{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T22:47:01Z","timestamp":1792104421806,"version":"4.4.0"},"reference-count":60,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,3,31]],"date-time":"2023-03-31T00:00:00Z","timestamp":1680220800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p><jats:bold>Backgrounds:<\/jats:bold> The circadian clock protein Rev-erb\u03b1 is a crucial regulator of circadian rhythms that affects multiple molecular, cellular, and physiology pathways that control susceptibility, injury, and recovery in the neurological disorders. Emerging evidence suggest that Rev-erb\u03b1 plays a key role in the inflammation and oxidative stress, two pivotal mechanisms in the pathogenesis, progression, and recovery process of ischemic stroke. However, it remains inconclusive whether Rev-erb\u03b1 activation is protective against ischemic brain damage. Nuclear factor erythroid 2-related factor 2 (Nrf2) pathway, a master regulator of inflammatory and oxidative responses. Our study aimed to determine whether pharmacological activation of Rev-erb\u03b1 by SR9009 protects against acute ischemic brain damage partly <jats:italic>via<\/jats:italic> Nrf2 pathway.<\/jats:p><jats:p><jats:bold>Methods:<\/jats:bold> Adult mice were pretreated with SR9009 or Nrf2 inhibitor all-trans-retinoic acid (ATRA) for 3\u00a0days prior to Sham or middle cerebral artery occlusion (MCAO) operation. After ischemia for 1\u00a0h and reperfusion for 24\u00a0h, the neurological function and cerebral infarction volume were determined, superoxide dismutase (SOD) activity, malondialdehyde (MDA) content and glutathione peroxidase (GSH-PX) activity in serum were detected by kit. The mRNA and\/or protein level of tumor necrosis factor-\u03b1 (TNF-\u03b1), interleukin-1\u03b2 (IL-1\u03b2), inducible nitric oxide synthase (iNOS), Period (Per)1, Brain and muscle arnt-like1 (Bmal1), Circadian locomotor output cycles kaput (Clock), Rev-erb\u03b1, Nrf2, heme oxygenase-1 (HO-1) and quinone oxidoreductase 1 (NQO1) in cerebral cortex were detected by q-PCR and Western blot.<\/jats:p><jats:p><jats:bold>Results:<\/jats:bold> We confirmed that SR9009 activated Rev-erb\u03b1 gene in the cerebral cortex under basal condition. At 24\u00a0h after reperfusion, SR9009 ameliorated acute neurological deficits, reduced infarct volume. Meanwhile, the inflammatory TNF-\u03b1, IL-1\u03b2, iNOS and MDA content levels were significant decreased, SOD and GSH-PX activity were obviously increased, which were markedly blunted (or abolished) by ATRA. SR9009 enhanced the induction of Nrf2 and its downstream target genes HO-1 and NQO1 after ischemic insult. In addition, we found that SR9009 restored Rev-erb\u03b1, Bmal1, Clock, Per1 genes expression in the cerebral cortex under ischemic condition.<\/jats:p><jats:p><jats:bold>Conclusion:<\/jats:bold> Taken together, Rev-erb\u03b1 activation by SR9009 protects against ischemic stroke damage, at least, partly through Nrf2 pathway.<\/jats:p>","DOI":"10.3389\/fphar.2023.1102567","type":"journal-article","created":{"date-parts":[[2023,3,31]],"date-time":"2023-03-31T06:46:41Z","timestamp":1680245201000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":15,"title":["Rev-erb\u03b1 agonist SR9009 protects against cerebral ischemic injury through mechanisms involving Nrf2 pathway"],"prefix":"10.3389","volume":"14","author":[{"given":"Mingyue","family":"Sheng","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xun","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qi","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junping","family":"Kou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gangling","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2023,3,31]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1713","DOI":"10.1161\/CIRCRESAHA.114.302995","article-title":"Short-term disruption of diurnal rhythms after murine myocardial infarction adversely affects long-term myocardial structure and function","volume":"114","author":"Alibhai","year":"2014","journal-title":"Circ. 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