title: Pharmacological, toxicological and neurochemical effects of delta 2(E)-valproate in animals.
abstract: The E isomer of 2-ene-valproic acid (delta 2(E)-VPA) is the major active metabolite of the antiepileptic drug valproate (VPA) in various species, including humans. Experimental studies on delta 2(E)-VPA and VPA indicate that delta 2(E)-VPA may be a useful antiepileptic drug itself. delta 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, delta 2(E)-VPA increases presynaptic gamma-aminobutyric acid (GABA) levels in the brain, presumably by an effect on GABA synthesis and/or GABA degradation. delta 2(E)-VPA is a much more potent inhibitor of the human brain GABA-degrading enzyme than VPA. In high doses delta 2(E)-VPA is more sedative in rodents than is VPA; LD50 values are about the same. In mouse and rat models for teratogenicity, delta 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 delta 2(E)-VPA is not hepatotoxic. In view of the rare but serious hepatotoxicity and teratogenicity of VPA in humans, delta 2(E)-VPA obviously merits interest as a valuable alternative drug in antiepileptic therapy.
authors.affiliation: Department of Pharmacology, Toxicology and Pharmacy, School of Veterinary Medicine, Hannover, FRG.
authors.forename: W
authors.initials: W
authors.lastname: Löscher
mesh_terms: D000014:Abnormalities, Drug-Induced; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology* / Q000633:toxicity; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology* / Q000633:toxicity; D008099:Liver / Q000187:drug effects*; D012640:Seizures / Q000188:drug therapy; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: D000927:Anticonvulsants; D005229:Fatty Acids, Monounsaturated; D005680:gamma-Aminobutyric Acid; C014168:2-propyl-2-pentenoic acid