Pharmacological, toxicological and neurochemical effects of Δ^2(E)-valproate in animals

Abstract

TheE isomer of 2-ene-valproic acid (Δ^2(E)-VPA) is the major active metabolite of the antiepileptic drug valproate (VPA) in various species, including humans. Experimental studies on Δ^2(E)-VPA and VPA indicate that Δ^2(E)-VPA may be a useful antiepileptic drug itself. Δ^2(E)-VPA has the same wide spectrum of anticonvulsant activity as VPA with a somewhat higher anticonvulsant potency in rodent and dog models of different seizure types. As VPA, Δ^2(E)-VPA increases presynaptic γ-aminobutyric acid (GABA) levels in the brain, presumably by an effect on GABA synthesis and/or GABA degradation. Δ^2(E)-VPA is a much more potent inhibitor of the human brain GABA-degrading enzyme than VPA. In high doses. Δ^2(E)-VPA is more sedative in rodents than is VPA; LD50 values are about the same. In mouse and rat models for teratogenicity, Δ^2(E)-VPA does not induce teratogenic effects, whereas VPA is teratogenic in these models. Pilot rat studies on liver toxicity of VPA and VPA metabolites suggest that Δ^2(E)-VPA is not hepatotoxic. In view of the rare but serious hepatotoxicity and teratogenicity of VPA in humans, Δ^2(E)-VPA obviously merits interest as a valuable alternative drug in antiepileptic therapy.