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 hosphonomethyl)-decahydroisoquinoline-3-carboxylic acid; less t han or equal to 0.5 mg/kg] or LY 233053 [cis-(+/-)-4-[(2H-tetrazol-5-y l) methyl] piperidine-2-carboxylic acid; less than or equal to 5 mg/kg ] with carbamazepine, diphenylhydantoin, phenobarbital, or valproate m agnesium against maximal electroshock-induced convulsions in mice. Met hods: Electroconvulsions were produced by means of an alternating curr ent (ear-clip electrodes. 0.2-s stimulus duration, tonic hindlimb exte nsion taken as the end point) delivered by a Hugo-Sachs stimulator (Ty pe 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 immunofluoresc ence. Results: Both LY 235959 and LY 233053 (less than or equal to 0.5 and 5 mg/kg, respectively) did not influence the electroconvulsive th reshold but potentiated the anticonvulsant action of all antiepileptic s studied, The combined treatment of LY 233053 (5 mg/kg) with carbamaz epine, 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 2359 59 with these antiepileptics. The combined treatment of valproate with either LY 235959 or LY 233053 was superior to valproate alone, as reg ards motor impairment, but not the impairment of long-term memory. Nei ther NMDA-receptor antagonist elevated the total plasma levels of anti epileptic drugs studied. Conclusions: It may be concluded that NMDA-re ceptor blockade leads to the enhanced anticonvulsive action of convent ional antiepileptics against maximal electroshock-induced seizures. A pharmacokinetic interaction does not seem probable.