Comparative evaluation of anticonvulsant and toxic potencies of valproic acid and 2-en-valproic acid in different animal models of epilepsy.

Abstract

The anticonvulsant potency of 2-propyl-2-pentenoic acid (2-en-VPA; trans isomer), a major metabolite of the antiepileptic valproic acid (VPA), was evaluated in different animal models of epilepsy and compared with the respective data for VPA. Four models were used: the maximal electroshock seizure (MES) test in mice, the pentylenetetrazol seizure test in mice, gerbils with 'major' (generalized tonic-clonic) seizures in response to specific sensory stimulation, and rats with chronically recurring, spontaneous 'petit mal' seizures. The overall anticonvulsant profile of 2-en-VPA in these models compared favourably with that of VPA. Both drugs were considerably more potent to block seizures in epileptic rats and gerbils than in the traditional MES and pentylenetetrazol mouse models. As regards toxicity, no side-effects were observed with effective doses of 2-en-VPA in rats and gerbils, whereas in the doses necessary to block MES and pentylenetetrazol seizures in mice (200-300 mg/kg i.p.) 2-en-VPA was more sedative than VPA. LD50 values determined for both drugs were comparable. A major difference between 2-en-VPA and VPA was found with respect to embryotoxicity. Single doses of VPA administered to pregnant mice gave rise to significant teratogenic effects (exencephaly, embryolethality , growth retardation), whereas 2-en-VPA was not embryotoxic, even at extremely high doses (600 mg/kg). The data suggest that 2-en-VPA may be a valuable alternative antiepileptic drug.