Immunosuppressants neurotoxicity : cyclosporine and taclorimus-induced tremors and convulsions

在本研究中，我们试图阐明介导环孢素诱发震颤和惊厥的机制。(1)单次和重复（1 x 7天）用环孢霉素（50 mg/kg i. p.）显着增强骆驼蓬碱-但不是氧化震颤素-诱导的震颤，表明参与单胺能，环孢菌素诱导的震颤机制。单次和重复治疗环孢素显着促进5-羟色胺营业额估计从丙磺舒诱导的5-羟基吲哚乙酸的积累，但任何一种治疗模式都未能改变去甲肾上腺素和多巴胺在小鼠大脑中的turmover。因此，环孢霉素增强的5-羟色胺神经元的活性可以解释为产生震颤。(2)环孢霉素（50 mg/kg，i. p.）显著增强荷包牡丹碱（GABA受体拮抗剂）诱导的惊厥强度，但不增强谷氨酸受体激动剂诱导的惊厥强度。通过测量小鼠脑中氨基氧乙酸诱导的GABA积累估计的GABA周转率被环孢霉素（50 mg/kg，腹腔注射）显著抑制。将培养的大鼠小脑颗粒细胞暴露于1 μ M环孢霉素24小时后，与完整颗粒细胞结合的特异性[^3H]蝇蕈醇（10 nM）降低至溶剂的53%。这些结果表明，环孢素抑制GABA能神经活动和GABA_A受体的结合特性。环孢霉素诱导的GABA系统抑制可能参与了多巴胺能神经元的激活.这些事件与环孢霉素治疗期间发生的不良中枢反应（包括震颤和惊厥）密切相关。-

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. -