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.