中国神经再生研究(英文版) ›› 2022, Vol. 17 ›› Issue (12): 2710-2716.doi: 10.4103/1673-5374.339488

• 原著:脑损伤修复保护与再生 • 上一篇    下一篇

坏死抑制蛋白1对脑室出血后继发性损伤的神经保护作用有限

  

  • 出版日期:2022-12-15 发布日期:2022-05-05
  • 基金资助:
    国家科技重大专项基金(2019ZX09301-147);四川大学华西医院博士后基金项目(2020HXBH160)

Necrostatin-1 decreases necroptosis and inflammatory markers after intraventricular hemorrhage in mice

Chang Liu1, #, Yi Cao2, #, Hao-Xiang Wang1, Long Zhao1, 3, Ya-Xing Chen1, Kun-Hong Zhong4, Gao-Wei Li1, Guo-Qing Wang1, Ke-Ru Huang1, Ai-Ping Tong4, *, Liang-Xue Zhou1, *   

  1. 1Department of Neurosurgery, West China Medical School, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China; 2Department of Neurosurgery, Chengdu Second People’s Hospital, Chengdu, Sichuan Province, China; 3Department of Neurosurgery, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan Province, China; 4State Key Laboratory of Biotherapy, West China Medical School, Sichuan University, Chengdu, Sichuan Province, China
  • Online:2022-12-15 Published:2022-05-05
  • Contact: Liang-Xue Zhou, MD, zhlxlll@163.com; Ai-Ping Tong, MD, aipingtong@scu.edu.cn.
  • Supported by:
    The work was funded by Major National Science and Technology Projects, China, No. 2019ZX09301-147 (to LXZ); and Postdoctoral Foundation of West China Hospital of Sichuan University, China, No. 2020HXBH160 (to YXC).

摘要:

坏死抑制蛋白1是坏死性凋亡的特异性抑制剂,可有效抑制神经系统疾病中的坏死性凋亡,从而抑制炎症、内质网应激和活性氧产生,继而显著改善神经功能。然而,其对脑室出血的作用仍然未知。实验以自体血侧脑室注射建立脑室出血小鼠模型,并于损伤前1h侧脑室注射坏死抑制蛋白1进行预处理。结果显示,虽然坏死抑制蛋白1能有效降低侧脑室周围坏死小体组分受体相互作用蛋白1、受体相互作用蛋白3和混合系激酶区域样蛋白以及磷酸化受体相互作用蛋白3和磷酸化混合系激酶区域样蛋白的表达,减少细胞死亡、小胶质细胞活化和炎症相关标志物白细胞介素1β、白细胞介素6和肿瘤坏死因子α水平,但是并不能减轻室管膜纤毛损伤和降低脑含水量。表明坏死抑制蛋白1具有脑室出血后局部抗炎和抗小胶质细胞活化的作用,但不会明显改善预后。

https://orcid.org/0000-0001-9991-6358 (Liang-Xue Zhou); https://orcid.org/0000-0002-1782-399X (Chang Liu)

关键词: 脑室出血, 坏死性凋亡, 坏死抑制蛋白1, 炎症, 脑积水, RIP1, RIP3, MLKL, 小胶质细胞, 室管膜纤毛

Abstract: Necrostatin-1, an inhibitor of necroptosis, can effectively inhibit necrotic apoptosis in neurological diseases, which results in the inhibition of inflammation, endoplasmic reticulum stress, and reactive oxygen species production and substantial improvement of neurological function. However, the effects of necrostatin-1 on intraventricular hemorrhage (IVH) remain unknown. In this study, we established a mouse model of IVH by injecting autologous blood into the lateral ventricle of the brain. We also injected necrostatin-1 into the lateral ventricle one hour prior to IVH induction. We found that necrostatin-1 effectively reduced the expression levels of the necroptosis markers receptor-interacting protein kinase (RIP)1, RIP3, mixed lineage kinase domain-like protein (MLKL), phosphorylated (p)-RIP3, and p-MLKL and the levels of interleukin-1β , interleukin-6, and tumor necrosis factor-α in the surrounding areas of the lateral ventricle. However, necrostatin-1 did not reduce ependymal ciliary injury or brain water content. These findings suggest that necrostatin-1 can prevent local inflammation and microglial activation induced by IVH but does not greatly improve prognosis.

Key words: ependymal cilia, hydrocephalus, inflammation, intraventricular hemorrhage, microglia, MLKL, necroptosis, necrostatin-1, RIP1, RIP3