Inhibitors of brain phospholipase A2 activity: Their neuropharmacological effects and therapeutic importance for the treatment of neurologic disorders

Abstract

The phospholipase A2 family includes secretory phospholipase A2, cytosolic phospholipase A2, plasmalogen-selective phospholipase A2, and calcium-independent phospholipase A 2. 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 A 2 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. Copyright © 2006 by The American Society for Pharmacology and Experimental Therapeutics.