帕金森病中的低氧反应与适应  

Hypoxic Response and Adaptation in Parkinson's Disease

作　　者：丁昊慧 赵梦楠 高向东 陈松 DING Haohui;ZHAO Mengnan;GAO Xiangdong;CHEN Song(Jiangsu Key Laboratory of Druggability Biopharmaceuticals,School of Life Science and Technology,China Pharmaceutical University,Nanjing 211198 China)

机构地区：[1]中国药科大学生命科学与技术学院江苏省生物药物成药性研究重点实验室,江苏南京211198

出　　处：《药物生物技术》2024年第5期561-566,共6页Pharmaceutical Biotechnology

基　　金：国家自然科学基金项目(N0.82173728);大学生创新创业训练计划项目(No.202410316082Y)。

摘　　要：哺乳动物的大脑对能量的需求非常高,并且极度依赖氧气供应,因此非常容易受到缺氧的影响。帕金森病(Parkinson's disease,PD)是一种常见的神经退行性疾病,其病理特征主要表现为中脑黑质致密部多巴胺能神经元的退化以及路易小体的形成。PD可能的分子致病机制包括α-突触核蛋白的错误折叠与聚集、线粒体功能障碍、蛋白清除障碍、神经炎症和氧化应激等。其中,线粒体功能障碍在PD发病机制中起着关键作用,重度脑缺氧可能通过影响线粒体氧化磷酸化、氧化应激水平和多巴胺代谢加速PD的进程。然而,许多研究表明,短暂和重复的轻度或中度低氧可以诱导细胞和生理水平的适应,涉及包括HIFs和Nrf2在内的许多分子通路,提高抗炎抗氧化能力,从而提高神经元对缺氧缺血、线粒体功能障碍、氧化应激和蛋白质异常聚集的耐受和存活率。因此,低氧通路相关分子可以用于缓解缺氧缺血性损伤、线粒体损伤和蛋白质聚集病理的研究。文章就PD病理生理与低氧之间的联系、低氧适应及低氧适应主要分子反应进行综述,为神经保护药物研发的新思路提供理论依据。The mammalian brain had very high energy requirements and was extremely dependent on oxygen supply,it was therefore highly susceptible to hypoxia.Parkinson's disease(PD),a prevalent neurodegenerative disorder,was characterized primarily by the degeneration of dopaminergic neurons situated in the substantia nigra pars compacta of the midbrain,along with the formation of Lewy bodies.The potential molecular pathogenic mechanisms of PD primarily encompassed the misfolding and aggregation ofα-synuclein,mitochondrial dysfunction,protein clearance disorder,neuroinflammation,and oxidative stress.Notably,mitochondrial dysfunction played a crucial role in the pathogenesis of PD.Severe cerebral hypoxia had the potential to expedite the progression of PD by influen-cing mitochondrial oxidative phosphorylation,oxidative stress,and dopamine metabolism.However,numerous studies had demonstrated that intermittent mild or moderate hypoxia could elicit adaptive responses at both cellular and physiological levels,involving many molecular mediators including HIFs and Nrf2,and ultimately enhance the resistance to inflammation and oxidation.Thus,the tolerance and survival rate of neurons to hypoxia,ischemia,mitochondrial dysfunction,oxidative stress and possible proteotoxic stress could be improved,which indicates that related targets could be studied to relieve the development of hypoxic-ischemic injury,mito-chondrial damage and protein aggregation.The connection between the pathophysiology of PD and hypoxia,as well as hypoxia adapta-tion and its key molecules were reviewed,providing a theoretical foundation for novel ideas in the development of neuroprotective drugs.

关 键 词：低氧 帕金森病 线粒体 活性氧 低氧诱导因子 核因子红细胞系2相关因子2 

分 类 号：R741[医药卫生—神经病学与精神病学]