales-Corral S, Tan DX, Reiter RJ, Valdivia-Velázquez M, Acosta-Martiínez JP, and Ortiz GG (2004) Kinetics of the neuroinflammation-oxidative stress correlation in rat brain following the injection of fibrillar amyloid-β onto the hippocampus in vivo. J Neuroimmunol 150: 20-28.
OpenUrl CrossRef PubMed

[225] ↵
Rosenberger TA, Villacreses NE, Contreras MA, Bonventre JV, and Rapoport SI (2003) Brain lipid metabolism in the cPLA₂ knockout mouse. J Lipid Res 44: 109-117.
OpenUrl Abstract/FREE Full Text

[226] ↵
Rosenberger TA, Villacreses NE, Hovda JT, Bosetti F, Weerasinghe G, Wine RN, Harry GJ, and Rapoport SI (2004) Rat brain arachidonic acid metabolism is increased by a 6-day intracerebral ventricular infusion of bacterial lipopolysaccharide. J Neurochem 88: 1168-1178.
OpenUrl CrossRef PubMed

[227] ↵
Ross BM (2003) Phospholipase A₂-associated processes in the human brain and their role in neuropathology and psychopathology, in Phospholipid Spectrum Disorders in Psychiatry and Neurology (Peet M, Glen L, and Horrobin DF eds) pp 163-182, Marius Press, Carnforth, Lancashire, UK.

[228] ↵
Ross BM, Hudson C, Erlich J, Warsh JJ, and Kish SJ (1997) Increased phospholipid breakdown in schizophrenia— evidence for the involvement of a calcium-independent phospholipase A₂. Arch Gen Psychiatry 54: 487-494.
OpenUrl CrossRef PubMed

[229] ↵
Ross BM, Kim DK, Bonventre JV, and Kish SJ (1995) Characterization of a novel phospholipase A₂ activity in human brain. J Neurochem 64: 2213-2221.
OpenUrl PubMed

[230] ↵
Ross BM and Turenne SD (2002) Chronic cocaine administration reduces phospholipase A₂ activity in rat brain striatum. Prostaglandins Leukotrienes Essent Fatty Acids 66: 479-483.
OpenUrl CrossRef PubMed

[231] ↵
Ross BM, Turenne S, Moszczynska A, Warsh JJ, and Kish SJ (1999) Differential alteration of phospholipase A₂ activities in brain of patients with schizophrenia. Brain Res 821: 407-413.
OpenUrl CrossRef PubMed

[232] ↵
Rybakowski JK, Borkowska A, Czerski PM, Dmitrzak-Weglarz M, and Hauser J (2003) The study of cytosolic phospholipase A₂ gene polymorphism in schizophrenia using eye movement disturbances as an endophenotypic marker. Neuropsychobiology 47: 115-119.
OpenUrl CrossRef PubMed

[233] ↵
Salvati S, Natali F, Attorri L, Raggi C, Di Biase A, and Sanchez M (2004) Stimulation of myelin proteolipid protein gene expression by eicosapentaenoic acid in C6 glioma cells. Neurochem Int 44: 331-338.
OpenUrl CrossRef PubMed

[234] ↵
Sandhya TL, Ong WY, Horrocks LA, and Farooqui AA (1998) A light and electron microscopic study of cytoplasmic phospholipase A₂ and cyclooxygenase-2 in the hippocampus after kainate lesions. Brain Res 788: 223-231.
OpenUrl CrossRef PubMed

[235] ↵
Sano M, Ernesto C, Thomas RG, Klauber MR, Schafer K, Grundman M, Woodbury P, Growdon J, Cotman DW, Pfeiffer E, et al. (1997) A controlled trial of selegiline, α-tocopherol, or both as treatment for Alzheimer's disease. N Engl J Med 336: 1216-1222.
OpenUrl CrossRef PubMed

[236] ↵
Sapirstein A and Bonventre JV (2000) Phospholipases A₂ in ischemic and toxic brain injury. Neurochem Res 25: 745-753.
OpenUrl CrossRef PubMed

