Inhibition of neuroinflammation by MIF inhibitor 3-({[4-(4-methoxyphenyl)-6-methyl-2-pyrimidinyl]thio}1methyl)benzoic acid (Z-312).
Inhibition of neuroinflammation by MIF inhibitor 3-({[4-(4-methoxyphenyl)-6-methyl-2-pyrimidinyl]thio}1methyl)benzoic acid (Z-312).
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DOI：
10.1016/j.intimp.2021.107868
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发表时间：
2021-06
影响因子：
5.6
通讯作者：
L. Zheng;Jiaojiao Chen;Li Zhang;Yu Zhang;Lei Xu;Tingjun Hou;Xuechu Zhen;Qijun Dai;Hua Liu
中科院分区：
文献类型：
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作者：
L. Zheng;Jiaojiao Chen;Li Zhang;Yu Zhang;Lei Xu;Tingjun Hou;Xuechu Zhen;Qijun Dai;Hua Liu
小胶质细胞过度激活介导的神经炎症在神经退行性疾病如帕金森病的发病机制中起重要作用。巨噬细胞移动抑制因子（Macrophage migration inhibitory factor，MIF）是一种多效的促炎细胞因子，通过诱导多种促炎细胞因子参与多种炎症性疾病的病理生理过程。化合物3-（{[4-（4-甲氧基苯基）-6-甲基-2-嘧啶基]硫基}甲基）苯甲酸（Z-312）是一种新型的MIF互变异构体抑制剂。本研究观察了Z-312对脂多糖（LPS）诱导的小胶质细胞炎性反应的影响，结果表明，Z-312能显著降低LPS诱导的小胶质细胞产生一氧化氮（NO）、白细胞介素（IL）-1β、肿瘤坏死因子（TNF）-α和IL-6。在机制上，核因子（NF）-κB的p65亚基的核转位，IκBα的降解和磷酸化，NF-κB转录活性以及p38丝裂原活化蛋白激酶（MAPK）和JNK的磷酸化在BV-2小胶质细胞中被Z-312预处理显著减弱。此外，Z-312抑制LPS激活的BV-2小胶质细胞的细胞培养基对共培养的小鼠HT 22神经母细胞瘤细胞的神经毒性作用。体内研究表明，Z-312显著改善LPS诱导的帕金森病（PD）小鼠模型中的小胶质细胞活化和随后的DA神经元丢失。这些结果表明，MIF抑制剂Z-312可能是一种有前途的神经保护剂，用于治疗神经炎症介导的神经系统疾病。
Microglial overactivation-mediated neuroinflammation contributes greatly to the pathogenesis of neurodegenerative diseases, such as Parkinson’s disease. Macrophage migration inhibitory factor (MIF) is a pleiotropic proinflammatory cytokine that is involved in the pathophysiology of various inflammatory diseases by inducing various proinflammatory cytokines. Compound 3-({[4-(4-methoxyphenyl)-6-methyl-2-pyrimidinyl]thio}methyl)benzoic acid (Z-312) is a novel small -molecule inhibitor of MIF tautomeric activity. In this study, we investigated the anti-inflammatory effects of Z-312 on liposaccharide (LPS)-induced neuroinflammationin vitroandin vivo.The results showed that Z-312 significantly decreased the production of nitric oxide (NO), interleukin (IL)-1β, tumor necrosis factor (TNF)-α and IL-6 in LPS-stimulated microglial cells. Mechanistically, nuclear translocation of the p65 subunit of nuclear factor (NF)-κB, degradation and phosphorylation of IκBα, NF-κB transcriptional activity and phosphorylation of p38 mitogen-activated protein kinase (MAPK) and JNK were markedly attenuated by pretreatment with Z-312 in BV-2 microglial cells. In addition, Z-312 suppressed the neurotoxic effects of cell culture medium of LPS-activated BV-2 microglia on cocultured mouse HT22 neuroblastoma cells. Anin vivostudy demonstrated that Z-312 markedly ameliorated microglial activation and subsequent DA neuron loss in an LPS-induced Parkinson’s disease (PD) mouse model. These results suggest that MIF inhibitor Z-312 may be a promising neuroprotective agent for the treatment of neuroinflammation-mediated neurological diseases.