The AMPA/kainate receptor antagonist, LY 300164, increases the anticonvulsant effects of diazepam.
The aim of this study was to evaluate the influence of 7-acetyl-5-(4-aminophenyl)-8,9-dihydro-8-methyl-7H-1,3-dioxolo(4,5 H)-2,3-benzodiazepine (LY 300164), a selective non-competitive antagonist at alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)/kainate receptors, on the protection provided by diazepam against electrically- and chemically-evoked seizures in rodents. LY 300164 (2 mg/kg) was devoid of any significant action upon each seizure parameter in kindled rats (seizure severity, seizure duration, after-discharge duration). LY 300164 (5 mg/kg) exerted a significant anticonvulsive effect as regards seizure and after-discharge durations. Combined treatment with LY 300164 (2 mg/kg) and diazepam (0.3125-1.25 mg/kg) resulted in the clear-cut anticonvulsive activity. It is noteworthy that the antiseizure potency of the combined treatment (diazepam 1.25 mg/kg plus LY 300164 2 mg/kg) was comparable to that of diazepam (10-20 mg/kg) alone. The combination of diazepam (1.25 mg/kg) with LY 300164 (2 mg/kg) did not induce any significant motor impairment in the rotorod test or memory deficit in the passive-avoidance task. In contrast, diazepam alone (10-20 mg/kg) had pronounced adverse effects in kindled animals. LY 300164 (up to 2 mg/kg) did not influence the threshold for electro- and pentylenetetrazol-induced convulsions but potentiated the anticonvulsive action of diazepam in the maximal electroshock and pentylenetetrazol test in mice, the ED50s of the benzodiazepine being reduced from 13 to 8.7 and from 0.29 to 0.049 mg/kg, respectively. As shown in the passive-avoidance task, combination of LY 300164 (2 mg/kg) with diazepam (8.7 mg/ kg) produced significant motor and long-term memory impairment. Diazepam alone (at the dose equal to its ED50 against maximal electroshock) also caused motor and memory deficits in mice. Interaction at the pharmacokinetic level, at least in plasma, can be excluded, because LY 300164 (2 mg/kg) did not affect the free plasma diazepam concentration. In conclusion, LY 300164 potentiates the protective action of diazepam in some animal models of seizures. This profitable interaction may create a new approach for the treatment of drug resistant epilepsy or status epilepticus.
Borowicz
K K
KK
Department of Pharmacology and Toxicology, Medical University, Lublin, Poland.
Kleinrok
Z
Z
Czuczwar
S J
SJ
D000679:Amygdala / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects; D001569:Benzodiazepines / Q000494:pharmacology*; D003975:Diazepam / Q000097:blood / Q000494:pharmacology*; D004347:Drug Interactions; D004357:Drug Synergism; D004597:Electroshock / Q000009:adverse effects; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D007696:Kindling, Neurologic / Q000187:drug effects; D008297:Male; D051379:Mice; D010433:Pentylenetetrazole / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors*; D018092:Kainic Acid Receptors / Q000037:antagonists & inhibitors*; D012640:Seizures / Q000139:chemically induced / Q000188:drug therapy
D000927:Anticonvulsants; D001569:Benzodiazepines; D003975:Diazepam; D018691:Excitatory Amino Acid Antagonists; D010433:Pentylenetetrazole; D018091:Receptors, AMPA; D018092:Kainic Acid Receptors; C085266:talampanel