Antagonism of various tonic convulsions in mice by dextrorphan and dizocilpine.
To define their efficacy and mechanism of action, the possible antagonistic effects of intravenously administered dextrorphan and dizocilpine, non-competitive N-methyl-D-aspartic acid (NMDA) receptor antagonists, on tonic convulsions and death in a variety of experimental mice models were compared. Dextrorphan not only produced dose-dependent protection against the tonic convulsions caused by an intracerebroventricular injection of NMDA, but also showed a broad spectrum of anticonvulsant activities against tonic convulsions caused by alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), kainic acid (KA), bicuculline, pentylenetetrazole or electroconvulsive shock. The anticonvulsant action of dizocilpine was found to be more efficacious for any type of tonic convulsions and was 20- to 70-fold more potent than that of dextrorphan. Dizocilpine, unlike dextrorphan, impaired motor function at doses showing its anticonvulsant activity. Bay k-8644 (a Ca2+ channel agonist)-induced seizures were not antagonized by dextrorphan. Dextrorphan and dizocilpine were characteristically selective for protective functions against death, especially with three subtypes of glutamate receptors, as death caused by NMDA but not by AMPA and KA was selectively and markedly inhibited by both dextrorphan and dizocilpine. In view of these results, the efficacy of dextrorphan and dizocilpine as antagonists of convulsant effects appears to be consistent with the interpretation that a variety of convulsants cause tonic convulsions via direct or indirect interaction with the NMDA receptor complex. Furthermore, it is suggested that influx of Ca(2+) and intracellular Ca(2+) activity, such as the Bay k-8644-modulated activation of Ca(2+) binding proteins, are not directly modified by the administration of dextrorphan, itself.
Akaike
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Department of Pharmacology, Nippon Roche Research Center, Kamakura, Japan.
Himori
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D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / Q000494:pharmacology; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects; D003292:Convulsants / Q000008:administration & dosage / Q000494:pharmacology; D003917:Dextrorphan / Q000494:pharmacology*; D016291:Dizocilpine Maleate / Q000494:pharmacology*; D004597:Electroshock; D004830:Epilepsy, Tonic-Clonic / Q000139:chemically induced / Q000401:mortality / Q000517:prevention & control*; D007276:Injections, Intraventricular; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D004856:Postural Balance / Q000187:drug effects; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors
D000927:Anticonvulsants; D003292:Convulsants; D016194:Receptors, N-Methyl-D-Aspartate; D003917:Dextrorphan; D016291:Dizocilpine Maleate; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester