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Intermittent Hypoxia-Induced Parvalbumin-Immunoreactive Interneurons Loss and Neurobehavioral Impairment is Mediated by NADPH-Oxidase-2

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Abstract

Obstructive sleep apnea usually contribute to psychiatric diseases and cognitive impairments in adults. Loss of parvalbumin (PV)-immunoreactive interneurons (PV-IN) in the brain cortex is an important feature of psychiatric diseases, such as schizophrenia. