Li Baolong, Zhang Zhe, Wang Hui, Zhang Dupiao, Han Tao, Chen Hongyu, Chen Jianpeng, Chen Zhengtai, Xie Yutong, Wang Liang, Bsoul Najeeb, Zhou Xijie, Yan Hede
Department of Orthopedics (Division of Hand and Microsurgery), The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang Province, China; Zhejiang Key Laboratory of structural malformations in children, Wenzhou, 325000, Zhejiang Province, China; Zhejiang Provincial Key Laboratory of Orthopaedics, Wenzhou, 325000, Zhejiang Province, China.
Department of Orthopedics (Division of Hand and Microsurgery), The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang Province, China; Zhejiang Key Laboratory of structural malformations in children, Wenzhou, 325000, Zhejiang Province, China; Zhejiang Provincial Key Laboratory of Orthopaedics, Wenzhou, 325000, Zhejiang Province, China.
Free Radic Biol Med. 2022 May 20;185:52-66. doi: 10.1016/j.freeradbiomed.2022.04.016. Epub 2022 Apr 30.
Schwann cells (SCs) are the major glial cells in peripheral nervous system. They unsheathe and myelinate axons and play an essential role in peripheral nerve regeneration. Several studies report that Parkin-mediated mitophagy is associated with various diseases. Melatonin promotes proliferation of central glial cells. Little is known about the effect of melatonin and Parkin-mediated mitophagy on peripheral nerve repair. In this study, using a rat model of a peripheral nerve injury (PNI) and in vitro model established by RSC96 cells treated with tert-butyl hydroperoxide (TBHP), we found that Parkin-mediated mitophagy can effectively reduce the production of mitochondrial reactive oxygen species (ROS), maintain the balance of mitochondrial membrane potential, maintain autophagic flux, and inhibit mitochondrial apoptosis. At the same time, we found that the increase of Parkin under stress is a manifestation of the RSC96 cells' resistance to oxidative stress to maintain RSC96 cells' balance. In our experiment, melatonin is similar to a Parkin agonist, up-regulating the expression of Parkin, enhancing all the positive results of Parkin in a stress state, such as inhibiting active oxygen production, maintaining autophagic flux, and inhibiting mitochondrial apoptosis. In addition, we design in vivo experiments to verify in In vitro experiments. In in vivo, melatonin promotes the expression of Parkin, maintains autophagic flux, inhibits apoptosis, promotes myelin regeneration, reduces the regeneration of collagen fibers around damaged tissues, and promotes peripheral nerve repair. When adenovirus was used to down-regulate the expression of Parkin, we found that all the positive effects of melatonin were attenuated. Collectively, these findings indicate that melatonin upregulates Parkin-mediated mitophagy and promotes peripheral nerve repair. The results provide a basis for development of effective drugs for PNI treatment.
雪旺细胞（SCs）是周围神经系统中的主要神经胶质细胞。它们包裹轴突并形成髓鞘，在周围神经再生中发挥着至关重要的作用。多项研究报告称，帕金蛋白介导的线粒体自噬与多种疾病有关。褪黑素可促进中枢神经胶质细胞的增殖。关于褪黑素和帕金蛋白介导的线粒体自噬对周围神经修复的影响，目前知之甚少。在本研究中，我们使用周围神经损伤（PNI）大鼠模型以及用过氧化叔丁基（TBHP）处理的RSC96细胞建立的体外模型，发现帕金蛋白介导的线粒体自噬可有效减少线粒体活性氧（ROS）的产生，维持线粒体膜电位平衡，维持自噬通量，并抑制线粒体凋亡。同时，我们发现应激状态下帕金蛋白的增加是RSC96细胞抵抗氧化应激以维持RSC96细胞平衡的一种表现。在我们的实验中，褪黑素类似于帕金蛋白激动剂，上调帕金蛋白的表达，增强帕金蛋白在应激状态下的所有积极作用，如抑制活性氧产生、维持自噬通量和抑制线粒体凋亡。此外，我们设计了体内实验来验证体外实验结果。在体内，褪黑素促进帕金蛋白的表达，维持自噬通量，抑制细胞凋亡，促进髓鞘再生，减少受损组织周围胶原纤维的再生，并促进周围神经修复。当使用腺病毒下调帕金蛋白的表达时，我们发现褪黑素的所有积极作用均减弱。总的来说，这些发现表明褪黑素上调帕金蛋白介导的线粒体自噬并促进周围神经修复。这些结果为开发治疗PNI的有效药物提供了依据。
