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首页> 外文期刊>The European Journal of Neuroscience >Immunophilin ligands can prevent progressive dopaminergic degeneration in animal models of Parkinson's disease.
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Immunophilin ligands can prevent progressive dopaminergic degeneration in animal models of Parkinson's disease.

机译：免疫亲和素配体可以预防帕金森氏病动物模型中的进行性多巴胺能变性。

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Slowing or halting the progressive dopaminergic (DA) degeneration in Parkinson's disease (PD) would delay the onset and development of motor symptoms, prolong the efficacy of pharmacotherapies and decrease drug-induced side-effects. We tested the potential of two orally administered novel immunophilin ligands to protect against DA degeneration in two animal models of PD. First, in an MPTP (N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) mouse model, we compared an immunophilin ligand (V-10,367) documented to bind the immunophilin FKBP12 with V-13,661, which does not bind FKBP12. Both molecules could prevent the loss of striatal DA innervation in a dose-dependent fashion during 10 days of oral administration. Second, to determine whether an immunophilin ligand can protect against progressive and slow DA degeneration typical of PD, an intrastriatal 6-hydroxydopamine-infusion rat model was utilized. Oral treatment with the FKBP12-binding immunophilin ligand began on the day of lesion and continued for 21 days. At this time point, post mortem analyses revealed that the treatment had prevented the progressive loss of DA innervation within the striatum and loss of DA neurons within the substantia nigra, related to functional outcome as measured by rotational behaviour. Notably, DA fibres extending into the area of striatal DA denervation were observed only in rats treated with the immunophilin ligand, indicating neuroprotection or sprouting of spared DA fibres. This is the first demonstration that immunophilin ligands can prevent a slow and progressive DA axonal degeneration and neuronal death in vivo. The effects of orally administered structurally related immunophilin ligands in acute and progressive models of DA degeneration are consistent with the idea that these compounds may have therapeutic value in PD.
机译：减慢或停止帕金森氏病（PD）中进行性多巴胺能（DA）的退化将延缓运动症状的发作和发展，延长药物治疗的效力并减少药物引起的副作用。我们在两种PD动物模型中测试了两种口服新型免疫亲和素配体预防DA变性的潜力。首先，在MPTP（N-甲基-4-苯基-1,2,3,6-四氢吡啶）小鼠模型中，我们比较了已证明与亲免疫素FKBP12结合的亲免疫素配体（V-10,367）与V-13,661，不绑定FKBP12。两种分子都可以在口服10天之内以剂量依赖的方式防止纹状体DA神经支配的丧失。其次，为了确定亲免素配体是否可以预防典型的PD进行性和缓慢的DA变性，采用了纹状体内6-羟基多巴胺输注大鼠模型。 FKBP12结合亲和素配体的口服治疗从病变当天开始，持续21天。在这个时间点，验尸分析显示，该治疗已防止了纹状体内DA神经支配的进行性丧失和黑质中DA神经元的丧失，这与通过旋转行为测量的功能结果有关。值得注意的是，仅在用亲免蛋白配体处理的大鼠中观察到延伸到纹状体DA去神经区域的DA纤维，表明神经保护或多余的DA纤维发芽。这是免疫亲和素配体可以在体内预防缓慢和进行性DA轴突变性和神经元死亡的第一个证明。口服给药的结构相关亲免素配体在急性和进行性DA退化模型中的作用与这些化合物可能在PD中具有治疗价值的想法是一致的。

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