Inhibition of GABA system involved in cyclosporine-induced convulsions.
In this study, we attempted to clarify the mechanisms mediating cyclosporine-evoked convulsions. Cyclosporine (50 mg/kg, i.p.) significantly enhanced the intensity of convulsions induced by bicuculline (GABA receptor antagonist), but not those induced by strychnine (glycine receptor antagonist), N-methyl-D-aspartic acid, quisqualic acid or kainic acid (glutamate receptor agonists). Bicuculline plus cyclosporine-induced convulsions were significantly suppressed by an activation of GABAergic transmission with diazepam, phenobarbital and valproate. The GABA turnover estimated by measuring aminooxyacetic acid-induced GABA accumulation in the mouse brain was significantly inhibited by cyclosporine (50 mg/kg, i.p.). When cultured rat cerebellar granule cells were exposed to 1 microM cyclosporine for 24 hr, the specific [3H]muscimol (10 nM) binding to intact granule cells decreased to 53% of vehicle controls. The present study provides the first evidence suggesting that cyclosporine inhibits GABAergic neural activity and binding properties of the GABAA receptor. These events are closely related to the occurrence of adverse central effects including tremors, convulsions, coma and encephalopathy under cyclosporine therapy.
Shuto
H
H
Department of Hospital Pharmacy, Faculty of Medicine, Kyushu University, Fukuoka, Japan.
Kataoka
Y
Y
Fujisaki
K
K
Nakao
T
T
Sueyasu
M
M
Miura
I
I
Watanabe
Y
Y
Fujiwara
M
M
Oishi
R
R
D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology; D001640:Bicuculline / Q000037:antagonists & inhibitors / Q000494:pharmacology; D001665:Binding Sites / Q000187:drug effects; D001921:Brain / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D016572:Cyclosporine / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D004357:Drug Synergism; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D018755:GABA Agonists / Q000494:pharmacology; D018756:GABA Antagonists / Q000494:pharmacology*; D005998:Glycine / Q000037:antagonists & inhibitors; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009118:Muscimol / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D012640:Seizures / Q000139:chemically induced* / Q000378:metabolism; D013331:Strychnine / Q000494:pharmacology; D016559:Tacrolimus / Q000031:analogs & derivatives / Q000494:pharmacology; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
C112418:32-ascomycinyloxyacetic acid; D000927:Anticonvulsants; D018690:Excitatory Amino Acid Agonists; D018755:GABA Agonists; D018756:GABA Antagonists; D009118:Muscimol; D005680:gamma-Aminobutyric Acid; D016572:Cyclosporine; D013331:Strychnine; D005998:Glycine; D016559:Tacrolimus; D001640:Bicuculline