NMDA receptor glycine site antagonist (indole-2-carboxylic acid) enhances the anticonvulsive activity of antiepileptic drugs

Indole-2-carboxylic acid an antagonist of the glycine site within NMDA receptor complex, significantly raised the threshold for electroconvulsions in mice, when given at doses 150-200 mg/kg. At a subprotective dose (100 mg/kg) it enhanced the protective activity of carbamazepine, phenobarbital and valproate, diphenylhydantoin being an exception. The activity of carbamazepine and valproate was also potentiated by indole-2-carboxylic acid administered at 50 mg/kg, moreover at the dose of 25 mg/kg it sill significantly lowered the ED50 of valproate. However, the combined treatment of this glycine site antagonist with all antiepileptic drugs studied impaired the motor performance of mice in the rotorod test. Indole-2-carboxylic acid alone at the dose range from 150 to 200 mg/kg induced motor impairment in mice. When co-administered with valproate. it significantly worsened passive avoidance behaviour. The plasma levels of antiepileptic drugs remained unchanged in the presence of indole-2-carboxylic acid. It may be concluded that although indole-2-carboxylic acid enhanced the protective activity of certain antiepileptics. its therapeutic use seems questionable due to pronounced adverse effects, as revealed by the behavioural tests.