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

被引:31
作者
Xie, Shucai [1 ,2 ]
Jiang, Xili [3 ]
Doycheva, Desislava Met [2 ]
Shi, Hui [2 ,4 ]
Jin, Peng [2 ,5 ]
Gao, Ling [2 ,6 ]
Liu, Rui [2 ,7 ]
Xiao, Jie [2 ,8 ]
Hu, Xiao [2 ,7 ]
Tang, Jiping [2 ]
Zhang, Lina [1 ,9 ]
Zhang, John H. [2 ,10 ]
机构
[1] Cent South Univ, Xiangya Hosp, Natl Clin Res Ctr Geriatr Disorders, Dept Crit Care Med, Changsha 410008, Hunan, Peoples R China
[2] Loma Linda Univ, Sch Med, Dept Physiol & Pharmacol, Loma Linda, CA 92350 USA
[3] Brain Hosp Hunan Prov, Peoples Hosp Hunan Prov 2, Dept Radiol, Changsha 410007, Hunan, Peoples R China
[4] Chongqing Med Univ, Yongchuan Hosp, Dept Neurosurg, Chongqing 402160, Peoples R China
[5] Fudan Univ, HuaShan Hosp, Dept Intens Care Unit, Shanghai 200040, Peoples R China
[6] Cent South Univ, Affiliated Haikou Hosp, Xiangya Sch Med, Dept Neurosurg, Haikou 570208, Hainan, Peoples R China
[7] Guizhou Prov Peoples Hosp, Dept Neurol, Guiyang 550002, Guizhou, Peoples R China
[8] Cent South Univ, Xiangya Hosp 3, Dept Emergency, Changsha 410013, Hunan, Peoples R China
[9] Cent South Univ, Xiangya Hosp, Natl Clin Res Ctr Geriatr, Changsha 410008, Hunan, Peoples R China
[10] Loma Linda Univ, Med Ctr, Dept Neurosurg & Anesthesiol, Loma Linda, CA 92354 USA
基金
美国国家卫生研究院;
关键词
GPR39; TC-G; 1008; Hypoxic-ischemic encephalopathy; Microglia; Neuroinflammation; SIRT1; PGC-1; alpha; Nrf2; OXIDATIVE STRESS; BRAIN-INJURY; ZINC; AGONIST; EXPRESSION; PROTECTS; ENCEPHALOPATHY; PGC-1-ALPHA; APOPTOSIS; DAMAGE;
D O I
10.1186/s12974-021-02289-7
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
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.
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页数:15
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