Activation of GPR39 with TC-G 1008 attenuates neuroinflammation via SIRT1/PGC-1α/Nrf2 pathway post-neonatal hypoxic-ischemic injury in rats.
Activation of GPR39 with TC-G 1008 attenuates neuroinflammation via SIRT1/PGC-1α/Nrf2 pathway post-neonatal hypoxic-ischemic injury in rats.
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DOI：
10.1186/s12974-021-02289-7
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发表时间：
2021-10-13
影响因子：
9.3
通讯作者：
Zhang JH
中科院分区：
文献类型：
--
作者：
Xie S;Jiang X;Doycheva DM;Shi H;Jin P;Gao L;Liu R;Xiao J;Hu X;Tang J;Zhang L;Zhang JH
缺氧缺血性脑病（HIE）是一种严重的缺氧性脑损伤，可导致婴儿过早死亡或长期残疾。神经炎症是HIE后致病级联反应的重要促成因素，也是继发性神经元死亡的介导因素。作为一种质膜G蛋白偶联受体，GPR39在多种疾病中表现出抗炎活性。本研究旨在通过抑制缺氧缺血（HI）损伤后的炎症来探索GPR39的神经保护功能，并阐述沉默调节蛋白1（SIRT1）/过氧化物酶体增殖物激活受体 - γ共激活因子1α（PGC - 1α）/核因子红细胞2相关因子2（Nrf2）在G蛋白偶联受体39（GPR39）介导的保护中的作用。
共有206只10日龄的斯普拉格 - 道利大鼠幼崽接受HIE或假手术。在HIE诱导后1小时、25小时、49小时和73小时经鼻给予TC - G 1008。给予SIRT1抑制剂EX527、GPR39 CRISPR和PGC - 1α CRISPR以阐明潜在机制。在HIE后进行脑梗死面积、短期和长期神经行为测试、尼氏染色、蛋白质印迹和免疫荧光染色。
GPR39及通路相关蛋白SIRT1、PGC - 1α和Nrf2的表达呈时间依赖性增加，在HIE后24小时或48小时达到峰值。经鼻给予TC - G 1008减少了梗死面积百分比，并改善了短期和长期的神经功能缺损。此外，TC - G 1008治疗显著增加了SIRT1、PGC - 1α和Nrf2的表达，但下调了白细胞介素 - 6（IL - 6）、白细胞介素 - 1β（IL - 1β）和肿瘤坏死因子 - α（TNF - α）的表达。GPR39 CRISPR、EX527和PGC - 1α CRISPR消除了HIE后GPR39的神经保护作用。
在新生大鼠HIE模型中，TC - G 1008部分通过SIRT1/PGC - 1α/Nrf2通路减轻神经炎症。TC - G 1008可能是新生儿HIE损伤后治疗的一个新的治疗靶点。
在线版本包含补充材料，可在10.1186/s12974 - 021 - 02289 - 7获取。
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-γ coactivator 1α (PGC-1α)/nuclear factor, erythroid 2 like 2(Nrf2) in G-protein-coupled receptor 39 (GPR39)-mediated protection. 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-1α 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. The expression of GPR39 and pathway-related proteins, SIRT1, PGC-1α 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-1α and Nrf2, but downregulated the expressions of IL-6, IL-1β, and TNF-α. GPR39 CRISPR EX527 and PGC-1α CRISPR abolished GPR39’s neuroprotective effects post-HIE. TC-G 1008 attenuated neuroinflammation in part via the SIRT1/PGC-1α/Nrf2 pathway in a neonatal rat model of HIE. TC-G 1008 may be a novel therapeutic target for treatment post-neonatal HIE injury. The online version contains supplementary material available at 10.1186/s12974-021-02289-7.
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影响因子：
3
作者：
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