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Our previous study demonstrated that dexmedetomidine (Dex) provided neuroprotection against neonatal hypoxic brain injury; however, the underlying mechanisms remain incompletely elucidated. Overactivation of NADPH oxidase 2 (NOX2) can cause neuronal apoptosis and neurological deficits. Hence, we aimed to investigate the role of neuronal NOX2 in Dex-mediated neuroprotection and to explore its potential mechanisms. Hypoxic injury was modeled in neonatal rodents in vivo and in cultured hippocampal neurons in vitro. Our results showed that pre- or post-treatment with Dex improved the neurological deficits and alleviated the hippocampal neuronal damage and apoptosis caused by neonatal hypoxia. In addition, Dex treatment significantly suppressed hypoxia-induced neuronal NOX2 activation; it also reduced oxidative stress, as evidenced by decreases in intracellular reactive oxygen species (ROS) production, malondialdehyde, and 8-hydroxy-2-deoxyguanosine, as well as increases in the antioxidant enzymatic activity of superoxide dismutase and glutathione peroxidase in neonatal rat hippocampi and in hippocampal neurons. Lastly, the posthypoxicneuroprotective action of Dex was almost completely abolished in NOX2-deficient neonatal mice and NOX2-knockdown neurons. In conclusion, our data demonstrated that neuronal NOX2-mediated oxidative stress is involved in the neuroprotection that Dex provides against apoptosis and neurological deficits in neonates following hypoxia.<\/jats:p>","DOI":"10.3390\/antiox11112199","type":"journal-article","created":{"date-parts":[[2022,11,8]],"date-time":"2022-11-08T11:31:51Z","timestamp":1667907111000},"page":"2199","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["Dexmedetomidine Attenuates Apoptosis and Neurological Deficits by Modulating Neuronal NADPH Oxidase 2-Derived Oxidative Stress in Neonates Following Hypoxic Brain Injury"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1864-6729","authenticated-orcid":false,"given":"Xiaohui","family":"Chen","sequence":"first","affiliation":[{"name":"Department of Anesthesiology, Shengli Clinical Medical College, Fujian Medical University, Fujian Provincial Hospital, Fuzhou 350001, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0193-2902","authenticated-orcid":false,"given":"Dongtai","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangzhou 510060, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pinzhong","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Shengli Clinical Medical College, Fujian Medical University, Fujian Provincial Hospital, Fuzhou 350001, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andi","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Shengli Clinical Medical College, Fujian Medical University, Fujian Provincial Hospital, Fuzhou 350001, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianhui","family":"Deng","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Shengli Clinical Medical College, Fujian Medical University, Fujian Provincial Hospital, Fuzhou 350001, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianjie","family":"Wei","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Shengli Clinical Medical College, Fujian Medical University, Fujian Provincial Hospital, Fuzhou 350001, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weian","family":"Zeng","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangzhou 510060, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6213-0789","authenticated-orcid":false,"given":"Xiaochun","family":"Zheng","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Shengli Clinical Medical College, Fujian Medical University, Fujian Provincial Hospital, Fuzhou 350001, China"},{"name":"Fujian Provincial Key Laboratory of Emergency Medicine, Fujian Provincial Key Laboratory of Critical Care Medicine, Fujian Provincial Co-Constructed Laboratory of \u201cBelt and Road\u201d, Fuzhou 350001, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,11,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1016\/j.earlhumdev.2010.05.010","article-title":"Epidemiology of neonatal encephalopathy and hypoxic-ischaemic encephalopathy","volume":"86","author":"Kurinczuk","year":"2010","journal-title":"Early Hum. 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