Activation of GPR39 with TC-G 1008 attenuates neuroinflammation via SIRT1/PGC-1 alpha/Nrf2 pathway post-neonatal hypoxic-ischemic injury in rats

作者全名："Xie, Shucai; Jiang, Xili; Doycheva, Desislava Met; Shi, Hui; Jin, Peng; Gao, Ling; Liu, Rui; Xiao, Jie; Hu, Xiao; Tang, Jiping; Zhang, Lina; Zhang, John H."

作者地址："[Xie, Shucai; Zhang, Lina] Cent South Univ, Xiangya Hosp, Natl Clin Res Ctr Geriatr Disorders, Dept Crit Care Med, Changsha 410008, Hunan, Peoples R China; [Xie, Shucai; Doycheva, Desislava Met; Shi, Hui; Jin, Peng; Gao, Ling; Liu, Rui; Xiao, Jie; Hu, Xiao; Tang, Jiping; Zhang, John H.] Loma Linda Univ, Sch Med, Dept Physiol & Pharmacol, Loma Linda, CA 92350 USA; [Jiang, Xili] Brain Hosp Hunan Prov, Peoples Hosp Hunan Prov 2, Dept Radiol, Changsha 410007, Hunan, Peoples R China; [Shi, Hui] Chongqing Med Univ, Yongchuan Hosp, Dept Neurosurg, Chongqing 402160, Peoples R China; [Jin, Peng] Fudan Univ, HuaShan Hosp, Dept Intens Care Unit, Shanghai 200040, Peoples R China; [Gao, Ling] Cent South Univ, Affiliated Haikou Hosp, Xiangya Sch Med, Dept Neurosurg, Haikou 570208, Hainan, Peoples R China; [Liu, Rui; Hu, Xiao] Guizhou Prov Peoples Hosp, Dept Neurol, Guiyang 550002, Guizhou, Peoples R China; [Xiao, Jie] Cent South Univ, Xiangya Hosp 3, Dept Emergency, Changsha 410013, Hunan, Peoples R China; [Zhang, Lina] Cent South Univ, Xiangya Hosp, Natl Clin Res Ctr Geriatr, Changsha 410008, Hunan, Peoples R China; [Zhang, John H.] Loma Linda Univ, Med Ctr, Dept Neurosurg & Anesthesiol, Loma Linda, CA 92354 USA"

通信作者："Zhang, LN (corresponding author), Cent South Univ, Xiangya Hosp, Natl Clin Res Ctr Geriatr Disorders, Dept Crit Care Med, Changsha 410008, Hunan, Peoples R China.; Zhang, JH (corresponding author), Loma Linda Univ, Sch Med, Dept Physiol & Pharmacol, Loma Linda, CA 92350 USA.; Zhang, LN (corresponding author), Cent South Univ, Xiangya Hosp, Natl Clin Res Ctr Geriatr, Changsha 410008, Hunan, Peoples R China.; Zhang, JH (corresponding author), Loma Linda Univ, Med Ctr, Dept Neurosurg & Anesthesiol, Loma Linda, CA 92354 USA."

来源：JOURNAL OF NEUROINFLAMMATION

ESI学科分类：NEUROSCIENCE & BEHAVIOR

WOS号：WOS:000707009700001

JCR分区：Q1

影响因子：9.3

年份：2021

卷号：18

期号：1

开始页：　

结束页：　

文献类型：Article

关键词：GPR39; TC-G 1008; Hypoxic-ischemic encephalopathy; Microglia; Neuroinflammation; SIRT1; PGC-1 alpha; Nrf2

摘要："Background Hypoxic-ischemic encephalopathy (HIE) is a severe anoxic brain injury that leads to premature mortality or long-term disabilities in infants. Neuroinflammation is a vital contributor to the pathogenic cascade post-HIE and a mediator to secondary neuronal death. As a plasma membrane G-protein-coupled receptor, GPR39, exhibits anti-inflammatory activity in several diseases. This study aimed to explore the neuroprotective function of GPR39 through inhibition of inflammation post-hypoxic-ischemic (HI) injury and to elaborate the contribution of sirtuin 1(SIRT1)/peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1 alpha)/nuclear factor, erythroid 2 like 2(Nrf2) in G-protein-coupled receptor 39 (GPR39)-mediated protection. Methods A total of 206 10-day-old Sprague Dawley rat pups were subjected to HIE or sham surgery. TC-G 1008 was administered intranasally at 1 h, 25 h, 49 h, and 73 h post-HIE induction. SIRT1 inhibitor EX527, GPR39 CRISPR, and PGC-1 alpha CRISPR were administered to elucidate the underlying mechanisms. Brain infarct area, short-term and long-term neurobehavioral tests, Nissl staining, western blot, and immunofluorescence staining were performed post-HIE. Results The expression of GPR39 and pathway-related proteins, SIRT1, PGC-1 alpha and Nrf2 were increased in a time-dependent manner, peaking at 24 h or 48-h post-HIE. Intranasal administration of TC-G 1008 reduced the percent infarcted area and improved short-term and long-term neurological deficits. Moreover, TC-G 1008 treatment significantly increased the expression of SIRT1, PGC-1 alpha and Nrf2, but downregulated the expressions of IL-6, IL-1 beta, and TNF-alpha. GPR39 CRISPR EX527 and PGC-1 alpha CRISPR abolished GPR39's neuroprotective effects post-HIE. Conclusions TC-G 1008 attenuated neuroinflammation in part via the SIRT1/PGC-1 alpha/Nrf2 pathway in a neonatal rat model of HIE. TC-G 1008 may be a novel therapeutic target for treatment post-neonatal HIE injury."

基金机构：National Institutes of HealthUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [NS104083]; Key Research and Development Project of Hainan Province [ZDYF2019147]

基金资助正文："This study was supported by grants from the National Institutes of Health (NS104083) to John H. Zhang, and a grant from Key Research and Development Project of Hainan Province (ZDYF2019147) to Shucai Xie."