{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T19:42:40Z","timestamp":1792179760548,"version":"4.4.0"},"reference-count":45,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"10","license":[{"start":{"date-parts":[[2024,10,1]],"date-time":"2024-10-01T00:00:00Z","timestamp":1727740800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Stroke"],"published-print":{"date-parts":[[2024,10]]},"abstract":"<jats:sec>\n                    <jats:title>BACKGROUND:<\/jats:title>\n                    <jats:p>In ischemia, acidosis occurs in\/around injured tissue and parallels disease progression. Therefore, targeting an acid-sensitive receptor offers unique advantages in achieving the spatial and temporal specificity required for therapeutic interventions. We previously demonstrated that increased expression of GPR68 (G protein-coupled receptor 68), a proton-sensitive G protein-coupled receptor, mitigates ischemic brain injury. Here, we investigated the mechanism underlying GPR68-dependent protection.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS:<\/jats:title>\n                    <jats:p>We performed biochemical and molecular analyses to examine poststroke signaling. We used in vitro brain slice cultures and in vivo mouse transient middle cerebral artery occlusion (tMCAO) models to investigate ischemia-induced injuries.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS:<\/jats:title>\n                    <jats:p>GPR68 deletion reduced PERK (protein kinase R-like ER kinase) expression in mouse brain. Compared with the wild-type mice, the GPR68-\/- (knockout) mice exhibited a faster decline in eIF2\u03b1 (eukaryotic initiation factor-2\u03b1) phosphorylation after tMCAO. Ogerin, a positive modulator of GPR68, stimulated eIF2\u03b1 phosphorylation at 3 to 6 hours after tMCAO, primarily in the ipsilateral brain tissue. Consistent with the changes in eIF2\u03b1 phosphorylation, Ogerin enhanced tMCAO-induced reduction in protein synthesis in ipsilateral brain tissue. In organotypic cortical slices, Ogerin reduced pH 6 and oxygen-glucose deprivation\u2013induced neurotoxicity. Following tMCAO, intravenous delivery of Ogerin reduced brain infarction in wild-type but not knockout mice. Coapplication of a PERK inhibitor abolished Ogerin-induced protection. Delayed Ogerin delivery at 5 hours after tMCAO remained protective, and Ogerin has a similar protective effect in females. Correlated with these findings, tMCAO induced GPR68 expression at 6 hours, and Ogerin alters post-tMCAO proinflammatory\/anti-inflammatory cytokine\/chemokine expression profile.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS:<\/jats:title>\n                    <jats:p>These data demonstrate that GPR68 potentiation leads to neuroprotection, at least in part, through enhancing PERK-eIF2\u03b1 activation in ischemic tissue but has little impact on healthy tissue.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/strokeaha.124.048163","type":"journal-article","created":{"date-parts":[[2024,9,3]],"date-time":"2024-09-03T05:00:49Z","timestamp":1725339649000},"page":"2510-2521","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":10,"title":["Time-Dependent Potentiation of the PERK Branch of UPR by GPR68 Offers Protection in Brain Ischemia"],"prefix":"10.1161","volume":"55","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3186-5002","authenticated-orcid":true,"given":"Wenyan","family":"Sun","sequence":"first","affiliation":[{"name":"Division of Pharmacology and Pharmaceutical Sciences, University of Missouri-Kansas City (W.S., V.T., G.D., S.J., X.Z.)."},{"name":"Now with: Tulane University, New Orleans, LA (W.S., V.T., X.Z.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5637-1076","authenticated-orcid":true,"given":"Virendra","family":"Tiwari","sequence":"additional","affiliation":[{"name":"Division of Pharmacology and Pharmaceutical Sciences, University of Missouri-Kansas City (W.S., V.T., G.D., S.J., X.Z.)."},{"name":"Now with: Tulane University, New Orleans, LA (W.S., V.T., X.Z.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Grace","family":"Davis","sequence":"additional","affiliation":[{"name":"Division of Pharmacology and 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