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

作　　者：Xi-Lei Liu Dong-Dong Sun Mu-Tian Zheng Xiao-Tian Li Han-Hong Niu Lan Zhang Zi-Wei Zhou Hong-Tao Rong Yi Wang Ji-Wei Wang Gui-Li Yang Xiao Liu Fang-Lian Chen Yuan Zhou Shu Zhang Jian-Ning Zhang 

机构地区：[1]Department of Neurosurgery,Tianjin Medical University General Hospital,Tianjin,China [2]Tianjin Neurological Institute,Key Laboratory of Post-Neuroinjury Repair and Regeneration in Central Nervous System,Tianjin,China [3]Graduate School,Tianjin Medical University,Tianjin,China [4]Department of Neurosurgery,Tianjin Huanhu Hospital,Tianjin Key Laboratory of Cerebral Vascular and Neurodegenerative Diseases,Tianjin Neurosurgical Institute,Tianjin,China [5]Department of Radiotherapy,Tianjin Medical University General Hospital,Tianjin,China [6]Department of Geriatrics,Tianjin Medical University General Hospital,Tianjin,China [7]Institute of Tianjin Geriatrics,Tianjin Medical University General Hospital,Tianjin,China

出　　处：《Neural Regeneration Research》2023年第1期141-149,共9页中国神经再生研究（英文版）

基　　金：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);the Clinical Research Fundation of Tianjin Medical University, No. 2018kylc002 (to YW)

摘　　要：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.

关 键 词：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 

分 类 号：R743.31[医药卫生—神经病学与精神病学]