中国神经再生研究(英文版)

中国神经再生研究(英文版) ›› 2022, Vol. 17 ›› Issue (5): 1138-1145.doi: 10.4103/1673-5374.324854

• 原著:周围神经损伤修复保护与再生 • 上一篇    下一篇

血管紧张素-(1-7)改善帕金森病自噬功能障碍减轻α-突触核蛋白的聚集

  

  • 出版日期:2022-05-15 发布日期:2021-11-22

Angiotensin-(1–7) reduces α-synuclein aggregation by enhancing autophagic activity in Parkinson’s disease

Qing Gao, Rui Chen, Liang Wu, Qing Huang, Xi-Xi Wang, You-Yong Tian*, Ying-Dong Zhang*   

  1. Department of Neurology, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu Province, China
  • Online:2022-05-15 Published:2021-11-22
  • Contact: Ying-Dong Zhang, MD, PhD, zhangyingdong@aliyun.com; You-Yong Tian, PhD, tyy9956@163.com.
  • Supported by:
    Department of Neurology, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu Province, China

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摘要：

帕金森病的特征性病理改变之一是黑质中α-突触核蛋白异常聚集所致的路易小体的形成。近来研究发现，血管紧张素-(1-7)(Angiotensin-(1-7))在包括帕金森病在内的许多神经变性疾病中都发挥重要作用，但具体机制目前尚不明确。为此，试验设计对雄性SD大鼠腹腔注射鱼藤酮4周来制作帕金森的动物模型。同时，在大鼠右侧黑质连续注射Angiotensin-(1-7)共4周来观察其是否对帕金森病动物模型有神经保护作用。(1)结果发现Angiotensin-(1-7)可缓解帕金森病大鼠的帕金森病症状，同时减轻其黑质中α-突触核蛋白的聚集；(2)实验又从SD乳鼠黑质中提取原代多巴胺能神经元，经鱼藤酮、Angiotensin-(1-7)和(或)A-779处理24 h后发现，Angiotensin-(1-7)通过与Mas受体结合，减轻了鱼藤酮细胞模型中神经元的凋亡及α-突触核蛋白的聚集；(3)最后，利用鱼藤酮、Angiotensin-(1-7)和(或)3-甲基腺嘌呤处理原代多巴胺能神经元24 h发现，Angiotensin-(1-7)可通过改善鱼藤酮细胞模型的自噬障碍进而增加对α-突触核蛋白的清除；(4)以上结果可以揭示了，血管紧张素-(1-7)通过改善帕金森病的自噬功能障碍来减轻α-突触核蛋白的聚集，而血管紧张素-(1-7)/Mas受体轴在帕金森病发病过程中发挥重要作用，同时提示Angiotensin-(1-7)对帕金森病潜在的治疗价值。

https://orcid.org/0000-0002-6470-5064 (Ying-Dong Zhang); https://orcid.org/0000-0001-9338-4346 (You-Yong Tian)

关键词: α-突触核蛋白, 凋亡, 自噬, 多巴胺能神经元, 路易小体, 神经退行性疾病, 帕金森病, 肾素-血管紧张素系统, 鱼藤酮, 黑质

Abstract: Abnormal accumulation of α-synuclein contributes to the formation of Lewy bodies in the substantia nigra, which is considered the typical pathological hallmark of Parkinson’s disease. Recent research indicates that angiotensin-(1–7) plays a crucial role in several neurodegenerative disorders, including Parkinson’s disease, but the underlying mechanisms remain elusive. In this study, we used intraperitoneal administration of rotenone to male Sprague-Dawley rats for 4 weeks to establish a Parkinson’s disease model. We investigated whether angiotensin-(1–7) is neuroprotective in this model by continuous administration of angiotensin-(1–7) into the right substantia nigra for 4 weeks. We found that angiotensin-(1–7) infusion relieved characteristic parkinsonian behaviors and reduced α-synuclein aggregation in the substantia nigra. Primary dopaminergic neurons were extracted from newborn Sprague-Dawley rat substantia nigras and treated with rotenone, angiotensin-(1–7), and/or the Mas receptor blocker A-779 for 24 hours. After binding to the Mas receptor, angiotensin-(1–7) attenuated apoptosis and α-synuclein aggregation in rotenone-treated cells. Primary dopaminergic neurons were also treated with angiotensin-(1–7) and/or the autophagy inhibitor 3-methyladenine for 24 hours. Angiotensin-(1–7) increased α-synuclein removal and increased the autophagy of rotenone-treated cells. We conclude that angiotensin-(1–7) reduces α-synuclein aggregation by alleviating autophagy dysfunction in Parkinson’s disease. Therefore, the angiotensin-(1–7)/Mas receptor axis plays an important role in the pathogenesis of Parkinson’s disease and angiotensin-(1–7) has potential therapeutic value for Parkinson’s disease. All experiments were approved by the Biological Research Ethics Committee of Nanjing First Hospital (approval No. DWSY-2000932) in January 2020.

Key words: α-synuclein, apoptosis, autophagy, dopaminergic neuron, Lewy bodies, neurodegenerative diseases, Parkinson’s disease,
renin-angiotensin system, rotenone, substantia nigra

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