Excitatory amino acid antagonists protect mice against MPP+ seizures.
Administration of 1-methyl-4-phenyl-pyridinium ion (MPP+) into the lateral ventricle of mice induced clonic convulsions and lethality in a dose- and age-dependent manner. MPP+ failed to induce seizures in 4-day-old mice, and the convulsant response to MPP+ was enhanced in aged mice. The seizures triggered by MPP+ in adult mice were blocked by coadministration of L-glutamate antagonists active at kainate/AMPA receptors such as gamma-D-glutamylaminomethylsulphonate and 2,3-dihydroxy-6-nitro-7-sulphamoyl-benzo[f]quinoxaline. The N-methyl-D-aspartate (NMDA) antagonist 2-amino-7-phosphonoheptanoate, but not kynurenate, also protected mice against MPP+ convulsions. Similarly, the benzodiazepine midazolam and the adenosine A1 agonist 2-chloroadenosine, but not antiepileptic drugs such as phenobarbital, trimethadione, ethosuximide, or acetazolamide, showed a protective efficacy against seizures. Additionally, the excitatory amino acid antagonists as well as phenobarbital, midazolam and 2-chloroadenosine protected mice against MPP+ lethality. These data suggest that convulsant action of MPP+ and its lethality in rodents may be mediated by excitatory amino acids.
Turski
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Research Laboratories of Schering AG, Berlin, Federal Republic of Germany.
Stephens
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DN
D000375:Aging / Q000502:physiology; D000596:Amino Acids / Q000037:antagonists & inhibitors*; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology; D005260:Female; D007276:Injections, Intraventricular; D008297:Male; D051379:Mice; D011726:Pyridinium Compounds / Q000037:antagonists & inhibitors*; D012640:Seizures / Q000139:chemically induced / Q000517:prevention & control*
D000596:Amino Acids; D000927:Anticonvulsants; D011726:Pyridinium Compounds; C026560:1-(4-methoxyphenyl)pyridinium