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 ED(50) 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.