title: Effects of valproate on glutamate metabolism in rat brain slices: a (13)C NMR study.
abstract: Sodium valproate is a drug widely used for the treatment of epilepsy and mood disorders. We studied the effect of valproate on cerebral energy metabolism by incubating rat brain slices with 5 mM [3-(13)C]glutamate in the absence and the presence of 1 mM valproate. Substrate removal and product formation were measured by enzymatic and carbon 13 NMR methods. Fluxes through the enzymatic steps involved were calculated with an original mathematical model. We demonstrate that, in the presence of valproate, glutamate consumption and aspartate accumulation and labeling were inhibited, whereas GABA accumulation and labeling were increased. Consistent with these observations, this drug inhibited the unidirectional flux from glutamate to α-ketoglutarate and fluxes through several enzymes (gamma aminobutyric acid aminotransferase, α-ketoglutarate dehydrogenase, succinate dehydrogenase, malate dehydrogenase, aspartate aminotransferase, malic enzyme, pyruvate dehydrogenase, pyruvate carboxylase and citrate synthase). By contrast, glutamic acid decarboxylase flux was increased. With 2 mM glutamate+1 mM valproate and with 5 mM glutamate+2 mM valproate, GABA and aspartate labelings were similarly altered. On the basis of the effects of valproate, it is concluded that our cellular model and our cellular metabolomic approach appear suitable to study the beneficial and adverse interactions of neurotropic compounds with the cerebral metabolic pathways.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Unit # 820 (Métabolomique et Maladies Métaboliques), 69372 Lyon Cedex 08, France. maha-elhage@hotmail.com
authors.forename: Maha
authors.initials: M
authors.lastname: El Hage
authors.forename: Gabriel
authors.initials: G
authors.lastname: Baverel
authors.forename: Guy
authors.initials: G
authors.lastname: Martin
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism*; D002247:Carbon Isotopes; D004734:Energy Metabolism / Q000187:drug effects; D018698:Glutamic Acid / Q000032:analysis / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D008297:Male; D009924:Organ Culture Techniques; D051381:Rats; D017208:Rats, Wistar; D014635:Valproic Acid / Q000494:pharmacology*
chemical_list: D002247:Carbon Isotopes; D018698:Glutamic Acid; D014635:Valproic Acid