[237] ↵
Schapira AH (1996) Oxidative stress and mitochondrial dysfunction in neurodegeneration. Curr Opin Neurol 9: 260-264.
OpenUrl CrossRef PubMed

[238] ↵
Scott KF, Graham GG, and Bryant KJ (2003) Secreted phospholipase A₂ enzymes as therapeutic targets. Expert Opin Ther Targets 7: 427-440.
OpenUrl CrossRef PubMed

[239] ↵
Seashols SJ, del Castillo Olivares A, Gil G, and Barbour SE (2004) Regulation of group VIA phospholipase A₂ expression by sterol availability. Biochim Biophys Acta 1684: 29-37.
OpenUrl PubMed

[240] ↵
Seno K, Okuno T, Nishi K, Murakami Y, Watanabe F, Matsuura T, Wada M, Fujii Y, Yamada M, Ogawa T, et al. (2000) Pyrrolidine inhibitors of human cytosolic phospholipase A₂. J Med Chem 43: 1041-1044.
OpenUrl CrossRef PubMed

[241] ↵
Serhan CN, Gotlinger K, Hong S, and Arita M (2004) Resolvins, docosatrienes, and neuroprotectins, novel ω-3-derived mediators, and their aspirin-triggered endogenous epimers: an overview of their protective roles in catabasis. Prostaglandins Other Lipid Mediat 73: 155-172.
OpenUrl CrossRef PubMed

[242] ↵
Shanker G and Aschner M (2003) Methylmercury-induced reactive oxygen species formation in neonatal cerebral astrocytic cultures is attenuated by antioxidants. Mol Brain Res 110: 85-91.
OpenUrl PubMed

[243] ↵
Shanker G, Hampson RE, and Aschner M (2004) Methylmercury stimulates arachidonic acid release and cytosolic phospholipase A₂ expression in primary neuronal cultures. Neurotoxicology 25: 399-406.
OpenUrl CrossRef PubMed

[244] ↵
Shin EJ, Jhoo JH, Kim WK, Jhoo WK, Lee C, Jung BD, and Kim HC (2004) Protection against kainate neurotoxicity by pyrrolidine dithiocarbamate. Clin Exp Pharmacol Physiol 31: 320-326.
OpenUrl CrossRef PubMed

[245] ↵
Shinzawa K and Tsujimoto Y (2003) PLA₂ activity is required for nuclear shrinkage in caspase-independent cell death. J Cell Biol 163: 1219-1230.
OpenUrl Abstract/FREE Full Text

[246] ↵
Shirai Y and Ito M (2004) Specific differential expression of phospholipase A₂ subtypes in rat cerebellum. J Neurocytol 33: 297-307.
OpenUrl CrossRef PubMed

[247] ↵
Shohami E, Shapira Y, Yadid G, Reisfeld N, and Yedgar S (1989) Brain phospholipase A₂ is activated after experimental closed head injury in the rat. J Neurochem 53: 1541-1546.
OpenUrl CrossRef PubMed

[248] ↵
Singer TP, Castagnoli N Jr, Ramsay RR, and Trevor AJ (1987) Biochemical events in the development of parkinsonism induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. J Neurochem 49: 1-8.
OpenUrl PubMed

[249] ↵
Smalheiser NR, Dissanayake S, and Kapil A (1996) Rapid regulation of neurite outgrowth and retraction by phospholipase A₂-derived arachidonic acid and its metabolites. Brain Res 721: 39-48.
OpenUrl CrossRef PubMed

[250] ↵
Song C, Chang XJ, Bean KM, Proia MS, Knopf JL, and Kriz RW (1999) Molecular characterization of cytosolic phospholipase A_2-β. J Biol Chem 274: 17063-17067.
OpenUrl Abstract/FREE Full Text

