Evidence of stimulation of the gamma-aminobutyric acid shunt by valproate and E-delta 2-valproate in neonatal rat brain.
The effect of valproate and its more active metabolite E-delta 2-valproate on the rate of glucose oxidation through different metabolic pathways in neonatal rat brain slices was studied. The presence of valproate or E-delta 2-valproate did not change the rate of [3,4-14C]glucose or [6-14C]glucose incorporation into CO2, suggesting that glucose oxidation through the pyruvate dehydrogenase-catalyzed reaction and through the tricarboxylic acid cycle was not affected by these drugs. However, both drugs significantly enhanced the rate of [2-14C]glucose oxidation, supporting the notion that the activity of the gamma-aminobutyric acid (GABA) shunt is specifically stimulated by valproate and, to a greater extent, by E-delta 2-valproate. The presence of methionine sulfoximine or gamma-hydroxybutyrate did not change the GABA shunt activity. Brain glutamate decarboxylase activity was significantly increased after incubation of the brain slices in the presence of valproate. Consequently, our results suggest that the mechanism of action of valproate is related to the increase in the levels of the inhibitory neurotransmitter GABA caused by the enhancement of flux through the glutamate decarboxylase-catalyzed reaction.
Bolaños
J P
JP
Departamento de Bioquimica y Biologia Molecular, Facultad de Farmacia, Universidad de Salamanca, Spain.
Medina
J M
JM
D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology*; D005947:Glucose / Q000378:metabolism; D066298:In Vitro Techniques; D010084:Oxidation-Reduction; D011768:Pyruvate Dehydrogenase Complex / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D014635:Valproic Acid / Q000494:pharmacology*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
D005229:Fatty Acids, Monounsaturated; D011768:Pyruvate Dehydrogenase Complex; D005680:gamma-Aminobutyric Acid; C014168:2-propyl-2-pentenoic acid; D014635:Valproic Acid; D005947:Glucose