中国神经再生研究(英文版)

中国神经再生研究(英文版) ›› 2023, Vol. 18 ›› Issue (4): 849-855.doi: 10.4103/1673-5374.353495

• 原著:脑损伤修复保护与再生 • 上一篇    下一篇

亲环素D诱导的线粒体损伤可造成小鼠脑出血后轴突损伤

  

  • 出版日期:2023-04-15 发布日期:2022-10-29
  • 基金资助:
    国家自然科学基金项目（81901267，82001263，81901193）；创伤、烧伤与复合损伤国家重点实验室项目（SKLYQ202002）；无锡市卫健委项目（2020ZHYB19）；无锡市科技局项目（Y20212045）

Cyclophilin D-induced mitochondrial impairment confers axonal injury after intracerebral hemorrhage in mice

Yang Yang1, 2, 3, 4, #, Kai-Yuan Zhang2, 3, 5, #, Xue-Zhu Chen2, 3, #, Chuan-Yan Yang2, 3, Ju Wang2, 3, Xue-Jiao Lei2, 3, Yu-Lian Quan2, 3, Wei-Xiang Chen2, 3, 5, Heng-Li Zhao6, Li-Kun Yang1, Yu-Hai Wang1, 4, *, Yu-Jie Chen2, 3, *, Hua Feng2, 3#br#   

  1. 1Department of Neurosurgery, The 904th Hospital of PLA, Anhui Medical University, Wuxi, Jiangsu Province, China;  2Department of Neurosurgery and State Key Laboratory of Trauma, Burn and Combined Injury, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China;  3Chongqing Key Laboratory of Precision Neuromedicine and Neuroregenaration, Third Military Medical University (Army Medical University), Chongqing, China;  4Wuxi Translational Medicine Center, Wuxi, Jiangsu Province, China;  5Department of Neurosurgery, General Hospital of Xinjiang Military Command of PLA, Urumqi, Xinjiang Uygur Autonomous Region, China;  6Department of Neurology, The Second Medical Center & National Clinical Research Center for Geriatric Diseases, Chinese PLA General Hospital, Beijing, China
  • Online:2023-04-15 Published:2022-10-29
  • Contact: Yu-Jie Chen, MD, PhD, yujiechen6886@foxmail.com or chenyj@tmmu.edu.cn; Yu-Hai Wang, MD, PhD, wangyuhai67@126.com.
  • Supported by:
    This work was supported by the National Natural Science Foundation of China, Nos. 81901267 (to YY), 82001263 (to WXC), 81901193 (to HLZ); a grant from State Key Laboratory of Trauma, Burn and Combined Injury, No. SKLYQ202002 (to YJC); a grant from Wuxi Municipal Health Commission No. 2020ZHYB19 (to YY); and a grant from Wuxi Science and Technology Bureau, No. Y20212045 (to LKY). 

PDF

107

摘要：

线粒体通透性转换孔是一种非特异性跨膜通道，既往有研究发现，抑制mPTP开放可缓解线粒体肿胀、钙超载和轴突变性，而亲环素D是线粒体通透性转换孔的重要组成部分，亲环素D是否能参与脑出血损伤尚不可知。实验以一种锥体神经元及轴突表达黄色荧光的Thy1-YFP小鼠为研究对象，将自体血和氧合血红蛋白注射到纹状体建立了脑出血体内模型，并以氧合血红蛋白诱导的PC12细胞在体外模拟脑出血。结果发现脑出血后早期轴突的变性取决于亲环素D激活和线粒体通透性转换孔开放诱导的肿胀线粒体的损伤。进一步在脑出血小鼠模型以及PC12细胞中检验亲环素D的作用机制，在损伤前以对亲环素D进行药物抑制（环孢菌素A）或遗传抑制（亲环素D短发夹RNA），均能减轻线粒体通透性转换孔开放和线粒体损伤。此外，亲环素D和线粒体通透性转换孔对线粒体的抑制还可保护皮质脊髓束的完整性，并减轻脑出血引起的运动功能障碍。实验结果表明，亲环素D是脑出血后轴突变性的关键递质。抑制亲环素D表达可保护线粒体的结构和功能，进一步改善脑出血后皮质脊髓束损伤及运动功能障碍，在动物实验层面上为预防脑出血后白质损伤后的轴突变性和随后的中枢神经疾病功能障碍提供了治疗靶点。

https://orcid.org/0000-0002-9905-9138 (Yu-Jie Chen); 

https://orcid.org/0000-0001-6472-5578 (Yang Yang) 

关键词: font-family:宋体, ">脑出血, 白质, 皮质脊髓束, 轴突损伤, 退缩小球, 线粒体损伤, 线粒体通透性转换孔, 亲环素font-family:Calibri, sans-serif, "> Dfont-family:宋体, ">, 环孢素font-family:Calibri, sans-serif, ">Afont-family:宋体, ">, 运动功能

Abstract: The mitochondrial permeability transition pore is a nonspecific transmembrane channel. Inhibition of mitochondrial permeability transition pore opening has been shown to alleviate mitochondrial swelling, calcium overload, and axonal degeneration. Cyclophilin D is an important component of the mitochondrial permeability transition pore. Whether cyclophilin D participates in mitochondrial impairment and axonal injury after intracerebral hemorrhage is not clear. In this study, we established mouse models of intracerebral hemorrhage in vivo by injection of autologous blood and oxyhemoglobin into the striatum in Thy1-YFP mice, in which pyramidal neurons and axons express yellow fluorescent protein. We also simulated intracerebral hemorrhage in vitro in PC12 cells using oxyhemoglobin. We found that axonal degeneration in the early stage of intracerebral hemorrhage depended on mitochondrial swelling induced by cyclophilin D activation and mitochondrial permeability transition pore opening. We further investigated the mechanism underlying the role of cyclophilin D in mouse models and PC12 cell models of intracerebral hemorrhage. We found that both cyclosporin A inhibition and short hairpin RNA interference of cyclophilin D reduced mitochondrial permeability transition pore opening and mitochondrial injury. In addition, inhibition of cyclophilin D and mitochondrial permeability transition pore opening protected corticospinal tract integrity and alleviated motor dysfunction caused by intracerebral hemorrhage. Our findings suggest that cyclophilin D is used as a key mediator of axonal degeneration after intracerebral hemorrhage; inhibition of cyclophilin D expression can protect mitochondrial structure and function and further alleviate corticospinal tract injury and motor dysfunction after intracerebral hemorrhage. Our findings provide a therapeutic target for preventing axonal degeneration of white matter injury and subsequent functional impairment in central nervous diseases.

Key words: axonal injury, corticospinal tract, cyclophilin D, cyclosporin A, intracerebral hemorrhage, mitochondrial impairment, mitochondrial permeability transition pore, motor dysfunction, retraction bulb, white matter