[251] ↵
St-Gelais F, Ménard C, Congar P, Trudeau LE, and Massicotte G (2004) Postsynaptic injection of calcium-independent phospholipase A₂ inhibitors selectively increases AMPA receptor-mediated synaptic transmission. Hippocampus 14: 319-325.
OpenUrl CrossRef PubMed

[252] ↵
Stephenson DT, Lemere CA, Selkoe DJ, and Clemens JA (1996) Cytosolic phospholipase A₂ (cPLA₂) immunoreactivity is elevated in Alzheimer's disease brain. Neurobiol Dis 3: 51-63.
OpenUrl CrossRef PubMed

[253] ↵
Stephenson D, Rash K, Smalstig B, Roberts E, Johnstone E, Sharp J, Panetta J, Little S, Kramer R, and Clemens J (1999) Cytosolic phospholipase A₂ is induced in reactive glia following different forms of neurodegeneration. Glia 27: 110-128.
OpenUrl CrossRef PubMed

[254] ↵
Stewart LR, White AR, Jobling MF, Needham BE, Maher F, Thyer J, Beyreuther K, Masters CL, Collins SJ, and Cappai R (2001) Involvement of the 5-lipoxygenase pathway in the neurotoxicity of the prion peptide PrP106-126. J Neurosci Res 65: 565-572.
OpenUrl CrossRef PubMed

[255] Stone SJ, Cui Z, and Vance JE (1998) Cloning and expression of mouse liver phosphatidylserine synthase-1 cDNA— overexpression in rat hepatoma cells inhibits the CDP-ethanolamine pathway for phosphatidylethanolamine biosynthesis. J Biol Chem 273: 7293-7302.
OpenUrl Abstract/FREE Full Text

[256] ↵
Street IP, Lin HK, Laliberté F, Ghomashchi F, Wang Z, Perrier H, Tremblay NM, Huang Z, Weech PK, and Gelb MH (1993) Slow- and tight-binding inhibitors of the 85-kDa human phospholipase A₂. Biochemistry 32: 5935-5940.
OpenUrl CrossRef PubMed

[257] ↵
Strokin M, Sergeeva M, and Reiser G (2003) Docosahexaenoic acid and arachidonic acid release in rat brain astrocytes is mediated by two separate isoforms of phospholipase A₂ and is differently regulated by cyclic AMP and Ca²⁺. Br J Pharmacol 139: 1014-1022.
OpenUrl CrossRef PubMed

[258] ↵
Sugaya K, Uz T, Kumar V, and Manev H (2000) New anti-inflammatory treatment strategy in Alzheimer's disease. Jpn J Pharmacol 82: 85-94.
OpenUrl CrossRef PubMed

[259] ↵
Sun GY, Xu JF, Jensen MD, and Simonyi A (2004) Phospholipase A₂ in the central nervous system: implications for neurodegenerative diseases. J Lipid Res 45: 205-213.
OpenUrl Abstract/FREE Full Text

[260] ↵
Svennerholm L (1994) Gangliosides-a new therapeutic agent against stroke and Alzheimer's disease. Life Sci 55: 2125-2134.
OpenUrl CrossRef PubMed

[261] ↵
Tabuchi S, Uozumi N, Ishii S, Shimizu Y, Watanabe T, and Shimizu T (2003) Mice deficient in cytosolic phospholipase A₂ are less susceptible to cerebral ischemia/reperfusion injury, in Brain Edema XII (Kuroiwa T, Baethmann A, Czernicki Z, Hoff JT, Ito U, Katayama Y, Mararou A, Mendelow AD, and Reulen HJ eds) pp 169-172, Springer-Verlag Wien, Vienna.

[262] ↵
Tagami M, Ikeda K, Yamagata K, Nara Y, Fujino H, Kubota A, Numano F, and Yamori Y (1999) Vitamin E prevents apoptosis in hippocampal neurons caused by cerebral ischemia and reperfusion in stroke-prone spontaneously hypertensive rats. Lab Invest 79: 609-615.
OpenUrl PubMed

[263] ↵
Tariq M, Khan HA, Al Moutaery K, and Al Deeb S (2001) Protective effect of quinacrine on striatal dopamine levels in 6-OHDA and MPTP models of Parkinsonism in rodents. Brain Res Bull 54: 77-82.
OpenUrl CrossRef PubMed

[264] ↵
Taylor WA (1988) Effects of Impact Injury of Rat Spinal Cord on Activities of Some Enzymes of Lipid Hydrolysis. Doctoral Dissertation, The Ohio State University, Columbus, OH.

