ReviewNeurochemical consequences of kainate-induced toxicity in brain: involvement of arachidonic acid release and prevention of toxicity by phospholipase A2 inhibitors
Introduction
Neural membranes are composed of phospholipids, glycolipids, cholesterol, and proteins. The phospholipids include glycerophospholipids and sphingomyelin. The glycerophospholipids are enriched in polyunsaturated fatty acid residues at the sn-2 position of the glycerol backbone. Oxygen free radicals generated during oxidative stress can attack polyunsaturated fatty acids in the neural membrane bilayer. This makes neural membranes highly susceptible to oxidative damage. The glycerophospholipid bilayer is penetrated to varying degrees by receptors, enzymes, and ion channels that protrude differentially through the membrane or are localized predominantly on the intracellular or extracellular membrane surface. One of the important functions of neural membranes is the regulation of ion homeostasis. The interaction of an agonist (glutamate) with a glutamate receptor results in the enhancement of glycerophospholipid metabolism, which not only regulates the activities of membrane-bound enzymes and ion channels but also modulates many physicochemical properties such as phase transition temperature, fluidity, and permeability [39].
During the past decade, significant information has accumulated on the importance of excitatory amino acids and their receptors, especially glutamate receptors, in neural membrane glycerophospholipid catabolism [35], [36], [37], [66], [127]. Degradation of neural membrane glycerophospholipids, induced by the stimulation of excitatory amino acid receptors, results in the generation of second messengers that carry extracellular signals into the nerve cell. This process is closely associated with synaptogenesis, neuronal plasticity, neuronal survival, and learning and memory processes, whereas the overstimulation of these receptors causes neural cell injury and neurodegeneration [35]. Excitatory amino acids receptors are classified into N-methyl-d-aspartate (NMDA), kainate (KA), 2-amino-3-hydroxy-5-methylisoxazole propionic acid (AMPA), l-2-amino-4-phosphonobutanoic acid (L-AP4) and trans-1-amino-cyclopentyl-1,3-dicarboxylate (trans-ACPD) receptors [75], [81]. Within the above subclasses, multiple subunits have now been identified. These subunits may form heteromeric assemblies that play important roles in modulating the activity of excitatory amino acid receptors [18], [84], [85].
Current interest in excitatory amino acids is due to the involvement of excitatory amino acid receptors in neural cell injury in a variety of neurological disorders [35], [36], [37], [66], [127]. Glutamate- and NMDA-induced cell injury is accompanied by the accumulation of calcium, marked degradation of membrane glycerophospholipids, and accumulation of free fatty acids and lipid peroxides [36]. Less information is available on the molecular mechanism of KA-induced neurotoxicity [23]. We have reported that KA-induced neurotoxicity also involves the stimulation of phospholipase A2, release of arachidonic acid from neural membrane phospholipids, accumulation of lipid peroxides, alterations in prostaglandins, decline in reduced glutathione (GSH) content, and accumulation of 4-hydroxynonenal, an especially neurotoxic end product of lipid peroxide decomposition [89], [90]. We have also observed that PLA2 inhibitors protect neural cells from KA-induced neural cell injury [68], [69]. These processes along with alterations of the energy status and the redox status of neural cells may be responsible for injury in KA-induced neurotoxicity. The purpose of this review is (1) to integrate and evaluate studies on the pathophysiological consequences of KA-induced arachidonic acid release on neural cell integrity and (2) discuss the therapeutic effects of PLA2 inhibitors on KA-induced neurotoxicity [68], [69]. It is hoped that this discussion will promote more studies on the molecular mechanism of KA-induced neuronal degeneration in brain tissue.
Section snippets
Properties, multiplicity, and neurotoxicity of KA receptors
Kainate is a nondegradable analog of glutamate (Fig. 1). It is 30- to 100-fold more potent than glutamate as a neuronal excitant. It is well known that systemic and intracerebral administration of KA in adult rats induces persistent seizures and seizure-mediated brain damage syndrome [23]. KA produces selective degeneration of neurons, especially in striatal and hippocampal areas of brain after intraventricular and intracerebral injections [6], [23], [63]. Axons and nerve terminals are more
KA receptor stimulation and arachidonic acid release from membrane glycerophospholipids
Arachidonic acid release from neural membrane glycerophospholipids is mainly catalyzed by two enzymic mechanisms. A direct mechanism for arachidonic acid release involves phospholipase A2 (PLA2). An indirect mechanism utilizes the phospholipase C (PLC)/diacylglycerol lipase pathway to release arachidonic acid [42]. The release of arachidonic acid within the brain tissue is of considerable physiological importance because this fatty acid has been shown to be a potent modulator of glutamatergic
Production of free radicals and lipid peroxides
Systemic administration of KA in rat brain results in production of free radicals [10], [17], [119], [120]. Similarly, KA also induces free radical generation in cerebral cell cultures [27]. Based on our recent studies, we propose that the stimulation of PLA2 during KA-induced neurotoxicity results in degradation of membrane glycerophospholipids and generation of free fatty acids (FFA). The accumulation of FFA can trigger an uncontrolled ‘arachidonic acid cascade’. This includes the synthesis
Prevention of KA-induced toxicity by PLA2 inhibitors
PLA2 is a superfamily of enzymes that hydrolyze fatty acids from the sn-2 position of neural membrane glycerophospholipids with the concomitant production of lysophospholipids [44], [45]. Studies on the classification, properties, metabolic importance, and role of isoforms of PLA2 in brain tissue and neuronal injury have been reviewed earlier by several investigators [24], [41], [44], [45], [109]. Brain tissue contains Ca2+-dependent cytosolic PLA2 (cPLA2, relative mol. mass 85 kDa), Ca2+
KA-induced neural cell death: apoptotic vs. necrotic
Early shrinkage of cytoplasm, chromatin condensation, and degradation of DNA into oligonucleosomal fragments characterize apoptotic cell death. In contrast, early swelling of the cytoplasm and organelles and rupture of the plasma membrane characterize necrotic cell death. During KA-induced neurotoxicity neural cells die by apoptosis as well as necrosis [46], [98], [113] (Ong et al., unpublished observations). Thus KA administration into the amygdala induces apoptotic cell death in distant
Conclusion and direction for future studies
Although considerable information is available on neurochemical aspects of KA-induced neurotoxicity, there are only a few reports on the involvement of PLA2 and arachidonic acid release [7], [33], [120] and neural membrane glycerophospholipid catabolism in KA-induced neurotoxicity [68], [69]. Our recent studies have indicated that PLA2 inhibitors can block KA-induced neurotoxicity. This suggests that PLA2 plays an important role in KA-induced neurodegeneration. Brain PLA2 stimulation is
Acknowledgements
We thank Prof. O. P. Ottersen, Department of Anatomy, Institute of Basic Medical Sciences, University of Oslo, Norway for a generous supply of glutathione polyclonal antibody, and Prof. G. Waeg for a generous supply of HNE monoclonal antibody. We also thank Siraj A. Farooqui for providing the figure showing structures for KA receptor agonists and antagonists and Tahira Farooqui for useful discussion and her help in preparation of this review. This work was supported by a grant from National
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