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 (1): 141-149.doi: 10.4103/1673-5374.344829

• 原著:脑损伤修复保护与再生 • 上一篇    下一篇

马拉维罗抑制神经炎症和星形细胞激活促进创伤性脑损伤的恢复

  

  • 出版日期:2023-01-15 发布日期:2022-06-17
  • 基金资助:

    国家自然科学基金（81930031，81720108015，81901525，82101440，81801234和82071389）；天津市科技计划项目（20JCQNJC01270，20JCQNJC00460，）；天津市自然科学基金（18JCQNJC81000）；天津市教委科研计划项目（2018KJ052），天津市卫生健康科技项目（QN20015），天津市教育委员会高等教育科技发展基金（2016YD02），天津市创新药物和医疗器械重点科技项目（19ZXYXSY00070）以及天津医科大学临床研究基金（2018kylc002）

Maraviroc promotes recovery from traumatic brain injury in mice by suppression of neuroinflammation and activation of neurotoxic reactive astrocytes

Xi-Lei Liu1, 2, 3, #, Dong-Dong Sun4, #, Mu-Tian Zheng1, 2, 3, #, Xiao-Tian Li1, 2, 3, Han-Hong Niu3, 5, Lan Zhang3, 6, 7, Zi-Wei Zhou1, 2, Hong-Tao Rong1, 2, Yi Wang1, 2, Ji-Wei Wang4, Gui-Li Yang2, Xiao Liu2, Fang-Lian Chen2, Yuan Zhou1, 2, *, Shu Zhang2, *, Jian-Ning Zhang1, 2, 3, *   

  1. 1Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, China; 2Tianjin Neurological Institute, Key Laboratory of Post-Neuroinjury Repair and Regeneration in Central Nervous System, Tianjin, China; 3Graduate School, Tianjin Medical University, Tianjin, China; 4Department of Neurosurgery, Tianjin Huanhu Hospital, Tianjin Key Laboratory of Cerebral Vascular and Neurodegenerative Diseases, Tianjin Neurosurgical Institute, Tianjin, China; 5Department of Radiotherapy, Tianjin Medical University General Hospital, Tianjin, China; 6Department of Geriatrics, Tianjin Medical University General Hospital, Tianjin, China; 7Institute of Tianjin Geriatrics, Tianjin Medical University General Hospital, Tianjin, China
  • Online:2023-01-15 Published:2022-06-17
  • Contact: Yuan Zhou, PhD, zy963000@126.com; Shu Zhang, PhD, gloria523@163.com; Jian-Ning Zhang, PhD, jianningzhang@hotmail.com.
  • Supported by:
    This work was supported by grants from the National Natural Science Foundation of China, Nos. 81930031 (to JNZ), 81720108015 (to JNZ), 81901525 (to SZ), 82101440 (to DDS), 81801234 (to YZ) and 82071389 (to GLY); the Natural Science Foundation of Tianjin, Nos. 20JCQNJC01270 (to JWW), 20JCQNJC00460 (to GLY), 18JCQNJC81000 (to HTR); Scientific Research Project of Tianjin Education Commission (Natural Science), No. 2018KJ052 (to ZWZ), Tianjin Health and Health Committee Science and Technology Project, No. QN20015 (to JWW), the Science & Technology Development Fund of Tianjin Education Commission for Higher Education, No. 2016YD02 (to YW), Tianjin Key Science and Technology Projects of Innovative Drugs and Medical Devices, No. 19ZXYXSY00070 (to YW) and the Clinical Research Fundation of Tianjin Medical University, No. 2018kylc002 (to YW).

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摘要：

神经炎症和含NLR家族Pyrin域蛋白3(NLRP3)的炎症体在创伤性脑损伤的初始损伤后的二次组织损伤中起着关键作用。马拉维罗，一种C-C趋化因子受体5型（CCR5）拮抗剂，已被视为许多神经炎症疾病的新治疗策略。为进一步了解马拉维罗对创伤性脑损伤引起的神经炎症的影响。实验发现Maraviroc干预创伤性脑损伤后小鼠模型可以调控小胶质细胞从M1型（促炎）向M2型（抑炎）转化，同时减少了外周血中性粒细胞和巨噬细胞在创伤灶周围浸润。紧接着，他们证实了Maraviroc可以抑制HMGB1/NFκB通路和NLRP3炎性小体激活，减少下游炎症因子释放，从而抑制创伤性脑损伤 神经炎症。此外，他们发现Maraviroc可以抑制神经毒性A1型星形胶质细胞激活，减少神经元凋亡，促进了创伤性脑损伤后神经功能恢复。这些结果表明，马拉维罗在创伤性脑损伤的治疗应用方面具有潜力, C-C趋化因子受体5型也可能是此类损伤的干预靶点。

https://orcid.org/0000-0002-4055-9947 (Yuan Zhou); https://orcid.org/0000-0003-3627-863X (Shu Zhang); https://orcid.org/0000-0002-7290-0994 (Jian-Ning Zhang)

Abstract: Neuroinflammation and the NACHT, LRR, and PYD domains-containing protein 3 inflammasome play crucial roles in secondary tissue damage following an initial insult in patients with traumatic brain injury (TBI). Maraviroc, a C-C chemokine receptor type 5 antagonist, has been viewed as a new therapeutic strategy for many neuroinflammatory diseases. We studied the effect of maraviroc on TBI-induced neuroinflammation. A moderate-TBI mouse model was subjected to a controlled cortical impact device. Maraviroc or vehicle was injected intraperitoneally 1 hour after TBI and then once per day for 3 consecutive days. Western blot, immunohistochemistry, and TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling) analyses were performed to evaluate the molecular mechanisms of maraviroc at 3 days post-TBI. Our results suggest that maraviroc administration reduced NACHT, LRR, and PYD domains-containing protein 3 inflammasome activation, modulated microglial polarization from M1 to M2, decreased neutrophil and macrophage infiltration, and inhibited the release of inflammatory factors after TBI. Moreover, maraviroc treatment decreased the activation of neurotoxic reactive astrocytes, which, in turn, exacerbated neuronal cell death. Additionally, we confirmed the neuroprotective effect of maraviroc using the modified neurological severity score, rotarod test, Morris water maze test, and lesion volume measurements. In summary, our findings indicate that maraviroc might be a desirable pharmacotherapeutic strategy for TBI, and C-C chemokine receptor type 5 might be a promising pharmacotherapeutic target to improve recovery after TBI.

Key words: C-C chemokine receptor type 5 (CCR5) antagonist, high mobility group protein B1 (HMGB1), maraviroc, M1 microglia, nuclear factor-κB pathway, NACHT, LRR, and PYD domains-containing protein 3 (NLRP3) inflammasome, neuroinflammation, neurological function, neurotoxic reactive astrocytes, traumatic brain injury ,  ,