The long-term objective of this proposal is to define the role of PAF (platelet-activating factor), a mediator of neuronal injury, and of phospholipase A2 activation in epileptic brain damage and in epileptogenesis. In experimental models of epilepsy, increased excitability, aberrant synaptic reorganization, and neuronal death take place. However, the specific messengers involved in these events are not known. We have discovered that PAF enhances excitatory neurotransmitter release and is an activator of gene expression. The goal of this proposal is to test the hypothesis that a) PAF contributes to increased excitability, seizure generation, and seizure-induced hippocampal damage; b) PAF-triggered gene expression participates in aberrant synaptic reorganization; c) PAF antagonists active at the presynaptic ending are neuroprotective in epileptic damage and PAF antagonists active on gene expression inhibit epileptogenesis; and d) over expression of PAF acetylhydrolase activity slows or prevents kindling development in transgenic rats. We will define the involvement of phospholipase A2 activation in seizure-induced damage and in kindling development by measuring the pool size and metabolism of PAF and the arachidonic acid cascade in hippocampus. We will use a rapid kindling model, kainic acid-induced seizures, and perforant path stimulation of hippocampal slices to ascertain how injury mediators participate in aberrant synaptic reorganization. We will identify PAF-responsive elements in the promoter of the inducible prostaglandin synthase gene in the hippocampus in models of epilepsy. Powerful analytical procedures, such as HPLC-mass spectrometry, will be used to study the biochemistry of second messengers. These will be combined with electrophysiological, histological and molecular biological studies and, in some cases, Ca2+ imaging. These studies will a) define metabolic pathways and events in epileptic damage that could be halted or slowed by novel neuroprotective mechanisms, b) characterize signal transduction pathways involved in aberrant synaptic reorganization, and may c) identify new drug strategies to prevent damage and circuitry reorganization in epilepsy.
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