[265] ↵
Terano T, Fujishiro S, Ban T, Yamamoto K, Tanaka T, Noguchi Y, Tamura Y, Yazawa K, and Hirayama T (1999) Docosahexaenoic acid supplementation improves the moderately severe dementia from thrombotic cerebrovascular diseases. Lipids 34 (Suppl): S345-S346.
OpenUrl CrossRef PubMed

[266] ↵
Thwin MM, Ong WY, Fong CW, Sato K, Kodama K, Farooqui AA, and Gopalakrishnakone P (2003) Secretory phospholipase A₂ activity in the normal and kainate injected rat brain, and inhibition by a peptide derived from python serum. Exp Brain Res 150: 427-433.
OpenUrl PubMed

[267] ↵
Tong W, Shah D, Xu JF, Diehl JA, Hans A, Hannink M, and Sun GY (1999) Involvement of lipid mediators on cytokine signaling and induction of secretory phospholipase A₂ in immortalized astrocytes (DITNC). J Mol Neurosci 12: 89-99.
OpenUrl PubMed

[268] ↵
Tran K, Wong JT, Lee E, Chan AC, and Choy PC (1996) Vitamin E potentiates arachidonate release and phospholipase A₂ activity in rat heart myoblastic cells. Biochem J 319: 385-391.
OpenUrl Abstract/FREE Full Text

[269] Trevisi L, Bova S, Cargnelli G, Ceolotto G, and Luciani S (2002) Endothelin-1-induced arachidonic acid release by cytosolic phospholipase A₂ activation in rat vascular smooth muscle via extracellular signal-regulated kinases pathway. Biochem Pharmacol 64: 425-431.
OpenUrl CrossRef PubMed

[270] ↵
Trigueros SDA, Kalyvas A, and David S (2003) Phospholipase A₂ plays an important role in myelin breakdown and phagocytosis during Wallerian degeneration. Mol Cell Neurosci 24: 753-765.
OpenUrl CrossRef PubMed

[271] ↵
Trimble LA, Street IP, Perrier H, Tremblay NM, Weech PK, and Bernstein MA (1993) NMR structural studies of the tight complex between a trifluoromethyl ketone inhibitor and the 85-kDa human phospholipase A₂. Biochemistry 32: 12560-12565.
OpenUrl CrossRef PubMed

[272] ↵
Turnbull S, Tabner BJ, Brown DR, and Allsop D (2003) Quinacrine acts as an antioxidant and reduces the toxicity of the prion peptide PrP106-126. NeuroReport 14: 1743-1745.
OpenUrl CrossRef PubMed

[273] ↵
Uozumi N and Shimizu T (2002) Roles for cytosolic phospholipase A₂α as revealed by gene-targeted mice. Prostaglandins Other Lipid Mediat 68-69: 59-69.
OpenUrl CrossRef PubMed

[274] ↵
Vanags DM, Larsson P, Feltenmark S, Jakobsson PJ, Orrenius S, Claesson HE, and Aguilar-Santelises M (1997) Inhibitors of arachidonic acid metabolism reduce DNA and nuclear fragmentation induced by TNF plus cycloheximide in U937 cells. Cell Death Differ 4: 479-486.
OpenUrl CrossRef PubMed

[275] ↵
Visioli F, Rodriguez de Turco EB, Kreisman NR, and Bazan NG (1994) Membrane lipid degradation is related to interictal cortical activity in a series of seizures. Metab Brain Dis 9: 161-170.
OpenUrl CrossRef PubMed

