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The Nod-like receptor protein-3 (NLRP3) inflammasome also plays a vital role in cerebral I\/R damage. However, the effect of UCP2 on NLRP3 inflammasome-mediated hyperglycemia and I\/R damage is not clear. In the present study, UCP2-knockout (UCP2<jats:sup>\u2212\/\u2212<\/jats:sup>) and wild-type (WT) mice were used to establish a model of middle cerebral artery occlusion (MCAO) and reperfusion under normo- and hyperglycemic conditions. HT22 cells were established as a model of oxygen\u2013glucose deprivation and reoxygenation (OGD\/R) with high glucose to mimic hyperglycemia and I\/R in vitro. HT22 cells were treated with\/without different concentrations of the UCP2-specific inhibitor genipin for different periods of time. The results showed that UCP2 deficiency significantly increased histopathological changes and apoptosis after cerebral I\/R damage in hyperglycemic mice. Moreover, UCP2 deficiency enhanced NLRP3 inflammasome activation in neurons when cerebral I\/R damage was exacerbated by hyperglycemia. Furthermore, UCP2 deficiency enhanced NLRP3 inflammasome activation and reactive oxygen species (ROS) production in HT22 cells under OGD\/R and high-glucose conditions. UCP2 deficiency aggravated hyperglycemia-induced exacerbation of cerebral I\/R damage. UCP2 deficiency also enhanced NLRP3 inflammasome activation and ROS production in neurons in vitro and in vivo. These findings suggest that UCP2 deficiency enhances NLRP3 inflammasome activation following hyperglycemia-induced exacerbation of cerebral I\/R damage in vitro and in vivo. UCP2 may be a potential therapeutic target for hyperglycemia-induced exacerbation of cerebral I\/R damage.<\/jats:p>","DOI":"10.1007\/s11064-021-03270-9","type":"journal-article","created":{"date-parts":[[2021,3,18]],"date-time":"2021-03-18T06:02:27Z","timestamp":1616047347000},"page":"1359-1371","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Uncoupling Protein 2 Deficiency Enhances NLRP3 Inflammasome Activation Following Hyperglycemia-Induced Exacerbation of Cerebral Ischemia and Reperfusion Damage In Vitro and In Vivo"],"prefix":"10.1007","volume":"46","author":[{"given":"Ting","family":"Zhang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9443-690X","authenticated-orcid":false,"given":"Mao-Tao","family":"He","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao-Peng","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Jing","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian-Zhong","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,3,18]]},"reference":[{"key":"3270_CR1","doi-asserted-by":"publisher","first-page":"99","DOI":"10.1016\/j.metabol.2016.11.011","volume":"67","author":"K Tziomalos","year":"2017","unstructured":"Tziomalos K, Dimitriou P, Bouziana SD, Spanou M, Kostaki S, Angelopoulou SM, Papadopoulou M, Giampatzis V, Savopoulos C, Hatzitolios AI (2017) Stress hyperglycemia and acute ischemic stroke in-hospital outcome. 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