Competitive NMDA receptor antagonists enhance the antielectroshock activity of various antiepileptics.
CGP 37849 (1 mg/kg i.p.) enhanced the protective action of carbamazepine, diphenylhydantoin and phenobarbital against maximal electroshock-induced convulsions in mice. At 0.25 mg/kg CGP 37849 was inactive and at 0.5 mg/kg it potentiated the anticonvulsive activity of phenobarbital. CGP 39551 (5 mg/kg i.p.) reduced the ED50 values of diphenylhydantoin and phenobarbital, being without influence on carbamazepine. In the dose of 1.25 mg/kg, CGP 39551 potentiated the antielectroshock action of diphenylhydantoin and at 2.5 mg/kg that of phenobarbital. Neither NMDA receptor antagonist elevated the total plasma levels of antiepileptic drugs. Consequently, a pharmacokinetic interaction (in terms of total plasma levels at least) seems unlikely to be responsible for the observed potentiation of the antiepileptic drugs' activity. Combinations of CGP 37849 with either carbamazepine or phenobarbital resulted in a motor and memory impairment quantified by the chimney test and passive avoidance task, respectively. Moreover, combined treatment with phenobarbital and CGP 39551 caused a memory deficit. In contrast, diphenylhydantoin combined with either CGP 37849 or 39551 was devoid of adverse effects. It may be concluded that NMDA receptor blockade results in enhanced anticonvulsive action of common antiepileptics against maximal electroshock-induced seizures.
Pietrasiewicz
T
T
Department of Pharmacology and Toxicology, Medical School, Lublin, Poland.
Czechowska
G
G
Dziki
M
M
Turski
W A
WA
Kleinrok
Z
Z
Czuczwar
S J
SJ
D015763:2-Amino-5-phosphonovalerate / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use / Q000633:toxicity; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology* / Q000633:toxicity; D001362:Avoidance Learning / Q000187:drug effects; D001522:Behavior, Animal / Q000187:drug effects*; D002220:Carbamazepine / Q000494:pharmacology / Q000627:therapeutic use; D004357:Drug Synergism; D004597:Electroshock; D008297:Male; D008568:Memory / Q000187:drug effects; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D010634:Phenobarbital / Q000494:pharmacology / Q000627:therapeutic use; D010672:Phenytoin / Q000494:pharmacology / Q000627:therapeutic use; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D012640:Seizures / Q000188:drug therapy*
D000927:Anticonvulsants; D016194:Receptors, N-Methyl-D-Aspartate; C064540:CGP 39551; C064539:2-amino-4-methyl-5-phosphono-3-pentenoic acid; D002220:Carbamazepine; D010672:Phenytoin; D015763:2-Amino-5-phosphonovalerate; D010634:Phenobarbital