Bolaños J P, Medina J M
Departamento de Bioquímica y Biología Molecular, Universidad de Salamanca, Spain.
Life Sci. 1994;55(20):PL397-402. doi: 10.1016/0024-3205(94)00323-8.
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.
丙戊酸盐及其主要代谢产物E-δ2-丙戊酸盐对γ-氨基丁酸（GABA）分流的刺激作用被认为会降低脑能量代谢。为了阐明这一假设，研究了这些药物对新生大鼠脑片底物利用的影响。两种药物均剂量依赖性地抑制乳酸利用的总体速率。丙戊酸盐和E-δ2-丙戊酸盐均抑制了由3-羟基丁酸合成固醇和脂肪酸的过程。葡萄糖利用速率不受丙戊酸盐和E-δ2-丙戊酸盐的影响。氨氧基乙酸对GABA转氨酶的抑制作用降低了由乳酸、3-羟基丁酸和葡萄糖生成脂肪的过程。线粒体丙酮酸载体抑制剂α-氰基-4-羟基肉桂酸强烈降低了乳酸、3-羟基丁酸和葡萄糖的利用速率，这表明抑制丙酮酸线粒体载体不是这些药物的作用方式。有人提出，丙戊酸盐和E-δ2-丙戊酸盐对质膜单羧酸载体的抑制作用，而非GABA分流的激活，是脑燃料利用受到抑制的原因。
