Dexmedetomidine Protects against Chemical Hypoxia-Induced Neurotoxicity in Differentiated Pc12 Cells Via Inhibition of Nadph Oxidase 2-Mediated Oxidative Stress

Dexmedetomidine (Dex) is a widely used sedative in anesthesia and critical care units, and it exhibits neuroprotective activity. However, the precise mechanism of Dex-exerted neuroprotection is not clear. Increased neuronal NADPH oxidase 2 (NOX2) contributes to oxidative stress and neuronal damage in various hypoxia-related neurodegenerative disorders. The present study investigated whether Dex regulated neuronal NOX2 to exert its protective effects under hypoxic conditions. Well-differentiated PC12 cells were exposed to cobalt chloride (CoCl(2)) to mimic a neuronal model of chemical hypoxia-mediated neurotoxicity. The data showed that Dex pretreatment of PC12 cells significantly suppressed CoCl(2)-induced neurotoxicity, as evidenced by the enhanced cell viability, restoration of cellular morphology, and reduction in apoptotic cells. Dex improved mitochondrial function and inhibited CoCl(2)-induced mitochondrial apoptotic pathways. We further demonstrated that Dex attenuated oxidative stress, downregulated NOX2 protein expression and activity, and inhibited intracellular calcium ([Ca(2+)]i) overload in CoCl(2)-treated PC12 cells. Moreover, knockdown of the NOX2 gene markedly improved mitochondrial function and attenuated apoptosis under hypoxic conditions. These results demonstrated that the protective effects of Dex against hypoxia-induced neurotoxicity in neural cells were mediated, at least partially, via inhibition of NOX2-mediated oxidative stress.

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