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Perinatal hypoxia is a universal cause of death and neurological deficits in neonates worldwide. Activation of microglial NADPH oxidase 2 (NOX2) leads to oxidative stress and neuroinflammation, which may contribute to hypoxic damage in the developing brain. Dexmedetomidine has been reported to exert potent neuroprotection in several neurological diseases, but the mechanism remains unclear. We investigated whether dexmedetomidine acts through microglial NOX2 to reduce neonatal hypoxic brain damage. <jats:italic>Methods<\/jats:italic>. The potential role of microglial NOX2 in dexmedetomidine\u2010mediated alleviation of hypoxic damage was evaluated in cultured BV2 microglia and neonatal rats subjected to hypoxia. <jats:italic>In vivo<\/jats:italic>, neonatal rats received dexmedetomidine (25\u2009<jats:italic>\u03bc<\/jats:italic>g\/kg, i.p.) 30\u2009min before or immediately after hypoxia (5% O<jats:sub>2<\/jats:sub>, 2\u2009h). Apocynin\u2010mediated NOX inhibition and lentivirus\u2010mediated NOX2 overexpression were applied to further assess the involvement of microglial NOX2 activation. <jats:italic>Results<\/jats:italic>. Pre\u2010 or posttreatment with dexmedetomidine alleviated hypoxia\u2010induced cognitive impairment, restored damaged synapses, and increased postsynaptic density\u201095 and synaptophysin protein expression following neonatal hypoxia. Importantly, dexmedetomidine treatment suppressed hypoxia\u2010induced microglial NOX2 activation and subsequent oxidative stress and the neuroinflammatory response, as reflected by reduced 4\u2010hydroxynonenal and ROS accumulation, and decreased nuclear NF\u2010<jats:italic>\u03ba<\/jats:italic>B p65 and proinflammatory cytokine levels in cultured BV2 microglia and the developing hippocampus. In addition, treating primary hippocampal neurons with conditioned medium (CM) from hypoxia\u2010activated BV2 microglia resulted in neuronal damage, which was alleviated by CM from dexmedetomidine\u2010treated microglia. Moreover, the neuroprotective effect of dexmedetomidine was reversed in NOX2\u2010overexpressing BV2 microglia and diminished in apocynin\u2010pretreated neonatal rats. <jats:italic>Conclusion<\/jats:italic>. Dexmedetomidine targets microglial NOX2 to reduce oxidative stress and neuroinflammation and subsequently protects against hippocampal synaptic loss following neonatal hypoxia.<\/jats:p>","DOI":"10.1155\/2021\/6643171","type":"journal-article","created":{"date-parts":[[2021,2,14]],"date-time":"2021-02-14T04:48:39Z","timestamp":1613278119000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":30,"title":["Dexmedetomidine Alleviates Hypoxia\u2010Induced Synaptic Loss and Cognitive Impairment via Inhibition of Microglial NOX2 Activation in the Hippocampus of Neonatal 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