GPR39 Agonist TC-G 1008 Promoted Mitochondrial Biogenesis and Improved Antioxidative Capability via CREB/PGC-1α Pathway Following Intracerebral Hemorrhage in Mice

作者全名："Zhang, Zhongyi; Yuan, Ye; Zhang, Xingyu; Gu, Lingui; Tang, Yuguang; Zhao, Yutong; Dai, Jinyu; Tao, Yihao; Xie, Zongyi"

作者地址："[Zhang, Zhongyi; Yuan, Ye; Zhang, Xingyu; Tang, Yuguang; Zhao, Yutong; Dai, Jinyu; Tao, Yihao; Xie, Zongyi] Chongqing Med Univ, Affiliated Hosp 2, Dept Neurosurg, Chongqing 400010, Peoples R China; [Gu, Lingui] Chinese Acad Med Sci & Peking Union Med Coll, Peking Union Med Coll Hosp, Ctr Malignant Brain Tumors, Dept Neurosurg,Natl Glioma MDT Alliance, Beijing 100730, Peoples R China"

通信作者："Tao, YH; Xie, ZY (通讯作者)，Chongqing Med Univ, Affiliated Hosp 2, Dept Neurosurg, Chongqing 400010, Peoples R China."

来源：TRANSLATIONAL STROKE RESEARCH

ESI学科分类：NEUROSCIENCE & BEHAVIOR

WOS号：WOS:001187196000001

JCR分区：Q1

影响因子：3.8

年份：2024

卷号：　

期号：　

开始页：　

结束页：　

文献类型：Article; Early Access

关键词：Intracerebral hemorrhage; Mitochondrial biogenesis; Antioxidative capability; G-protein-coupled receptor 39; TC-G 1008

摘要："Mitochondrial dysfunction and excessive reactive oxygen species production due to impaired mitochondrial biogenesis have been proven to exacerbate secondary brain injury after intracerebral hemorrhage (ICH). The G-protein-coupled receptor 39 (GPR39) agonist TC-G 1008 has been shown to exert anti-oxidative stress effect in acute hypoxic brain injury. Herein, our study aimed to investigate the potential effects of TC-G 1008 on neuronal mitochondrial biogenesis and antioxidative stress in a mouse model of ICH and explore the underlying mechanisms. A total of 335 male C57/BL6 mice were used to establish an autologous blood-induced ICH model. Three different dosages of TC-G 1008 were administered via oral gavage at 1 h, 25 h, and 49 h post-ICH. The GPR39 siRNA and cAMP response element-binding protein (CREB) inhibitor 666-15 were administered via intracerebroventricular injection before ICH insult to explore the underlying mechanisms. Neurobehavioral function tests, Western blot, quantitative polymerase chain reaction, immunofluorescence staining, Fluoro-Jade C staining, TUNEL staining, dihydroethidium staining, transmission electron microscopy, and enzyme-linked immunosorbent assay were performed. Expression of endogenous GPR39 gradually increased in a time-dependent manner in the peri-hematoma tissues, peaking between 24 and 72 h after ICH. Treatment with TC-G 1008 significantly attenuated brain edema, hematoma size, neuronal degeneration, and neuronal death, as well as improved neurobehavioral deficits at 72 h after ICH. Moreover, TC-G 1008 upregulated the expression of mitochondrial biogenesis-related molecules, including PGC-1 alpha, NRF1, TFAM, and mitochondrial DNA copy number, associated with antioxidative stress markers, such as Nrf2, HO-1, NQO1, SOD, CAT, and GSH-Px. Furthermore, treatment with TC-G 1008 preserved neuronal mitochondrial function and structure post-ICH. Mechanistically, the protective effects of TC-G 1008 on neuronal mitochondrial biogenesis and antioxidative stress were partially reversed by GPR39 siRNA or 666 -15. Our findings indicated that GPR39 agonist TC-G 1008 promoted mitochondrial biogenesis and improved antioxidative capability after ICH, partly through the CREB/PGC-1 alpha signaling pathway. TC-G 1008 may be a potential therapeutic agent for patients with ICH."

基金机构：National Natural Science Foundation of China

基金资助正文：No Statement Available