Activation of α7 Nicotinic Acetylcholine Receptor Protects Against 1-Methyl-4-Phenylpyridinium-Induced Astroglial Apoptosis
Activation of α7 Nicotinic Acetylcholine Receptor Protects Against 1-Methyl-4-Phenylpyridinium-Induced Astroglial Apoptosis
复制标题
α7 烟碱乙酰胆碱受体的激活可防止 1-甲基-4-苯基吡啶鎓诱导的星形胶质细胞凋亡
DOI：
10.3389/fncel.2019.00507
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发表时间：
2019-11-12
影响因子：
5.3
通讯作者：
Fan, Yi
中科院分区：
文献类型：
--
作者：
Hua, Ye;Yang, Beibei;Fan, Yi
星形胶质细胞是最大的胶质细胞亚型，在正常脑功能和帕金森病（PD）等病理状况中起着至关重要的作用。恢复星形胶质细胞的功能是治疗帕金森病的一个有前景的新靶点。星形胶质细胞可表达多种类型的神经递质受体，包括功能性α - 7烟碱乙酰胆碱受体（α - 7nAChR）。先前，我们发现非选择性α 7nAChR激动剂尼古丁通过α 7nAChR依赖途径对h2o2诱导的星形胶质细胞凋亡具有保护作用。然而，星形胶质α - 7nAChR抗凋亡反应的分子机制尚未被研究。在本研究中，我们通过药理抑制和基因敲除α 7nAChR，评估α 7nAChR激动剂PNU-282987对1-甲基-4-苯基吡啶（MPP+）处理的原代培养星形细胞的抗凋亡作用。PNU-282987能提高星形胶质细胞活力，减轻MPP+诱导的细胞凋亡，减少GFAP(+)/TUNEL+细胞数量。PNU-282987上调抗凋亡蛋白Bcl-2的表达，下调凋亡蛋白Bax和cleaved-caspase-3的表达。此外，PNU-282987对JNK-p53-caspase-3信号的抑制可能是其神经保护作用的基础。因此，PNU-282987通过α - 7nAChR-JNK-p53信号通路改善MPP+诱导的星形胶质细胞凋亡。我们的研究结果提示PNU-282987可能是一种潜在的恢复PD治疗星形胶质细胞功能的药物。
Astrocytes, as the largest population of glial subtype, play crucial roles in normal brain function and pathological conditions, such as Parkinson's disease (PD). Restoring the functions of astrocyte is a promising new therapeutic target for PD. Astrocytes can express multiple types of neurotransmitter receptors, including functional alpha 7 nicotinic acetylcholine receptor (alpha 7nAChR). Previously, we found that a non-selective alpha 7nAChR agonist nicotine exerted a protective effect against H2O2-induced astrocyte apoptosis via an alpha 7nAChR-dependent pathway. However, the molecular mechanism of the antiapoptotic response of astroglial alpha 7nAChR has not been studied. In the present study, using pharmacological inhibition and genetic knockout of alpha 7nAChR, we assessed the antiapoptotic effects of an alpha 7nAChR agonist PNU-282987 in primary cultured astrocytes treated with 1-methyl-4-phenylpyridinium (MPP+). PNU-282987 promoted the viability of astrocytes, alleviated MPP+ induced apoptosis, and decreased the number of GFAP(+)/TUNEL+ cells. Meanwhile, PNU-282987 upregulated the expression of the antiapoptotic protein Bcl-2 and downregulated the expression of the apoptotic protein Bax and cleaved-caspase-3. Moreover, the suppression of the JNK-p53-caspase-3 signaling may underlie the neuroprotective property of PNU-282987. Therefore, PNU-282987 ameliorates astroglial apoptosis induced by MPP+ through alpha 7nAChR-JNK-p53 signaling. Our findings suggest that PNU-282987 may be a potential drug for restoring astroglial functions in the treatment of PD.