Anticonvulsant activity of intracerebroventricularly administered valproate and valproate analogues. A dose-dependent correlation with changes in brain aspartate and GABA levels in DBA/2 mice

Abstract

Valproate and the branch-chain valproate analogues, 2-propyl-hexanoate and 2-ethyl-hexanoate, block sound-induced seizures in DBA/2 mice following their intracerebroventricular administration, the ED50 values for the suppression the clonic phase of the seizures being 6.0, 5.0, and 10.2 mumoles respectively. The straight-chain analogues, butyrate and pentanoate , have no anticonvulsant activity. Systemic administration of branched-chain valproate analogues has previously shown a progressive increase in the anticonvulsant activity of the analogues with an increase in the chain-length of the molecules. This relationship is abolished when the same analogues are injected directly into the ventricles. The icv administration of the 2 straight-chain, inactive analogues produces no effect on brain aspartate and GABA levels (with the exception of a butyrate-induced 34% rise in forebrain GABA level). There is a dose-dependent decrease in aspartate levels in cerebellum and forebrain (up to 45-55% reduction), and a dose-dependent increase in GABA levels in forebrain (up to 30-75% rise) 30 min after the icv administration of the 3 anticonvulsant branched-chain fatty acids. 2-Propyl-hexanoate does not affect the cerebellar GABA level significantly, while valproate and 2-ethyl-hexanoate administration produce 20-40% increases in cerebellar GABA levels.