Excitable Membrane-Derived Lipid Mediators: Glutamate Release and Regulation of Gene Expression
Ischemia and seizures lead to the accumulation of free arachidonic (AA) and docosahexaenoic acids (DHA); diacylglycerol, due to activation of phospholipase A2; and phospholipase C. The platelet-activating factor (PAF) precursor, 1-alkyl-2-acyl-sn-glycerophosphocholine, is enriched in polyunsaturated fatty acids such as the 2-acyl group. Under resting conditions PAF is undetectable in brain, but it accumulates after injury. The PAF antagonist BN 52021 elicits neuroprotection during brain ischemia-reperfusion and inhibits AA accumulation and inositol lipid degradation. This work led to the discovery of presynaptic PAF binding sites upon which the neuroprotective BN 52021 acts. PAF plays at least two major roles in the nervous system: as a modulator of synapse function and as a mediator of inflammation/injury. Depending upon the degree of neuronal activity, there appear to be roles, on the one hand, for PAF as a retrograde messenger in long-term potentiation, and, on the other hand, for PAF acting on neural responses to injury. PAF activates immediate-early gene expression through an intracellular PAF binding site. An early increase in inducible prostaglandin G/H synthase (TIS-10, COX-2) expression takes place after brain injury. The intracellular PAF antagonist BN 50730 inhibits this effect, as does dexamethasone. These PAF-mediated synaptic and gene expression events may represent intracellular pathways of signal transduction in repair, neuronal plasticity, and cell death. Moreover, these events may be involved in epileptogenesis and the remodeling of synaptic circuitry. Thus, excitable membrane-derived lipid mediators as new targets may be explored for pharmacological intervention in stroke and other cerebrovascular diseases, epileptic damage, neurotrauma, and neurodegenerative diseases.
KeywordsArachidonic Acid Excitable Membrane Inhibitory Avoidance Task Gerbil Brain Retrograde Messenger
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