Parkinson's disease (PD) is the second most common neurodegenerative disorder, characterized by the loss of dopaminergic neurons in the substantia nigra and the deposition of Lewy bodies. Mitochondrial dysfunction, oxidative stress, and autophagy dysfunction are involved in the pathogenesis of PD. Ghrelin is a brain-gut peptide that has been reported that protected against 1-methyl-4-phenyl-1,2,3,6- tetrahydropyran (MPTP)/MPP⁺-induced toxic effects. In the present work, human neuroblastoma SH-SY5Y cells were exposed to rotenone as a PD model to explore the underlying mechanism of ghrelin. We found that ghrelin inhibited rotenone-induced cytotoxicity, mitochondrial dysfunction, and apoptosis by improving cell viability, increasing the ratio of red/green of JC-1, inhibiting the production of reactive oxidative species (ROS), and regulating Bcl-2, Bax, Cytochrome c, caspase-9, and caspase-3 expression. Besides, ghrelin promoted mitophagy accompanied by up-regulating microtubule-associated protein 1 Light Chain 3B-II/I(LC3B-II/I) and Beclin1 but decreasing the expression of p62. Moreover, ghrelin promoted PINK1/Parkin mitochondrial translocation. Additionally, we investigated that ghrelin activated the AMPK/SIRT1/PGC1α pathway and pharmacological inhibition of AMPK and SIRT1 abolished the cytoprotection of ghrelin, decreased the level of mitophagy, and PINK1/Parkin mitochondrial translocation. Taken together, our findings suggested that mitophagy and AMPK/SIRT1/PGC1α pathways were related to the cytoprotection of ghrelin. These findings provided novel insights into the underlying mechanisms of ghrelin, further mechanistic studies on preclinical and clinical levels are required to be conducted with ghrelin to avail and foresee it as a potential agent in the treatment and management of PD.

帕金森病 (PD) 是第二种最常见的神经退行性疾病，其特征是黑质中多巴胺能神经元的丧失和路易小体的沉积。线粒体功能障碍、氧化应激和自噬功能障碍参与了PD的发病机制。Ghrelin 是一种脑肠肽，据报道可抵御 1-methyl-4-phenyl-1,2,3,6-四氢吡喃 (MPTP)/MPP ⁺- 引起的毒性作用。在目前的工作中，人类神经母细胞瘤 SH-SY5Y 细胞暴露于鱼藤酮作为 PD 模型，以探索生长素释放肽的潜在机制。我们发现，ghrelin 通过提高细胞活力、增加 JC-1 的红/绿比、抑制活性氧化物质 (ROS) 的产生以及调节 Bcl-2、Bax 来抑制鱼藤酮诱导的细胞毒性、线粒体功能障碍和细胞凋亡。 , 细胞色素c、caspase-9 和 caspase-3 表达。此外，ghrelin 促进线粒体自噬，同时上调微管相关蛋白 1 轻链 3B-II/I(LC3B-II/I) 和 Beclin1，但降低 p62 的表达。此外，ghrelin 促进 PINK1/Parkin 线粒体易位。此外，我们研究了 ghrelin 激活了 AMPK/SIRT1/PGC1α 通路，对 AMPK 和 SIRT1 的药理学抑制会消除 ghrelin 的细胞保护作用，降低线粒体自噬水平和 PINK1/Parkin 线粒体易位。总之，我们的研究结果表明线粒体自噬和 AMPK/SIRT1/PGC1α 通路与 ghrelin 的细胞保护作用有关。这些发现为了解 ghrelin 的潜在机制提供了新的见解，