单位：[1]Huazhong Univ Sci & Technol,Tongji Hosp,Inst Organ Transplantat,Tongji Med Coll,Wuhan,Peoples R China器官移植研究所华中科技大学同济医学院附属同济医院器官移植[2]Chinese Acad Med Sci, Key Lab Organ Transplantat, NHC Key Lab Organ Transplantat, Key Lab Organ Transplantat, Wuhan, Peoples R China[3]Huazhong Univ Sci & Technol, Union Hosp, Tongji Med Coll, Dept Neurol, Wuhan, Peoples R China华中科技大学同济医学院附属协和医院[4]Wuhan Int Educ Ctr, Wuhan Yangtze Int Sch, Wuhan, Peoples R China[5]Huazhong Univ Sci & Technol, Acad Pharm, Tongji Med Coll, Wuhan, Peoples R China
Background: Cerebral ischemia-reperfusion injury (CIRI) inevitably occurs after vascular recanalization treatment for ischemic stroke. The accompanying inflammatory cascades have a major impact on outcome and regeneration after ischemic stroke. Evidences have demonstrated that TLR/MyD88/NF-kappa B signaling contributes to CIRI. This study aimed to investigate the druggability of MyD88 in the central nervous system (CNS) and the neuroprotective and anti-neuroinflammatory effects of the MyD88 inhibitor TJ-M2010-5 on CIRI. Methods: A middle cerebral artery occlusion (MCAO) model was used to simulate CIRI in mice. BV-2 cells were stimulated with oxygen glucose deprivation/reoxygenation (OGD/R) or lipopolysaccharide, and SH-SY5Y cells were induced by OGD/R in vitro. Neurological deficit scores and cerebral infarction volumes were evaluated. Immunofluorescence staining was performed to measure neuronal damage and apoptosis in the brain. The anti-neuroinflammatory effect of TJ-M2010-5 was evaluated by analyzing the expression of inflammatory cytokines, activation of microglia, and infiltration of peripheral myeloid cells. The expression of proteins of the MyD88/NF-kappa B and ERK pathway was detected by Simple Western. The concentrations of TJ-M2010-5 in the blood and brain were analyzed by liquid chromatography-mass spectrometry. Results: The cerebral infarction volume decreased in mice treated with TJ-M2010-5, with the most prominent decrease being approximately 80% of the original infarction volume. Neuronal loss and apoptosis were reduced following TJ-M2010-5 treatment. TJ-M2010-5 inhibited the infiltration of peripheral myeloid cells and the activation of microglia. TJ-M2010-5 also downregulated the expression of inflammatory cytokines and inhibited the MyD88/NF-kappa B and ERK pathway. Furthermore, TJ-M2010-5 showed good blood-brain barrier permeability and no neurotoxicity. Conclusion: TJ-M2010-5 has an excellent therapeutic effect on CIRI as a novel CNS drug candidate by inhibiting excessive neuroinflammatory responses.
基金：
National Natural Science Foundation of China; [81974017]
第一作者单位：[1]Huazhong Univ Sci & Technol,Tongji Hosp,Inst Organ Transplantat,Tongji Med Coll,Wuhan,Peoples R China[2]Chinese Acad Med Sci, Key Lab Organ Transplantat, NHC Key Lab Organ Transplantat, Key Lab Organ Transplantat, Wuhan, Peoples R China
通讯作者：
通讯机构：[1]Huazhong Univ Sci & Technol,Tongji Hosp,Inst Organ Transplantat,Tongji Med Coll,Wuhan,Peoples R China[2]Chinese Acad Med Sci, Key Lab Organ Transplantat, NHC Key Lab Organ Transplantat, Key Lab Organ Transplantat, Wuhan, Peoples R China
推荐引用方式(GB/T 7714)：
Li Zeyang,Zhao Minghui,Zhang Xiaoqian,et al.TJ-M2010-5, a novel CNS drug candidate, attenuates acute cerebral ischemia-reperfusion injury through the MyD88/NF-κB and ERK pathway[J].FRONTIERS IN PHARMACOLOGY.2022,13:doi:10.3389/fphar.2022.1080438.
APA：
Li, Zeyang,Zhao, Minghui,Zhang, Xiaoqian,Lu, Yiran,Yang, Yang...&Zhou, Ping.(2022).TJ-M2010-5, a novel CNS drug candidate, attenuates acute cerebral ischemia-reperfusion injury through the MyD88/NF-κB and ERK pathway.FRONTIERS IN PHARMACOLOGY,13,
MLA：
Li, Zeyang,et al."TJ-M2010-5, a novel CNS drug candidate, attenuates acute cerebral ischemia-reperfusion injury through the MyD88/NF-κB and ERK pathway".FRONTIERS IN PHARMACOLOGY 13.(2022)
医学