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首页> 外文期刊>The European Journal of Neuroscience >Neuroimmunophilin ligands exert neuroregeneration and neuroprotection in midbrain dopaminergic neurons.
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Neuroimmunophilin ligands exert neuroregeneration and neuroprotection in midbrain dopaminergic neurons.

机译：神经免疫亲和素配体在中脑多巴胺能神经元中发挥神经再生和神经保护作用。

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Immunosuppressant drugs, like FK506, and nonimmunosuppressant compounds like, GPI1046 and L685818, are immunophilin ligands that specifically bind to immunophilins, like FK506 binding protein 12 (FKBP12). Several lines of evidence show that these ligands exert neurotrophic properties in neural injury models and in PC12 cells. However, the mechanism of the neurotrophic function of the immunophilin ligands is poorly known. In the present study, we use MPP+ and 6-OHDA toxicity models to examine both neuroprotective and neuroregenerative effects of immunophilin ligands on primary cultures of midbrain dopaminergic neurons. We find that FK506, GPI1046 and L685818 at concentrations from 0.01 to 1 &mgr;M partially, but significantly, protect dopaminergic neurons against both MPP+ and 6-OHDA toxicity. By Western blot analysis, we also find that all three compounds prevent tyrosine hydroxylase (TH) loss induced by MPP+ and 6-OHDA treatments. Morphologic analysis of dopaminergic neurons, by immunocytochemistry, shows that MPP+ and 6-OHDA cause the retraction and loss of neuronal processes, while FK506, GPI1046 and L685818 promote regeneration of these processes as indicated by increases in process number and length. To examine if FKBP12 is required for neurotrophic effects of immunophilin ligands, we cultured dopaminergic neurons from FKBP12 knockout mice and find that FK506 still protects dopaminergic neurons against MPP+ toxicity. These results suggest that FKBP12 is not essential for the neurotrophic properties of immunophilin ligands, and immunophilin ligands are a new class of neuroprotective and neuroregenerative agents that may have therapeutic potential in a variety of neurological disorders.
机译：免疫抑制剂药物（例如FK506）和非免疫抑制剂化合物（例如GPI1046和L685818）是特异性结合免疫球蛋白（例如FK506结合蛋白12（FKBP12））的免疫亲和素配体。几条证据表明，这些配体在神经损伤模型和PC12细胞中具有神经营养特性。但是，对亲免蛋白配体的神经营养功能的机制知之甚少。在本研究中，我们使用MPP +和6-OHDA毒性模型来检查免疫亲和素配体对中脑多巴胺能神经元原代培养物的神经保护和神经再生作用。我们发现浓度从0.01到1μM的FK506，GPI1046和L685818部分但显着地保护多巴胺能神经元免受MPP +和6-OHDA毒性。通过蛋白质印迹分析，我们还发现所有这三种化合物均可以防止MPP +和6-OHDA处理引起的酪氨酸羟化酶（TH）丢失。通过免疫细胞化学对多巴胺能神经元的形态学分析表明，MPP +和6-OHDA会引起神经元过程的退缩和丢失，而FK506，GPI1046和L685818则促进了这些过程的再生，如过程数量和长度的增加所表明。为了检查免疫亲和素配体的神经营养作用是否需要FKBP12，我们从FKBP12基因敲除小鼠中培养了多巴胺能神经元，发现FK506仍能保护多巴胺能神经元免受MPP +毒性。这些结果表明，FKBP12对于亲免蛋白配体的神经营养特性不是必不可少的，并且亲免蛋白配体是一类新型的神经保护剂和神经再生剂，可能在多种神经系统疾病中具有治疗潜力。

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