TJ-M2010-5, a novel CNS drug candidate, attenuates acute cerebral ischemia-reperfusion injury through the MyD88/NF-κB and ERK pathway.
TJ-M2010-5, a novel CNS drug candidate, attenuates acute cerebral ischemia-reperfusion injury through the MyD88/NF-κB and ERK pathway.
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TJ-M2010-5是一种新的中枢神经系统候选药物，通过MyD88/NF-κB和ERK通路减轻急性脑缺血再灌注损伤。
DOI：
10.3389/fphar.2022.1080438
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发表时间：
2022
影响因子：
5.6
通讯作者：
Zhou, Ping
中科院分区：
文献类型：
--
作者：
Li, Zeyang;Zhao, Minghui;Zhang, Xiaoqian;Lu, Yiran;Yang, Yang;Xie, Yalong;Zou, Zhimiao;Zhou, Liang;Shang, Runshi;Zhang, Limin;Jiang, Fengchao;Du, Dunfeng;Zhou, Ping
背景：缺血性脑卒中血管再通治疗后不可避免地会发生脑缺血再灌注损伤（CIRI）。伴随的炎症级联反应对缺血性卒中后的预后和再生有重要影响。有证据表明TLR/MyD 88/NF-κB信号通路参与了CIRI的发生。本研究旨在研究MyD 88在中枢神经系统（CNS）中的可药性以及MyD 88抑制剂TJ-M2010-5对CIRI的神经保护和抗神经炎症作用。 方法：采用小鼠大脑中动脉阻塞（MCAO）模型模拟CIRI。BV-2细胞经氧糖剥夺/再给氧（OGD/R）或脂多糖刺激后，SH-SY 5 Y细胞经OGD/R诱导后，用MTT法检测细胞增殖。评估神经功能缺损评分和脑梗死体积。进行免疫荧光染色以测量脑中的神经元损伤和凋亡。通过分析炎性细胞因子的表达、小胶质细胞的活化和外周髓样细胞的浸润来评价TJ-M2010-5的抗神经炎作用。采用Simple Western法检测MyD 88/NF-κB和ERK通路蛋白的表达。采用液相色谱-质谱联用技术分析血和脑组织中TJ-M2010-5的浓度。 结果如下：在用TJ-M2010-5处理的小鼠中，脑梗塞体积减小，其中最显著的减小是原始梗塞体积的约80%。TJ-M2010-5处理后神经元丢失和凋亡减少。TJ-M2010-5抑制外周髓样细胞浸润和小胶质细胞活化。TJ-M2010-5还可下调炎症细胞因子的表达，抑制MyD 88/NF-κB和ERK通路。TJ-M2010-5具有良好的血脑屏障通透性，无神经毒性。 结论：TJ-M2010-5通过抑制过度的神经炎症反应，对CIRI具有良好的治疗作用，是一种新型的中枢神经系统候选药物。
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-κB 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-κB 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-κB 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.
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影响因子：
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DOI：
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发表时间：
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期刊：
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