[276] ↵
Vogtherr M, Grimme S, Elshorst B, Jacobs DM, Fiebig K, Griesinger C, and Zahn R (2003) Antimalarial drug quinacrine binds to C-terminal helix of cellular prion protein. J Med Chem 46: 3563-3564.
OpenUrl CrossRef PubMed

[277] ↵
Walsh DM and Selkoe DJ (2004) Deciphering the molecular basis of memory failure in Alzheimer's disease. Neuron 44: 181-193.
OpenUrl CrossRef PubMed

[278] ↵
Walters ET (1994) Injury-related behavior and neuronal plasticity: an evolutionary perspective on sensitization, hyperalgesia, and analgesia. Int Rev Neurobiol 36: 325-427.
OpenUrl PubMed

[279] ↵
Wang TG, Qin L, Liu B, Liu YX, Wilson B, Eling TE, Langenbach R, Taniura S, and Hong JS (2004a) Role of reactive oxygen species in LPS-induced production of prostaglandin E-2 in microglia. J Neurochem 88: 939-947.
OpenUrl CrossRef PubMed

[280] ↵
Wang XH, Yan GT, Wang LH, Hao XH, Zhang K, and Xue H (2004b) The mediating role of cPLA₂ in IL-1β and IL-6 release in LPS-induced HeLa cells. Cell Biochem Funct 22: 41-44.
OpenUrl CrossRef PubMed

[281] ↵
Wang ZG (2003) Role of redox state in modulation of ion channel function by fatty acids and phospholipids. Br J Pharmacol 139: 681-683.
OpenUrl CrossRef PubMed

[282] ↵
Weerasinghe GR, Rapoport SI, and Bosetti F (2004) The effect of chronic lithium on arachidonic acid release and metabolism in rat brain does not involve secretory phospholipase A₂ or lipoxygenase/cytochrome P450 pathways. Brain Res Bull 63: 485-489.
OpenUrl CrossRef PubMed

[283] ↵
Wei EP, Lamb RG, and Kontos HA (1982) Increased phospholipase C activity after experimental brain injury. J Neurosurg 56: 695-698.
OpenUrl PubMed

[284] ↵
Wei S, Ong WY, Thwin MM, Fong CW, Farooqui AA, Gopalakrishnakone P, and Hong WJ (2003) Differential activities of secretory phospholipase A₂ (sPLA₂)inrat brain and effects of sPLA₂ on neurotransmitter release. Neuroscience 121: 891-898.
OpenUrl CrossRef PubMed

[285] ↵
Wells K, Farooqui AA, Liss L, and Horrocks LA (1995) Neural membrane phospholipids in Alzheimer disease. Neurochem Res 20: 1329-1333.
OpenUrl CrossRef PubMed

[286] ↵
Wolf MJ, Izumi Y, Zorumski CF, and Gross RW (1995) Long-term potentiation requires activation of calcium-independent phospholipase A₂. FEBS Lett 377: 358-362.
OpenUrl CrossRef PubMed

[287] Xing M, Wilkins PL, McConnell BK, and Mattera R (1994) Regulation of phospholipase A₂ activity in undifferentiated and neutrophil-like HL60 cells: linkage between impaired responses to agonists and absence of protein kinase C-dependent phosphorylation of cytosolic phospholipase A₂. J Biol Chem 269: 3117-3124.
OpenUrl Abstract/FREE Full Text

[288] ↵
Xu JF, Yu S, Sun AY, and Sun GY (2003) Oxidant-mediated AA release from astrocytes involves cPLA₂ and iPLA₂. Free Radic Biol Med 34: 1531-1543.
OpenUrl CrossRef PubMed

[289] ↵
Yagi K, Shirai Y, Hirai M, Sakai N, and Saito N (2004) Phospholipase A₂ products retain a neuron specific γ isoform of PKC on the plasma membrane through the C1 domain—a molecular mechanism for sustained enzyme activity. Neurochem Int 45: 39-47.
OpenUrl CrossRef PubMed

