中国神经再生研究(英文版) ›› 2023, Vol. 18 ›› Issue (8): 1750-1756.doi: 10.4103/1673-5374.361531

• 原著:脑损伤修复保护与再生 • 上一篇    下一篇

抑制压电型机械敏感离子通道组件1可抑制脑出血后的脱髓鞘

  

  • 出版日期:2023-08-15 发布日期:2023-02-23
  • 基金资助:
    国家自然科学基金项目(81901193和81901267)

Piezo1 suppression reduces demyelination after intracerebral hemorrhage

Jie Qu1, Hang-Fan Zong2, Yi Shan1, Shan-Chun Zhang3, Wei-Ping Guan3, Yang Yang4, Heng-Li Zhao3, *   

  1. 1Department of Emergency, The Sixth Medical Center of Chinese PLA General Hospital, Beijing, China; 2The Second Medical Center & National Clinical Research Center for Geriatric Diseases, Chinese PLA General Hospital, Beijing, China; 3Department of Neurology, The Second Medical Center & National Clinical Research Center for Geriatric Diseases, Chinese PLA General Hospital, Beijing, China; 4Department of Neurosurgery and State Key Laboratory of Trauma, Burn and Combined Injury, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
  • Online:2023-08-15 Published:2023-02-23
  • Contact: Heng-Li Zhao, PhD, qqtf_20070910@163.com.
  • Supported by:
    This work was supported by the National Natural Science Foundation of China, Nos. 81901193 (to HLZ) and 81901267 (to YY).

摘要:

压电型机械敏感离子通道组件1(Piezo1)是一种机械门控钙通道,最近有研究发现,抑制压电型机械敏感离子通道组件1可减弱精神素和脂多糖诱导的脱髓鞘。由于脑出血中存在少突胶质细胞损伤和脱髓鞘现象,因此实验探索了压电型机械敏感离子通道组件1对脑出血中的作用。首先在右侧基底节注射自体血建立脑出血小鼠模型,发现压电型机械敏感离子通道组件1可在脑出血后早期(48h内)即大量表达,且主要分布在少突胶质细胞中。而腹腔注射Dooku1抑制压电型机械敏感离子通道组件1后,脑出血小鼠 脑水肿显著减轻,损伤组织中髓鞘缺失及退变得到缓解,少突胶质细胞凋亡明显减少,且神经功能明显改善。进一步研究显示,抑制压电型机械敏感离子通道组件1可通过介导PERK-ATF4-CHOP以及肌醇需要酶1信号通路,减轻少突胶质细胞内内质网应激反应及细胞凋亡。上述结果提示,压电型机械敏感离子通道组件1是治疗脑出血的潜在靶点之一,可通过抑制压电型机械敏感离子通道组件1过减轻脑出血后少突胶质细胞内内质网应激反应及细胞凋亡,保护髓鞘,从而改善脑出血后的神经功能。

https://orcid.org/0000-0002-4414-5303 (Heng-Li Zhao)

关键词: 脑出血, 压电型机械敏感离子通道组件1, 白质损伤, 少突胶质细胞, 内质网应激, 细胞凋亡, 脱髓鞘, 脑卒中, 钙离子稳态, 髓磷脂碱性蛋白

Abstract: Piezo1 is a mechanically-gated calcium channel. Recent studies have shown that Piezo1, a mechanically-gated calcium channel, can attenuate both psychosine- and lipopolysaccharide-induced demyelination. Because oligodendrocyte damage and demyelination occur in intracerebral hemorrhage, in this study, we investigated the role of Piezo1 in intracerebral hemorrhage. We established a mouse model of cerebral hemorrhage by injecting autologous blood into the right basal ganglia and found that Piezo1 was largely expressed soon (within 48 hours) after intracerebral hemorrhage, primarily in oligodendrocytes. Intraperitoneal injection of Dooku1 to inhibit Piezo1 resulted in marked alleviation of brain edema, myelin sheath loss, and degeneration in injured tissue, a substantial reduction in oligodendrocyte apoptosis, and a significant improvement in neurological function. In addition, we found that Dooku1-mediated Piezo1 suppression reduced intracellular endoplasmic reticulum stress and cell apoptosis through the PERK-ATF4-CHOP and inositol-requiring enzyme 1 signaling pathway. These findings suggest that Piezo1 is a potential therapeutic target for intracerebral hemorrhage, as its suppression reduces intracellular endoplasmic reticulum stress and cell apoptosis and protects the myelin sheath, thereby improving neuronal function after intracerebral hemorrhage. 

Key words: apoptosis, Ca2+ homeostasis, endoplasmic reticulum stress, intracerebral hemorrhage, myelin basic protein, myelin degradation, oligodendrocyte, Piezo1, stroke, white matter injury