The competitive NMDA antagonist, D-CPP-ene, potentiates the anticonvulsant activity of conventional antiepileptics against maximal electroshock-induced seizures in mice

Abstract

D-CPP-ene [3-(2-carboxypiperazine-4-yl)-1-propenyl-1-phosphonic acid; a competitive antagonist of N- methyl- D- aspartic acid] in a dose of 2 mg kg (i.p.) significantly increased the threshold for electroconvulsions. When given in a dose half that affecting the electroconvulsive threshold, D-CPP-ene potentiated the anticonvulsant activity of carbamazepine, diazepam, diphenylhydantoin, phenobarbital and valproate against maximal electroshock (50 mA)-induced seizures in mice. However, this NMDA antagonist did not influence the plasma levels of the antiepileptic drugs studied, so a pharmacokinetic interaction, in terms of total plasma levels at least, is not probable. The chimney test and retention testing in mice revealed that the combined treatment of D-CPP-ene at 1.0 mg kg (i.p.) with either diazepam, diphenylhydantoin, phenobarbital or valproate (providing a 50% protection against maximal electroshock convulsions) resulted in motor impairment and caused impairment of long-term memory. On the other hand, a combination of D-CPP-ene and carbamazepine was devoid of adverse effects. It can be concluded that the potential utility of D-CPP-ene in combination with conventional antiepileptic drugs does not seem promising, except for carbamazepine.