Valproic acid (VPA) is a new, valuable, and chemically unique anticonvulsant of unknown mode of action. VPA raises levels of brain gamma-aminobutyric acid (GABA), an important inhibitory neurotransmitter which is probably involved in seizure control. GABA is synthesized directly from glutamate, thus determining the relationship between glutamate and GABA synthesis induced by VPA is key to understanding the mechanism of its anticonvulsant activity. This proposal will evaluate the hypothesis that VPA increases GABA synthesis from glutamate by inhibiting brain mitochondrial 2-ketoglutarate dehydrogenase complex (KDHC). This would result in diversion of glutamate and citrate cycle metabolites away from direct oxidation and into GABA synthesis. Initial studies revealed that a VPA metabolite, 2,3-ene VPA, inhibits rat brain KDHC at micromolar concentration by forming an irreversible complex with the E2 component of KDHC. The predicted elevations in glutamate efflux from rat brain mitochondria have been measured. Further studies will focus on the metabolic changes induced by VPA in isolated rat brain mitochondria. Specifically we will study: 1) the interaction of the active metabolite (2,3-ene VPA) with purified brain KDHC. 2). VPA induced changes in the flux of citrate cycle metabolites in brain, and 3). Correlation of changes in brain citrate cycle metabolites with changes in neurotransmitter (GABA) synthesis. The findings from these studies will not only lead to and understanding of the actions of VPA at a molecular level and a basis for the in vitro evaluation of new anticonvulsants but also will yield new insight into the important area of neurotransmitter synthesis and brain bioenergetics.
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| Parker Jr, W D; Frerman, F; Haas, R et al. (1988) Myxothiazol resistance in human mitochondria. Biochim Biophys Acta 936:133-8 |
