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首页> 外文期刊>Current drug targets. CNS and neurological disorders >FK506 and its analogs - therapeutic potential for neurological disorders.
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FK506 and its analogs - therapeutic potential for neurological disorders.

机译：FK506及其类似物-神经系统疾病的治疗潜力。

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Immunophilin ligands such as FK506 and Cyclosporin A, used in immunosuppression, are well-characterized drugs. In the past, they had been the center of attention as a putative therapeutic strategy for neuroregeneration and neuroprotection. In contrast to Cyclosporin A, FK506 readily crosses the brain-blood-barrier and, thus together with its derivatives, may represent a novel approach to the treatment of neurological disorders. FK506 exerts profound neuroprotective and neuroregenerative effects in vivo and in vitro. The mechanism underlying neuroregeneration is fairly well understood. It is independent of the inhibition of calcineurin, which is responsible for the immunosuppression, but operates via the binding of FKBP52 and the heat shock protein (Hsp) 90. In contrast, the underlying pathways of neuroprotection are far less understood. Protection is apparently independent of calcineurin, as shown by non-calcineurin inhibiting derivatives, such as V-10,367 and GPI-1046, but the intracellular actions remain to be defined. FK506 has been shown to interfere with the apoptotic pathway of neuronal cells, including inhibiting JNK activity, cytochrome c release, caspase 3 activation, and CD95 ligand expression. These effects are in part mediated by the inhibition of calcineurin and may not contribute to protection. Our recent studies suggest that the protective properties of FK506 and its non-calcineurin inhibiting derivatives are realized by a fast induction of heat shock proteins. The induction of the heat shock response by immunophilin ligands might prove to be an interesting target for neuroregeneration and neuroprotection.
机译：免疫抑制中使用的免疫亲和素配体（例如FK506和环孢菌素A）是特征明确的药物。过去，它们作为神经再生和神经保护的推定治疗策略已成为关注的焦点。与环孢菌素A相反，FK506可以轻松穿越脑血屏障，因此，与其衍生物一起，可能代表了一种治疗神经系统疾病的新方法。 FK506在体内和体外发挥着深远的神经保护和神经再生作用。神经再生的基本机制已广为人知。它独立于钙调神经磷酸酶的抑制，钙调神经磷酸酶负责免疫抑制，但通过FKBP52和热休克蛋白（Hsp）90的结合起作用。相反，神经保护的基本途径尚不清楚。保护作用显然独立于钙调神经磷酸酶，如非钙调神经磷酸酶抑制衍生物如V-10,367和GPI-1046所示，但细胞内作用仍有待确定。已显示FK506干扰神经元细胞的凋亡途径，包括抑制JNK活性，细胞色素c释放，胱天蛋白酶3活化和CD95配体表达。这些作用部分是由钙调神经磷酸酶的抑制介导的，可能无助于保护。我们最近的研究表明，FK506及其非钙化神经磷酸酶抑制衍生物的保护特性是通过快速诱导热休克蛋白来实现的。亲免蛋白配体诱导的热休克反应可能被证明是神经再生和神经保护的有趣目标。

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