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Prog Brain Res. 1998;118:281-91.

The neuromessenger platelet-activating factor in plasticity and neurodegeneration.

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  • 1Louisiana State University Medical Center, School of Medicine, Neuroscience Center of Excellence, New Orleans 70112, USA.

Abstract

Synaptic activation leads to the formation of arachidonic acid, platelet-activating factor (PAF, 1-O-alkyl-2-acyl-sn-3-phosphocholine) and other lipid messengers. PAF is a potent bioactive phospholipid in synaptic plasticity. PAF enhances presynaptic glutamate release, is a retrograde messenger in long-term potentiation and enhances memory formation. PAF also couples synaptic events with gene expression by stimulating a FOS/JUN/AP-1 transcriptional signaling system, as well as transcription of COX-2 (inducible prostaglandin synthase). Since the COX-2 gene is also involved in synaptic plasticity, the PAF-COX-2 pathway may have physiological significance. Seizures, ischemia and other forms of brain injury promote phospholipase A2 (PLA2) overactivation, resulting in the accumulation of bioactive lipids at the synapse. PAF, under these pathological conditions, behaves as a neuronal injury messenger by at least two mechanisms: (a) enhancing glutamate release; and, (b) by sustained augmentation of COX-2 transcription. These events link PAF with neurodegeneration. The upstream intracellular pathways of signal transduction involved in neuronal or photoreceptor cell apoptosis are not well understood and involve stress sensitive kinases. PAF is a transcriptional activator of the COX-2 gene. BN 50730, a potent intracellular PAF antagonist, blocks COX-2 induction. COX-2 transcription and protein expression are upregulated in the hippocampus in kainic acid induced epileptogenesis. There is a selectively elevated induction of COX-2 (72-fold) by kainic acid preceding neuronal cell death. BN 50730 administered by i.c.v. injection blocks seizure-induced COX-2 induction. Overall, PAF is a dual modulator of neural function and becomes an endogenous neurotoxin when over produced.

PMID:
9932449
[PubMed - indexed for MEDLINE]
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