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Ghrelin protects dopaminergic neurons against MPTP neurotoxicity through promoting autophagy and inhibiting endoplasmic reticulum mediated apoptosis.
Brain Research ( IF 2.9 ) Pub Date : 2020-07-22 , DOI: 10.1016/j.brainres.2020.147023
Huiqing Wang 1 , Shanshan Dou 2 , Junge Zhu 1 , Ziqi Shao 1 , Chunmei Wang 2 , Baohua Cheng 2
Affiliation  

Parkinson's disease (PD) is the second most common progressive neurodegenerative disorder, the important pathology of PD due to the prominent loss of the dopaminergic neurodegeneration in the substantia nigra pars compacta (SNpc) and striatum (STR). Although the etiology of PD is not fully understood, aggregation of α-synuclein, impaired autophagy, and endoplasmic reticulum stress (ERS) are involved in the pathogenesis of PD. Previously it has been demonstrated that Ghrelin is a kind of peptide protected dopaminergic neurons against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyran (MPTP)-induced neurotoxicity, but the detailed mechanism remains to be elucidated. In the present work, we investigated the effects of Ghrelin on autophagy and ERS-mediated apoptosis in the MPTP-lesioned PD mice model. We found that Ghrelin was neuroprotective against MPTP-induced dopaminergic neurodegeneration. Subsequently, we investigated Ghrelin inhibited the accumulation and phosphorylation of α-synuclein induced by MPTP. Moreover, Ghrelin promoted autophagy indicated by the up-regulation of microtubule-associated protein 1 Light Chain 3B-II/I (LC3B-II/I) and Beclin1, as well as decreasing the level of p62 in the SNpc and STR. Besides, the activation of the ERS-related apoptosis signaling pathway including IRE1α and Caspase-12 signaling pathway induced by MPTP was suppressed by Ghrelin treatment. Furthermore, Ghrelin also decreased Caspase-3 expression. Taken together, our results indicated that Ghrelin may exert neuroprotective effects via regulating α-synuclein activities, enhancing autophagy, and ameliorating ERS-mediated apoptosis in MPTP-lesioned mice, which provides a new target for potential pharmacologic interventions of PD treatment in the future.



中文翻译:

Ghrelin 通过促进自噬和抑制内质网介导的细胞凋亡来保护多巴胺能神经元免受 MPTP 神经毒性。

帕金森病 (PD) 是第二种最常见的进行性神经退行性疾病,是 PD 的重要病理学,由于黑质致密部 (SN pc) 和纹状体 (STR)。虽然 PD 的病因尚不完全清楚,但 α-突触核蛋白的聚集、自噬受损和内质网应激 (ERS) 参与了 PD 的发病机制。先前已证明 Ghrelin 是一种肽保护的多巴胺能神经元,可抵抗 1-methyl-4-phenyl-1,2,3,6-tetrahydropyran (MPTP) 诱导的神经毒性,但详细机制仍有待阐明。在目前的工作中,我们研究了 Ghrelin 对 MPTP 损伤的 PD 小鼠模型中自噬和 ERS ​​介导的细胞凋亡的影响。我们发现 Ghrelin 对 MPTP 诱导的多巴胺能神经变性具有神经保护作用。随后,我们研究了 Ghrelin 抑制 MPTP 诱导的 α-突触核蛋白的积累和磷酸化。而且,电脑和STR。此外,Ghrelin 处理抑制了 MPTP 诱导的 ERS ​​相关凋亡信号通路包括 IRE1α 和 Caspase-12 信号通路的激活。此外,Ghrelin 还降低了 Caspase-3 的表达。总之,我们的结果表明,Ghrelin 可能通过调节 α-突触核蛋白活性、增强自噬和改善 MPTP 损伤小鼠的 ERS ​​介导的细胞凋亡发挥神经保护作用,这为未来 PD 治疗的潜在药物干预提供了新的靶点。

更新日期:2020-07-28
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