The anticonvulsant profile of GYKI 52 466

Abstract

A number of neurosteroids exert antiseizure and/or neuroprotective properties. The aim of this study was to evaluate the effect of the neurosteroid alphaxalone on the protective action of conventional antiepileptics in four seizure tests. Alphaxalone (up to 5 mg/kg) did not exert a significant action against amygdala-kindled seizures in rats, or against pentetrazole- or aminophylline-induced convulsions in mice. The neuroactive steroid at the dose of 2.5 mg/kg significantly raised the threshold for electroconvulsions in mice. At 2.5 mg/kg, alphaxalone diminished the protective activity of valproate against maximal electroshock and at 2.5–5 mg/kg against pentetrazole-induced seizures in mice. However, alphaxalone (2.5 mg/kg) did not affect the protective activity of carbamazepine, diphenylhydantoin, phenobarbital or clonazepam against maximal electroshock and at 5 mg/kg did not affect that of phenobarbital, clonazepam and ethosuximide against pentetrazole-induced convulsions. Insignificant results were also obtained in the case of co-administration of alphaxalone with phenobarbital, valproate, clonazepam and carbamazepine against aminophylline-evoked seizures in mice. Also, in the kindling model of epilepsy, combinations of the neuroactive steroid (2.5 mg/kg) with valproate, carbamazepine, phenobarbital, diphenylhydantoin or clonazepam at their subprotective doses did not result in pro- or anticonvulsant activity. Valproate (284 mg/kg; the dose used in combination with alphaxalone) produced significant memory deficits in mice. Alphaxalone (2.5 mg/kg), valproate (at its ED50 value of 226 mg/kg) and the combination of valproate (284 mg/kg) with alphaxalone (2.5 mg/kg) did not affect long-term memory, evaluated in the passive avoidance task with mice. Alphaxalone administered alone or in combination with valproate caused no motor impairment in experimental animals. Finally, alphaxalone (2.5 and 5 mg/kg) significantly increased the free plasma levels of valproate, strongly indicating that the neuroactive steroid-induced reduction of the protective activity of valproate is not related to pharmacokinetic phenomena. Summing up, alphaxalone does not seem to be a promising candidate for adjunctive treatment of epilepsy.