Ovariectomy aggravates convulsions and hippocampal gamma-aminobutyric acid inhibition induced by cyclosporin A in rats.
The possible cyclosporin A application for rheumatoid arthritis that develops preferentially in middle-aged women raises concerns about adverse effects of cyclosporin A, including neurotoxicity in patients with climacterium. The present study was aimed at elucidating the effect of cyclosporin A on the convulsive activity and gamma-aminobutyric acid (GABA) neural activity of the hippocampus in ovariectomized rats, as a menopause/climacterium model. Ovariectomy markedly aggravated the effect of repeated administration of cyclosporin A (40 mg/kg, once a day for 5 or 6 days), convulsions and reduction of the basal GABA levels and aminooxyacetic acid-evoked GABA accumulation. These aggravations were blocked by estradiol replacement. The present findings demonstrated that ovariectomy increased the susceptibility to cyclosporin A-induced convulsions by accelerating an inhibitory action of cyclosporin A on GABA neural activity in the hippocampus, this being blocked by estrogen replacement. Menopause/climacterium is, therefore, included in the risk factors for cyclosporin A-induced neurotoxicity and this risk is lowered by estrogen replacement therapy.
Tominaga
K
K
Department of Hospital Pharmacy, Faculty of Medicine, Kyushu University, 3-1-1 Maidashi, Higashi-ku, 812-8582, Fukuoka, Japan.
Yamauchi
A
A
Shuto
H
H
Niizeki
M
M
Makino
K
K
Oishi
R
R
Kataoka
Y
Y
D000625:Aminooxyacetic Acid / Q000009:adverse effects / Q000494:pharmacology; D000818:Animals; D018501:Antirheumatic Agents / Q000009:adverse effects* / Q000494:pharmacology; D016572:Cyclosporine / Q000009:adverse effects* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004958:Estradiol / Q000494:pharmacology; D005260:Female; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D010052:Ovariectomy / Q000009:adverse effects*; D051381:Rats; D017208:Rats, Wistar; D012640:Seizures / Q000209:etiology / Q000473:pathology*; D009435:Synaptic Transmission / Q000187:drug effects; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
D018501:Antirheumatic Agents; D000625:Aminooxyacetic Acid; D004958:Estradiol; D005680:gamma-Aminobutyric Acid; D016572:Cyclosporine