Activation of α7-nAChRs protects SH-SY5Y cells from 1-methyl-4-phenylpyridinium-induced apoptotic cell death via ERK/p53 signaling pathway
Activation of α7-nAChRs protects SH-SY5Y cells from 1-methyl-4-phenylpyridinium-induced apoptotic cell death via ERK/p53 signaling pathway
复制标题
α7-nAChR 的激活通过 ERK/p53 信号通路保护 SH-SY5Y 细胞免受 1-甲基-4-苯基吡啶鎓诱导的细胞凋亡
DOI：
10.1002/jcp.28484
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发表时间：
2019-10-01
影响因子：
5.6
通讯作者：
Zhang, Guangdong
中科院分区：
文献类型：
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作者：
Xu, Shi;Yang, Beibei;Zhang, Guangdong
流行病学研究表明，吸烟者患帕金森病 (PD) 的风险降低。尼古丁作为烟草产品的关键成分，被认为是吸烟神经保护作用的可能候选者。 α7 烟碱乙酰胆碱受体（α7-nAChR）是哺乳动物大脑中最丰富的 nAChR 之一。尽管尼古丁被认为是通过作用于烟碱受体（包括 α7-nAChR）来发挥这种保护作用； α7-nAChR 防止多巴胺能神经元丢失的机制非常复杂。使用尼古丁和选择性 α 7-nAChR 激动剂 PNU-282987，我们首先证实将它们添加到接受 1-甲基-4-苯基吡啶鎓 (MPP+) 攻击的 SH-SY5Y 细胞中可以提供神经保护并导致细胞凋亡减少。然后，我们发现尼古丁和 PNU-282987 预处理通过激活 α7-nAChRs/MAPK/p53 轴显示出神经保护性抗凋亡作用。此外，我们使用 RNA 干扰来沉默 SH-SY5Y 细胞中 α 7-nAChR 的表达，发现抑制 α 7-nAChR 表达会减弱尼古丁和 PNU-282987 的抗凋亡作用，而不是 MPP+ 的毒性作用。此外，敲低α7-nAChR只能降低尼古丁和PNU-282987对磷酸化细胞外信号调节激酶（ERK）的抑制作用，而不能降低c-Jun氨基末端激酶和p38的抑制作用。因此，我们的研究结果表明 ERK/MAPK 信号传导在 α 7-nAChR 的神经保护作用中发挥重要作用，并表明 α 7-nAChR 激动剂可能被验证为 PD 的新型治疗方法。
Epidemiologic studies have shown a reduced risk of developing Parkinson's disease (PD) among cigarette smokers. Nicotine, as a key component in tobacco products, is thought as a possible candidate for action of smoking in neuroprotection. alpha 7 nicotinic acetylcholine receptors (alpha 7-nAChRs) is one of the most abundant nAChRs in the mammalian brain. Although nicotine is thought to exert this protective action by acting on nicotinic receptors, including the alpha 7-nAChRs; the mechanisms underlying how alpha 7-nAChRs protect against dopaminergic neuron loss are highly complex. Using nicotine and a selective alpha 7-nAChR agonist PNU-282987, we first confirmed that their addition to SH-SY5Y cells challenged with 1-methyl-4-phenylpyridinium (MPP+) could afford neuroprotection and result in a reduction in apoptotic cell death. Then, we found that the pretreatment with nicotine and PNU-282987 showed the neuroprotective antiapoptotic effects via activating the alpha 7-nAChRs/MAPK/p53 axis. Furthermore, we used RNA interference to silence the expression of alpha 7-nAChRs in SH-SY5Y cells and found that suppressing alpha 7-nAChR expression diminished the antiapoptotic effects of nicotine and PNU-282987, not the toxic effects of MPP+. Moreover, alpha 7-nAChR knockdown could only decrease the inhibitory effects of nicotine and PNU-282987 on the phosphorylated extracellular signal-regulated kinase (ERK), not c-Jun amino-terminal kinase and p38. Therefore, our findings indicate the important roles of ERK/MAPK signaling in the neuroprotective effects of alpha 7-nAChRs and suggest that alpha 7-nAChR agonists may be validated as novel treatments for PD.