Comparison of the pharmacological and biochemical profiles of valproic acid (VPA) and its cerebral metabolite (2-en-VPA) after oral administration in mice.

The pharmacological and biochemical profiles of valproate (VPA) and its cerebral metabolite (2-en-VPA) have been compared in order to determine the potential therapeutic value of the latter. After oral administration, 2-en-VPA was approximately half as potent as VPA in a number of chemical seizure models (pentylenetetrazol, B-mercaptopropionic acid, bicuculline, picrotoxinin), but more potent in tests of sedative activity (rotarod and loss of righting reflex). Whereas VPA possessed anxiolytic activity in mice, 2-en-VPA appeared to be inactive. The anticonvulsant activity of 2-en-VPA was shorter-lasting than that of VPA. The activity of 4 mmol/kg 2-en-VPA lasted less than 2 hours, while the same dose of VPA provided protection for over 5 hours. Both molecules increased brain GABA content to a similar extent, but again the action of 2-en-VPA was short-lasting. The low potency, poor ratio of sedative:anticonvulsant activity, and short-lived action of 2-en-VPA suggest that the molecule is poorly adapted for use as an antiepileptic agent.