[290] ↵
Yang H-C, Farooqui AA, and Horrocks LA (1994a) Effects of glycosaminoglycans and glycosphingolipids on cytosolic phospholipases A₂ from bovine brain. Biochem J 299: 91-95.
OpenUrl Abstract/FREE Full Text

[291] ↵
Yang H-C, Farooqui AA, and Horrocks LA (1994b) Effects of sialic acid and sialoglycoconjugates on cytosolic phospholipases A₂ from bovine brain. Biochem Biophys Res Commun 199: 1158-1166.
OpenUrl CrossRef PubMed

[292] ↵
Yang HC, Mosior M, Ni B, and Dennis EA (1999) Regional distribution, ontogeny, purification, and characterization of the Ca²⁺-independent phospholipase A₂ from rat brain. J Neurochem 73: 1278-1287.
OpenUrl CrossRef PubMed

[293] ↵
Yao JK and Van Kammen DP (2004) Membrane phospholipids and cytokine interaction in schizophrenia, in Disorders of Synaptic Plasticity and Schizophrenia (Smythies J ed) pp 297-326, Academic Press, San Diego, CA.

[294] ↵
Yao JK, Leonard S, and Reddy RD (2000) Membrane phospholipid abnormalities in postmortem brains from schizophrenic patients. Schizophr Res 42: 7-17.
OpenUrl CrossRef PubMed

[295] ↵
Yegin A, Akbas SH, Ozben T, and Korgun DK (2002) Secretory phospholipase A₂ and phospholipids in neural membranes in an experimental epilepsy model. Acta Neurol Scand 106: 258-262.
OpenUrl CrossRef PubMed

[296] ↵
Yeo JF, Ong WY, Ling SF, and Farooqui AA (2004) Intracerebroventricular injection of phospholipases A₂ inhibitors modulates allodynia after facial carrageenan injection in mice. Pain 112: 148-155.
OpenUrl CrossRef PubMed

[297] ↵
Yoo MH, Woo CH, You HJ, Cho SH, Kim BC, Choi JE, Chun JS, Jhun BH, Kim TS, and Kim JH (2001) Role of the cytosolic phospholipase A₂-linked cascade in signaling by an oncogenic, constitutively active Ha-Ras isoform. J Biol Chem 276: 24645-24653.
OpenUrl Abstract/FREE Full Text

[298] ↵
Yoshihara Y and Watanabe Y (1990) Translocation of phospholipase A₂ from cytosol to membranes in rat brain induced by calcium ions. Biochem Biophys Res Commun 170: 484-490.
OpenUrl CrossRef PubMed

[299] ↵
Yoshihara Y, Yamaji M, Kawasaki M, and Watanabe Y (1992) Ontogeny of cytosolic phospholipase A₂ activity in rat brain. Biochem Biophys Res Commun 185: 350-355.
OpenUrl CrossRef PubMed

[300] ↵
Yoshinaga N, Yasuda Y, Murayama T, and Nomura Y (2000) Possible involvement of cytosolic phospholipase A₂ in cell death induced by 1-methyl-4-phenylpyridinium ion, a dopaminergic neurotoxin, in GH3 cells. Brain Res 855: 244-251.
OpenUrl CrossRef PubMed

[301] ↵
Zanassi P, Paolillo M, and Schinelli S (1998) Coexpression of phospholipase A₂ isoforms in rat striatal astrocytes. Neurosci Lett 247: 83-86.
OpenUrl CrossRef PubMed

[302] ↵
Zhang B, Tanaka J, Yang L, Yang L, Sakanaka M, Hata R, Maeda N, and Mitsuda N (2004) Protective effect of vitamin E against focal brain ischemia and neuronal death through induction of target genes of hypoxia-inducible factor-1. Neuroscience 126: 433-440.
OpenUrl CrossRef PubMed

[303] ↵
Zhao Y, Joshi-Barve S, Barve S, and Chen LH (2004) Eicosapentaenoic acid prevents LPS-induced TNF-α expression by preventing NF-κB activation. J Am Coll Nutr 23: 71-78.
OpenUrl CrossRef PubMed

