Valproate: a reappraisal of its pharmacodynamic properties and mechanisms of action

Valproate is currently one of the major antiepileptic drugs with efficacy for the treatment of both generalized and partial seizures in adults and children. Furthermore, the drug is increasingly used for therapy of bipolar and schizoaffective disorders, neuropathic pain and for prophylactic treatment of migraine. These various therapeutic effects are reflected in preclinical models, including a variety of animal models of seizures or epilepsy. The incidence of toxicity associated with the clinical use of valproate is low, but two rare toxic effects, idiosyncratic fatal hepatotoxicity and teratogenicity, necessitate precautions in risk patient populations. Studies from animal models on structure-relationships indicate that the mechanisms leading to hepatotoxicity and teratogenicity are distinct and also differ from the mechanisms of anticonvulsant action of valproate. 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 synthesis and release 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 attenuate neuronal excitation induced by NMDA-type glutamate receptors. In addition to effects on amino acidergic neurotransmission, valproate exerts direct effects on excitable membranes, although the importance of this action is equivocal. Microdialysis data suggest that valproate alters dopaminergic and serotonergic functions. Valproate is metabolized to several pharmacologically active metabolites, but because of the low plasma and brain concentrations of these compounds it is not likely that they contribute significantly to the anticonvulsant and toxic effects of treatment with the parent drug. By the experimental observations summarized in this review, most clinical effects of valproate can be explained, although much remains to be learned at a number of different levels of valproate's mechanisms of action.