Competitive NMDA-Receptor antagonists, LY 235959 and LY 233053, enhance the protective efficacy of various antiepileptic drugs against maximal electroshock-induced seizures in mice

Purpose: The objective of this study was to evaluate an interaction of two competitive N-methyl-D-aspartate (NMDA)-receptor antagonists, LY 235959 [(-)-3R,4aS,6R,8aR-6-(phosphonomethyl)-decahydroisoquinoline-3-carboxylic acid; less than or equal to 0.5 mg/kg] or LY 233053 [cis-(+/-)-4-[(2H-tetrazol-5-yl) methyl] piperidine-2-carboxylic acid; less than or equal to 5 mg/kg] with carbamazepine, diphenylhydantoin, phenobarbital, or valproate magnesium against maximal electroshock-induced convulsions in mice. Methods: Electroconvulsions were produced by means of an alternating current (ear-clip electrodes. 0.2-s stimulus duration, tonic hindlimb extension taken as the end point) delivered by a Hugo-Sachs stimulator (Type 221, Freiburg, FRG). Adverse effects were evaluated in the chimney test (motor performance) and passive-avoidance task (long-term memory). Plasma levels of antiepileptic drugs were measured by immunofluorescence. Results: Both LY 235959 and LY 233053 (less than or equal to 0.5 and 5 mg/kg, respectively) did not influence the electroconvulsive threshold but potentiated the anticonvulsant action of all antiepileptics studied, The combined treatment of LY 233053 (5 mg/kg) with carbamazepine, diphenylhydantoin, or phenobarbital (providing a 50% protection against maximal electroshock) resulted in the impairment of long-term memory. No adverse effects were observed with combinations of LY 235959 with these antiepileptics. The combined treatment of valproate with either LY 235959 or LY 233053 was superior to valproate alone, as regards motor impairment, but not the impairment of long-term memory. Neither NMDA-receptor antagonist elevated the total plasma levels of antiepileptic drugs studied. Conclusions: It may be concluded that NMDA-receptor blockade leads to the enhanced anticonvulsive action of conventional antiepileptics against maximal electroshock-induced seizures. A pharmacokinetic interaction does not seem probable.