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Inhibitors of Brain Phospholipase A2 Activity: Their Neuropharmacological Effects and Therapeutic Importance for the Treatment of Neurologic Disorders

Abstract

I. Introduction

II. Multiplicity of Phospholipases A2 in Brain

A. Secretory Phospholipase A2

B. Cytosolic Phospholipases A2

C. Plasmalogen-Selective Phospholipase A2

D. Calcium-Independent Phospholipases A2

III. Involvement of Phospholipase A2 Activity in Brain Injury

IV. Physiological and Pharmacological Effects of Phospholipase A2 Inhibitors

A. Arachidonyl Trifluoromethyl Ketone

B. Methyl Arachidonyl Fluorophosphonate

C. Bromoenol Lactone

D. Benzenesulfonamides and Alkoxybenzamidines

E. 3-(Pyrrol)-2-propionic Acid

F. 2-Oxoamide and 1,3-Disubstituted Propan-2-ones

G. Choline Derivatives with a Long Aliphatic Chain

H. Pyrrolidine-Based Inhibitors of Phospholipase A2

I. Antimalarial Drugs

J. Lithium Ion and Carbamazepine

K. Vitamin E and Gangliosides

L. Cytidine 5-Diphosphoamines

M. Long-Chain Polyunsaturated Fatty Acids

N. Phospholipase A2 Antisense Oligonucleotides and Interfering RNA

V. Phospholipase A2 Activity in Kainic Acid-Induced Neural Cell Injury

VI. Protection of Kainic Acid-Induced Neural Cell Injury by Phospholipase A2 Inhibitors

VII. Phospholipase A2 Activity in Neurological Disorders

A. Ischemia

B. Alzheimer's Disease

C. Experimental Model of Parkinson's Disease

D. Multiple Sclerosis and Experimental Autoimmune Encephalomyelitis

E. Prion Diseases

F. Spinal Cord Injury

G. Head Injury

H. Epilepsy

I. Schizophrenia and Depressive Disorders

VIII. Use of Phospholipase A2 Inhibitors for the Treatment of Neurological Disorders

IX. Prevention of Pain by Phospholipase A2 Inhibitors

X. Perspective and Direction for Future Studies

Acknowledgments

Footnotes

References

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Inhibitors of Brain Phospholipase A2 Activity: Their Neuropharmacological Effects and Therapeutic Importance for the Treatment of Neurologic Disorders

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Inhibitors of Brain Phospholipase A₂ Activity: Their Neuropharmacological Effects and Therapeutic Importance for the Treatment of Neurologic Disorders

II. Multiplicity of Phospholipases A₂ in Brain

A. Secretory Phospholipase A₂

B. Cytosolic Phospholipases A₂

C. Plasmalogen-Selective Phospholipase A₂

D. Calcium-Independent Phospholipases A₂

III. Involvement of Phospholipase A₂ Activity in Brain Injury

IV. Physiological and Pharmacological Effects of Phospholipase A₂ Inhibitors

H. Pyrrolidine-Based Inhibitors of Phospholipase A₂

N. Phospholipase A₂ Antisense Oligonucleotides and Interfering RNA

V. Phospholipase A₂ Activity in Kainic Acid-Induced Neural Cell Injury

VI. Protection of Kainic Acid-Induced Neural Cell Injury by Phospholipase A₂ Inhibitors

VII. Phospholipase A₂ Activity in Neurological Disorders

VIII. Use of Phospholipase A₂ Inhibitors for the Treatment of Neurological Disorders

IX. Prevention of Pain by Phospholipase A₂ Inhibitors

Inhibitors of Brain Phospholipase A₂ Activity: Their Neuropharmacological Effects and Therapeutic Importance for the Treatment of Neurologic Disorders

Inhibitors of Brain Phospholipase A₂ Activity: Their Neuropharmacological Effects and Therapeutic Importance for the Treatment of Neurologic Disorders