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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\u2013ischemic (HI) injury and to elaborate the contribution of sirtuin 1(SIRT1)\/peroxisome proliferator-activated receptor-\u03b3 coactivator 1\u03b1 (PGC-1\u03b1)\/nuclear factor, erythroid 2 like 2(Nrf2) in G-protein-coupled receptor 39 (GPR39)-mediated protection.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>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\u00a0h, 25\u00a0h, 49\u00a0h, and 73\u00a0h post-HIE induction. SIRT1 inhibitor EX527, GPR39 CRISPR, and PGC-1\u03b1 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.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>The expression of GPR39 and pathway-related proteins, SIRT1, PGC-1\u03b1 and Nrf2 were increased in a time-dependent manner, peaking at 24\u00a0h 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\u03b1 and Nrf2, but downregulated the expressions of IL-6, IL-1\u03b2, and TNF-\u03b1. GPR39 CRISPR EX527 and PGC-1\u03b1 CRISPR abolished GPR39\u2019s neuroprotective effects post-HIE.\n<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusions<\/jats:title>\n                <jats:p>TC-G 1008 attenuated neuroinflammation in part via the SIRT1\/PGC-1\u03b1\/Nrf2 pathway in a neonatal rat model of HIE. TC-G 1008 may be a novel therapeutic target for treatment post-neonatal HIE injury.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s12974-021-02289-7","type":"journal-article","created":{"date-parts":[[2021,10,13]],"date-time":"2021-10-13T11:32:47Z","timestamp":1634124767000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":52,"title":["Activation of GPR39 with TC-G 1008\u00a0attenuates neuroinflammation via SIRT1\/PGC-1\u03b1\/Nrf2 pathway post-neonatal hypoxic\u2013ischemic injury in rats"],"prefix":"10.1186","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2620-3637","authenticated-orcid":false,"given":"Shucai","family":"Xie","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xili","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Desislava Met","family":"Doycheva","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Shi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peng","family":"Jin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ling","family":"Gao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rui","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Xiao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao","family":"Hu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiping","family":"Tang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lina","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4319-4285","authenticated-orcid":false,"given":"John H.","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,10,13]]},"reference":[{"key":"2289_CR1","first-page":"9","volume":"1","author":"D Adstamongkonkul","year":"2017","unstructured":"Adstamongkonkul D, Hess DC. 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