This project will determine how valproic acid (VPA) raises brain concentrations of gamma-aminobutyric acid (GABA), an inhibitory neurotransmitter. Valproic acid (VPA) is a new, valuable, and chemically unique drug with multiple therapeutic uses including treatment of mood disorders, adjunctive therapy in schizophrenia, and treatment of seizure and movement disorders. VPA raises levels of brain GABA. Since VPA does not inhibit GABA degradation it must increase synthesis. GABA is synthesized directly from glutamate, thus determining the relationship between glutamate and increased GABA synthesis is key to understanding the mechanism of VPA induced GABA elevation. This proposal will evaluate the novel hypothesis that VPA increases GABA synthesis from glutamate by inhibiting brain mitochondrial 2-ketoglutarate dehydrogenase complex (KDHC) resulting in diversion of glutamate and citrate cycle metabolites away from direct oxidation and into GABA synthesis. Our studies show that a VPA metabolite, 2,3-ene VPA, inhibits rat brain KDHC at micromolar concentrations 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 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, 3) correlation of changes in brain citrate cycle metabolites with changes in neurotransmitter (GABA) synthesis. These data will lead to understanding of the actions of VPA at a molecular level and a basis for the in vitro evaluation of new drugs and will also yield new insight into relationships between brain bioenergetics and neurotransmitter synthesis.
|Luder, A S; Parks, J K; Frerman, F et al. (1990) Inactivation of beef brain alpha-ketoglutarate dehydrogenase complex by valproic acid and valproic acid metabolites. Possible mechanism of anticonvulsant and toxic actions. J Clin Invest 86:1574-81|