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The present article aimed to explore the impact of tamarixetin on ischemic stroke and elucidate the underlying mechanisms. Effects of tamarixetin on ischemic stroke were evaluated in rats using the middle cerebral artery occlusion and reperfusion (MCAO\/R) model, by assessing the neurological deficit scores, brain water content, brain infraction, and neuronal damage. The levels of proinflammatory cytokines, NLRP3 inflammasome activation, reactive oxygen species (ROS) production, and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase expression were measured in MCAO\/R rats and lipopolysaccharide\u2010stimulated cells. Tamarixetin administration improved the neurological dysfunction and neuronal loss in MCAO\/R rats. In addition, tamarixetin reduced microglial hyperactivation and proinflammatory cytokines expression in vivo and in vitro. Tamarixetin attenuated NF\u2013\u03baB p65 phosphorylation and promoter activity, reduced NLRP3 expression and caspase\u20101 cleavage, and downregulated IL\u20101\u03b2 and IL\u201018 secretions to suppress NLRP3 inflammasome activation. The levels of superoxide anion, hydrogen peroxide, and ROS were also suppressed by tamarixetin. The downregulation of NADP<jats:sup>+<\/jats:sup> and NADPH levels, and gp91phox expression indicated the ameliorative effects of tamarixetin on NADPH oxidase activation. In the gp91phox knockdown cells treated with lipopolysaccharide, the effects of tamarixetin on NADPH oxidase activation, ROS generation, and NLRP3 inflammasome activation were diminished. Moreover, tamarixetin protects neurons against microglial hyperactivation in vitro. Our findings support the potential of tamarixetin as a therapeutic agent for ischemic stroke, and its mechanism of action involves the inhibition of NADPH oxidase\u2013NLRP3 inflammasome signaling.<\/jats:p>","DOI":"10.1002\/ptr.8263","type":"journal-article","created":{"date-parts":[[2024,7,8]],"date-time":"2024-07-08T07:35:38Z","timestamp":1720424138000},"page":"4286-4306","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Tamarixetin ameliorates cerebral ischemia\u2013reperfusion injury via suppressing nicotinamide adenine dinucleotide phosphate oxidase 2\/nucleotide\u2010binding oligomerization domain like receptor family pyrin domain\u2010containing 3 inflammasome activation"],"prefix":"10.1002","volume":"38","author":[{"given":"Yanqiu","family":"Yang","sequence":"first","affiliation":[{"name":"Key Laboratory of Bioresource Research and Development of Liaoning Province, College of Life and Health Sciences Northeastern University  Shenyang China"},{"name":"National Frontiers Science Center for Industrial Intelligence and Systems Optimization, Key Laboratory of Data Analytics and Optimization for Smart Industry, Ministry of Education Northeastern University  Shenyang China"},{"name":"College of Information Science and Engineering Northeastern University  Shenyang China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Feng","family":"Wang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Bioresource Research and Development of Liaoning Province, College of Life and Health Sciences Northeastern University  Shenyang China"},{"name":"National Frontiers Science Center for Industrial Intelligence and Systems Optimization, Key Laboratory of Data Analytics and Optimization for Smart Industry, Ministry of Education Northeastern University  Shenyang 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Education Northeastern University  Shenyang China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Libin","family":"Xu","sequence":"additional","affiliation":[{"name":"Key Laboratory of Bioresource Research and Development of Liaoning Province, College of Life and Health Sciences Northeastern University  Shenyang China"},{"name":"National Frontiers Science Center for Industrial Intelligence and Systems Optimization, Key Laboratory of Data Analytics and Optimization for Smart Industry, Ministry of Education Northeastern University  Shenyang China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yueyang","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Pharmacology Shenyang Pharmaceutical University  Shenyang China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yeshu","family":"Liu","sequence":"additional","affiliation":[{"name":"Key Laboratory of Bioresource Research and Development of Liaoning Province, 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