The non-competitive AMPA/kainate receptor antagonist, GYKI 52466, potentiates the anticonvulsant activity of conventional antiepileptics

Abstract

1-(4-Aminophenyl)-4-methyl-7,8-methylenedioxy-5 H-2,3-benzodiazepine hydrochloride (GYKI 52466), up to 5 mg/kg, did not influence the electroconvulsive threshold but potentiated the anticonvulsant activity of valproate, carbamazepine and diphenylhydantoin against maximal electroshock-induced convulsions in mice. No potentiation was observed in the case of phenobarbital. Moreover, this non-NMDA receptor antagonist did not influence the plasma levels of the antiepileptic drugs studied, so a pharmacokinetic interaction, in terms of total and free plasma levels, is not probable. The combined treatment of GYKI 52466 with either carbamazepine or diphenylhydantoin (providing a 50% protection against maximal electroshock) was devoid of significant side effects (motor and long-term memory impairment). Valproate applied at a dose equal to its ED 50 caused serious worsening of motor coordination and long-term memory. It is noteworthy that the combined treatment of GYKI 52466 with valproate was superior to valproate alone, as regards adverse effects. The results suggest that concomitant administration of GYKI 52466 with some conventional antiepileptic drugs may offer a novel approach in the treatment of epilepsy.