Influence of MK-801 on the anticonvulsant activity of antiepileptics.
MK-801 (a potent non-competitive antagonist of N-methyl-D-aspartic acid-mediated events) in subcutaneous doses of 0.1 and 0.2 mg/kg increased the threshold for electroconvulsions and in doses of 0.0031 and 0.0125 mg/kg enhanced the protective activity of valproate against maximal electroshock-induced convulsions in mice. Valproate-induced side-effects (evaluated by means of dark-avoidance acquisition and retention testing and the chimney test) at its ED50 against maximal electroshock (i.e. 268 mg/kg) were pronounced whereas they were absent in the case of a combined treatment with MK-801 (0.0125 mg/kg) and valproate (91 mg/kg). This treatment provided 50% protection against maximal electroshock-induced seizures. Moreover, MK-801 (0.0125 and 0.05 mg/kg) potentiated the anticonvulsant action of phenobarbital, reducing phenobarbital-induced motor impairment totally at 0.05 mg/kg, but did not influence the protection offered by carbamazepine and diphenylhydantoin at 0.05 mg/kg. The N-methyl-D-aspartic acid antagonist did not affect the total plasma levels of either valproate or phenobarbital (as measured by immunofluorescence), so a pharmacokinetic interaction, in terms of total plasma levels at least, is unlikely to be involved in the observed effects. The finding that the combined treatment of MK-801 with valproate or phenobarbital, apart from the distinct potentiation of their anticonvulsant activities, is devoid of side-effects should be carefully considered.
Urbańska
E
E
Department of Pharmacology, Medical School, Lublin, Poland.
Dziki
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Kleinrok
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Czuczwar
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Turski
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D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects; D016291:Dizocilpine Maleate / Q000494:pharmacology*; D004357:Drug Synergism; D004597:Electroshock; D007858:Learning / Q000187:drug effects; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D010634:Phenobarbital / Q000494:pharmacology; D012640:Seizures / Q000188:drug therapy*; D014635:Valproic Acid / Q000494:pharmacology
D000927:Anticonvulsants; D014635:Valproic Acid; D016291:Dizocilpine Maleate; D010634:Phenobarbital