Low-affinity kainate receptor-mediated events reduce the protective activity of phenobarbital and diphenylhydantoin against maximal electroshock in mice.
(2S,2R)-4-Methylglutamic acid (SYM 2081), a potent selective agonist of GluR5 and GluR6 kainate receptor subtypes, applied at the dose of 15.5 mg/kg, equal to its CD(16) value (i.e., a dose required to induce convulsions in 16% of mice), significantly decreased the electroconvulsive threshold from 7.0 to 5.8 mA. When administered at the dose of 11.5 mg/kg, equal to 75% of its CD(16), it markedly attenuated the protective activity of phenobarbital and diphenylhydantoin, but not that of valproate, carbamazepine, or diazepam against maximal electroshock-induced seizures in mice. The respective ED(50) values were increased from 18.5 to 23.8 mg/kg for phenobarbital, and from 11.7 to 14.7 mg/kg for diphenylhydantoin. Since the free plasma levels of both antiepileptic drugs were not influenced by SYM 2081, the pharmacokinetic interaction does not seem to be involved in the observed results. In conclusion, low-affinity kainate receptor-mediated events might be a factor reducing the protective efficacy of some antiepileptic drugs. Furthermore, the activation of GluR5 and GluR6 kainate receptor subtypes by endogenous glutamate during seizures may be associated with the drug-resistance phenomenon.
Borowicz
K K
KK
Department of Pathophysiology, Lublin Medical University, Jaczewskiego 8, Lublin 20-090, Poland.
Zadrozniak
M
M
Czuczwar
S J
SJ
D000818:Animals; D004597:Electroshock / Q000379:methods; D005971:Glutamates / Q000494:pharmacology; D008297:Male; D051379:Mice; D018696:Neuroprotective Agents / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D010634:Phenobarbital / Q000494:pharmacology*; D010672:Phenytoin / Q000494:pharmacology*; D018092:Kainic Acid Receptors / Q000819:agonists / Q000502:physiology*
D005971:Glutamates; D018696:Neuroprotective Agents; D010634:Phenobarbital; D010672:Phenytoin; D018092:Kainic Acid Receptors; C046105:4-methylglutamic acid