Inhibition of neonatal brain fuel utilization by valproate and E-delta 2-valproate is not a consequence of the stimulation of the gamma-aminobutyric acid shunt.
Stimulation of the gamma-aminobutyric acid (GABA) shunt by valproate and its major metabolite, E-delta 2-valproate, has been proposed to decrease brain energy metabolism. In order to elucidate this hypothesis, the effect of these drugs on substrate utilization in neonatal rat brain slices was studied. The overall rate of lactate utilization was dose-dependently inhibited by both drugs. Valproate and E-delta 2-valproate inhibited both sterol and fatty acid syntheses from 3-hydroxybutyrate. The rate of glucose utilization was not affected by valproate nor E-delta 2-valproate. The inhibition of the GABA aminotransferase by aminooxyacetate decreased lipogenesis from lactate, 3-hydroxybutyrate and glucose. The inhibitor of the mitochondrial pyruvate carrier, alpha-cyano-4-hydroxycinnamate, strongly decreased the rate of lactate, 3-hydroxybutyrate and glucose utilization, suggesting that the inhibition of pyruvate mitochondrial carrier is not the mode of action of these drugs. It is suggested that inhibition of plasma membrane monocarboxylate carrier by valproate and E-delta 2-valproate, but not the activation of the GABA shunt, is responsible for the inhibition of the brain fuel utilization.
Departamento de Bioquímica y Biología Molecular, Universidad de Salamanca, Spain.
J P
JP
Bolaños
J M
JM
Medina
D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D004734:Energy Metabolism / Q000187:drug effects; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology; D007773:Lactates / Q000378:metabolism; D019344:Lactic Acid; D051381:Rats; D017208:Rats, Wistar; D014635:Valproic Acid / Q000031:analogs & derivatives / Q000494:pharmacology*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
D005229:Fatty Acids, Monounsaturated; D007773:Lactates; D019344:Lactic Acid; D005680:gamma-Aminobutyric Acid; C014168:2-propyl-2-pentenoic acid; D014635:Valproic Acid