Excitatory amino acid-elicited tonic convulsions in mice and N-methyl-D-aspartate receptor activation: role of Ca(2+) influx and involvement of intracellular Ca(2+)-dependent biochemical processes.
Intravenously administered nimodipine (an L-type Ca(2+) antagonist) as well as dizocilpine (an N-methyl-D-aspartate--NMDA--antagonist) showed a wide spectrum of anticonvulsant activity in intracerebroventricular mouse models for excessive activation of excitatory amino acid receptors. The duration of Bay k-8644 (L-type Ca(2+) agonist; intracerebroventricular administration) caused seizures was significantly reduced by intravenously administered nimodipine. Intracisternal administration of Bay k-8644 lowered the convulsion threshold of an intracerebroventricular injection of NMDA. Intracisternal administration of omega-conotoxin GVIA (N-type Ca(2+) antagonist) only tended to inhibit the NMDA-induced tonic convulsions. Intracisternal administration of staurosporine (a protein kinase C inhibitor) or calmidazolium (a calmodulin antagonist) was effective in inhibiting the NMDA-induced tonic convulsions. Calmidazolium, unlike staurosporine, produced side effects at a dose showing its anticonvulsant activity. From these results, it is suggested that excessive activation of excitatory amino acid receptors results in tonic convulsions by virtue of a massive increase of Ca(2+) influx mainly through NMDA receptor channels, and at least in part through L-type Ca(2+) channels, and in subsequent activation of protein kinase C and possibly calmodulin.
Akaike
Nobuhide
N
Department of Pharmacology, Nippon Roche Research Center, Kamakura, Japan. nobuiso@venus.dti.ne.jp
Himori
Norio
N
D000818:Animals; D002118:Calcium / Q000378:metabolism / Q000502:physiology*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D015220:Calcium Channels / Q000378:metabolism; D004830:Epilepsy, Tonic-Clonic / Q000139:chemically induced* / Q000378:metabolism; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology*; D007424:Intracellular Fluid / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*
D002121:Calcium Channel Blockers; D015220:Calcium Channels; D018690:Excitatory Amino Acid Agonists; D016194:Receptors, N-Methyl-D-Aspartate; D002118:Calcium