1998 Fiscal Year Final Research Report Summary
Immunosuppressants neurotoxicity : cyclosporine and taclorimus-induced tremors and convulsions
| Project/Area Number |
09672328
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
応用薬理学・医療系薬学
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| Research Institution | KYUSHU UNIVERSITY |
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Principal Investigator |
KATAOKA Yasufumi Kyushu University, Department of Hospital Pharmacy, Associated Professor, 医学部, 助教授 (70136513)
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| Co-Investigator(Kenkyū-buntansha) |
OISHI Ryozo Kyushu University, Department of Hospital Pharmacy Professsor, 医学部, 教授 (90112325)
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| Project Period (FY) |
1997 – 1998
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| Keywords | Immunosupressants / Cyclosporine / Neurotoxocity / Tremors / Convulsions / Brain / Serotonin / GABA |
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| Research Abstract |
In this study, we attempted to clarify the mechanisms mediating cyclosporine- evoked tremors and convulsions. (1) Both single and repeated (1 x 7 days) treatment with cyclosporine (50 mg/kg i.p.) significantly enhanced harmine- but not oxotremorine- induced tremors, suggesting an involvement of monoaminergic, mechanisms in cyclosporine-induced tremors. Both single and repeated treatment with cyclosporine significantly facilitated the serotonin turnover as estimated from the probenecid-induced accumulation of 5-hydroxyindoleacetic acid, but either mode of treatment failed to change the turmover of noradrenaline and dopamine in the mouse brain . Therefore, cyclosporine-enhanced activity of serotonin neurons may be interpreted as producing tremors. (2) Cyclosporine (50 mg/kg, i.p.) significantly enhanced the intensity of convulsions induced by bicuculline (GABA receptor antagonist), but not those induced by glutamate receptor agonists. The GABA turnover estimated by measuring aminooxyacetic acid-induced GABA accumulations in the mouse brain was significantly inhibited by cyclosporine (50 mg/kg, i.p.). When cultured rat cerebellar granule cells were exposed to 1 muM cyclosporine for 24 hr, the specific [^3H]muscimol (10 nM) binding to intact granule cells decreased to 53 % of vehicle. These findings suggest that cyclosporine inhibits GABAergic neural activity and binding properties of GABA_A receptor. Cyclosporine- induced GABA system inhibition may be involved in serotonergic activation. These events are closely related to the occurrence of adverse central effects including tremors and convulsions under cyclosporine therapy. -
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