Immunosuppressants neurotoxicity : The mechanism of immunosuppressants-induced neurotoxicity and the prediction of its risk with gene polymorphisms.

环孢素A（CsA）和他克莫司（TCL）作为一种有效的免疫抑制剂被广泛应用于实体器官移植中预防同种异体移植排斥反应和治疗各种自身免疫性疾病，包括类风湿性关节炎。尽管这些免疫抑制剂的疗效很高，但它们也有副作用，包括肾功能障碍、心血管疾病、胃肠道疾病和神经系统并发症。这些事件在器官移植患者中发生的频率相对较高（20-40%）。脑微血管内皮细胞的紧密连接和p -糖蛋白（P-gp）（一种多药外排泵）阻止了CsA和TCL进入脑。但CsA和TCL的神经系统不良反应，包括震颤、癫痫发作和脑病，强烈提示CsA和TCL可能通过血脑屏障（BBB）转运。本研究的目的是阐明免疫抑制剂诱导神经毒性的机制，并预测其毒性。发现多药耐药1基因（ABCB1）突变与神经毒性事件之间存在潜在的正相关。ABCB1基因21外显子2677位突变可能是预测tcl诱导的神经毒性的有用探针。血脑屏障是由内皮细胞、脑周细胞和星形胶质细胞组成的高度组织的多细胞复合体。脑周细胞和星形胶质细胞诱导和维持血脑屏障功能。周细胞和星形胶质细胞的存在显著加重了csa诱导的脑微血管内皮细胞的高通透性和P-gp功能障碍。这种恶化似乎是由于脑周细胞中转化生长因子-□（TGF-□）的产生受到抑制，星形胶质细胞中NO的产生增加。光照期给药后大鼠震颤持续时间明显高于暗期给药。这一发现表明，在昼夜周期的活跃阶段给药可以改善TCL神经毒性。我们初步认为，ABCB1基因多态性和脑内TGF-β生成抑制和/或NO生成增强的病理状态可能是免疫抑制剂诱导神经毒性的危险因素。少

Cyclosporin A(CsA) and tacrolimus(TCL), are widely used as a potent immunosuppressant to prevent allograft rejection in solid organ transplantation and to treat various autoimmune diseases including rheumatoid arthritis. Despite its high efficacy, theses immunosuppressants have adverse effects including renal dysfunction, cardiovascular disorders, gastrointestinal disorders and neurological complications. These events occur with a relatively high frequency (20-40%) in organ-transplanted patients. The entry of CsA and TCL into the brain is prevented by the tight junctions and P-glycoprotein(P-gp), a multi-drug efflux pump, of the brain microvascular endothelial cells. But the adverse neurolocical effects of CsA and TCL, including tremors, seizures and encephalopathy, strongly suggest the possibility of CsA and TCL transport across the blood-brain barrier(BBB). The objective of this study is to clarify the mechanism of immunosuppressants-induced neurotoxicity and the prediction of its ri … More sk with gene polymorphisms.1.Potentially positive correlations between mutation in the multidrug resistant 1 gene(ABCB1) and neurotoxic events were detected. Mutation at position 2677 in exon 21 of ABCB1 gene may be an useful probe to predict TCL-induced neurotoxicity.2.The BBB is a highly organized multicellular complex consisting of an endothelium, brain pericytes and astrocytes. Brain pericyte and astrocyte induce and maintain BBB function. The presence of pericytes and astrocytes markedly aggravated CsA-induced hyperpermeability and P-gp dysfunction in brain microvascular endothelial cells. This aggravation appears to occur due to the inhibition of transforming growth factor- □(TGF-□) production in brain pericytes and the enhancement of NO production in astrocytes.3.The administration of TCL in the light phase produced a significantly greater increase than that in the dark phase in the duration of harmine-induced tremors in rats. This finding suggests that TCL neurotoxicity may be ameliorated by administration in the active phase of the diurnal cycle.We tentatively conclude that the polymorphism in the ABCB1 gene and the pathological conditions accompanied with the inhibition of TGF-β production and/or the enhancement of NO production in the brain are included in the risk factors for immunosuppressants-induced neurotoxicity. Less