Valproic acid (VPA) represents a new class of anticonvulsant of major therapeutic benefit. While its mode of action remains unknown, a considerable body of evidence suggests that it raises brain gamma-aminobutyric acid (GABA) levels. The initial phase of the proposed research will evaluate the hypothesis that VPA operates through inhibition of a citrate cycle enzyme (succinate:CoA ligase) with resulting diversion of glutamate away from alpha-ketoglutarate synthesis toward GABA synthesis. In addition, this project will explore differences in oxidative metabolism between synaptic and cell body mitochondria isolated from rat brain. This will be accomplished through polarographic measurements of oxygen uptake in isolated rat brain mitochondria and observation of changes induced by VPA and its metabolites. Isolated mitochondria will also be evaluated through measurement of metabolite flux by HPLC following introduction in vitro of various 14C labeled substrates. Perturbations in GABA and citrate cycle metabolism induced by VPA will be analyzed. This HPLC approach will open up a previously unavailable avenue for study of dynamic responses of intact, coupled brain mitochondria to a variety of changing metabolic conditions. This HPLC method will compliment the PI's interest in brain oxidative metabolism and will be applied to other problems of citrate cycle metabolism.
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