JR14a: A novel antagonist of C3aR attenuates neuroinflammation in cerebral ischemia-reperfusion injury

作者全名：Tang, Jiutang; Maihemuti, Nueraili; Fang, Yu; Tan, Junyi; Jia, Mengjie; Mu, Qinglan; Huang, Keli; Gan, Hui; Zhao, Jing

作者地址：[Tang, Jiutang; Maihemuti, Nueraili; Tan, Junyi; Jia, Mengjie; Mu, Qinglan; Huang, Keli; Gan, Hui; Zhao, Jing] Chongqing Med Univ, Med Coll, Ctr Neurosci Res, Sch Basic Med, Rd 1, Chongqing 40016, Peoples R China; [Tang, Jiutang; Fang, Yu] Chongqing Tradit Chinese Med Hosp, Chongqing 400021, Peoples R China

通信作者：Gan, H; Zhao, J (通讯作者)，Chongqing Med Univ, Med Coll, Ctr Neurosci Res, Sch Basic Med, Rd 1, Chongqing 40016, Peoples R China.

来源：BRAIN RESEARCH BULLETIN

ESI学科分类：NEUROSCIENCE & BEHAVIOR

WOS号：WOS:001248390800003

JCR分区：Q2

影响因子：3.5

年份：2024

卷号：213

期号：　

开始页：　

结束页：　

文献类型：Article

关键词：Cerebral ischemia-reperfusion injury (CIRI); JR14a; C3aR; Inflammation

摘要：Cerebral ischemia-reperfusion injury (CIRI), a prevalent stroke-related complication, can lead to severe brain damage. Inflammation is a crucial factor in CIRI pathogenesis, and the complement component 3a receptor (C3aR) could be a key mediator in the post-CIRI inflammatory cascade. In this study, the role of C3aR in CIRI was investigated utilizing a middle cerebral artery occlusion (MCAO) model in C3aR knockout (KO) mice. Magnetic resonance imaging (MRI) and neurofunctional assessments revealed that C3aR KO mice exhibited significantly diminished cerebral infarction and improved neurological impairments. Consequently, the focus shifted to searching for a small molecule antagonist of C3aR. JR14a, a new potent thiophene antagonist of C3aR, was injected intraperitoneally into mice 1-h post-MCAO model implementation. The mass spectrometry (MS) results indicated the ability of JR14a to penetrate the blood-brain barrier. Subsequent TTC staining and neurofunctional assessments revealed the efficacy of JR14a in reducing cerebral infarct volume and neurological impairment following MCAO. In addition, immunofluorescence (IF) and immunohistochemistry (IHC) demonstrated attenuated microglial activation, neutrophil infiltration, and blood-brain barrier disruption by JR14a in the MCAO model. Furthermore, enzyme-linked immunosorbent assay (ELISA) and Western blotting supported the role of JR14a in downregulating the expression levels of C3aR, tumor necrosis factor-alpha (TNF-alpha), and interleukin-6 (IL-6), as well as the phosphorylation of p65. In conclusion, the findings suggested that C3aR could be a potential therapeutic target for CIRI, and JR14a emerged as a promising treatment candidate.

基金机构：National Natural Science Foundation of China [82071305]; National Natural Science Foundation of China (youth fund) [82301512]; China Postdoctoral Science Foundation [2022MD723734]; Chongqing Post-doctoral Science Foundation [CST2023NSCQ-BHX0121]; Natural Science Foundation of Chongqing Science and Technology Committee, China [CSTC2021jcyj-msxmX0001]; Program for Youth Innovation in Future Medicine, Chongqing Medical University

基金资助正文：This research was supported by the National Natural Science Foundation of China (Grant No. 82071305 to Jing Zhao) , National Natural Science Foundation of China (youth fund) (Grant No. 82301512 to Hui Gan) , the China Postdoctoral Science Foundation (Grant No. 2022MD723734 to Hui Gan) , Chongqing Post-doctoral Science Foundation (Grant No. CST2023NSCQ-BHX0121 to Hui Gan) , the Natural Science Foundation of Chongqing Science and Technology Committee, China (Grant No. CSTC2021jcyj-msxmX0001 to Jing Zhao) , and Program for Youth Innovation in Future Medicine, Chongqing Medical University to Jing Zhao.