P7C3 inhibits GSK3β activation to protect dopaminergic neurons against neurotoxin-induced cell death in vitro and in vivo.
P7C3 inhibits GSK3β activation to protect dopaminergic neurons against neurotoxin-induced cell death in vitro and in vivo.
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P7C3 抑制 GSK3 β 激活，以保护多巴胺能神经元免受神经毒素诱导的体外和体内细胞死亡
DOI：
10.1038/cddis.2017.250
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发表时间：
2017-06-01
影响因子：
9
通讯作者：
Wang G
中科院分区：
文献类型：
--
作者：
Gu C;Zhang Y;Hu Q;Wu J;Ren H;Liu CF;Wang G
帕金森病（Parkinson's disease，PD）是第二大神经退行性疾病。虽然其发病机制尚不清楚，但线粒体功能障碍在PD的病理学中起着至关重要的作用。P7 C3是一种氨丙基咔唑，在包括PD在内的几种神经退行性疾病中具有显著的神经保护能力。在这里，我们表明，P7 C3稳定线粒体膜电位，减少活性氧的产生，并抑制细胞色素c释放的MES 23.5细胞（多巴胺（DA）细胞系）暴露于1-甲基-4-苯基吡啶（MPP+）。在MES 23.5细胞中，P7 C3抑制MPP+诱导的糖原合成酶激酶3 β（GSK 3 β）活化。P7 C3还抑制p53活性并抑制Bax上调以保护细胞免受MPP+毒性。此外，P7 C3对GSK 3 β活性的抑制可显著减弱p53的激活。此外，P7 C3阻断中脑中的GSK 3 β和p53活化，并防止1-甲基-4-苯基-1，2，3，4-四氢吡啶小鼠黑质中DA神经元的丢失。因此，我们的研究表明P7 C3通过抑制GSK 3 β-p53-Bax通路保护DA神经元免受神经毒素诱导的细胞死亡，从而为P7 C3在PD的潜在临床治疗提供了理论基础。
Parkinson’s disease (PD) is the second most prevalent neurodegenerative disease. Although its pathogenesis remains unclear, mitochondrial dysfunction plays a vital role in the pathology of PD. P7C3, an aminopropyl carbazole, possesses a significant neuroprotective ability in several neurodegenerative disorders, including PD. Here, we showed that P7C3 stabilized mitochondrial membrane potential, reduced reactive oxygen species production, and inhibited cytochrome c release in MES23.5 cells (a dopaminergic (DA) cell line) exposed to 1-methyl-4-phenylpyridinium (MPP+). In MES23.5 cells, P7C3 inhibited glycogen synthase kinase-3 beta (GSK3β) activation induced by MPP+. P7C3 also inhibited p53 activity and repressed Bax upregulation to protect cells from MPP+ toxicity. In addition, the activation of p53 was significantly attenuated with the inhibition of GSK3β activity by P7C3. Furthermore, P7C3 blocked GSK3β and p53 activation in the midbrain, and prevented DA neuronal loss in the substantia nigra in 1-methyl-4-phenyl-1,2,3,4-tetrahydropyridine mice. Thus, our study demonstrates that P7C3 protects DA neurons from neurotoxin-induced cell death by repressing the GSK3β-p53-Bax pathway both in vitro and in vivo, thus providing a theoretical basis for P7C3 in the potential clinical treatment of PD.
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影响因子：
14.9
作者：
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