Effects of the antiepileptic drug valproate on metabolism and function of inhibitory and excitatory amino acids in the brain

Abstract

Valproate is currently one of the major antiepileptic drugs in clinical use. Because of its wide spectrum of anticonvulsant activity against different seizure types, it has repeatedly been suggested that valproate acts through a combination of several mechanisms. As shown in this review, there is substantial evidence that valproate increases GABA turnover and thereby potentiates GABAergic functions in some specific brain regions, such as substantia nigra, thought to be involved in the control of seizure generation and propagation. Furthermore, valproate seems to reduce the release of the epileptogenic amino acid gamma-hydroxybutyric acid and to block cell firing induced by NMDA-type glutamate receptors. In addition to effects on amino acidergic neurotransmission, valproate presumably exerts a direct action on ion channels, thereby limiting sustained repetitive neuronal firing. Recent microdialysis data suggest that valproate also alters dopaminergic and serotonergic functions. These diverse effects of valproate might explain why the drug not only exerts anticonvulsant activity but also other pharmacodynamic and pharmacotherapeutic actions, such as antipsychotic and antidystonic efficacy.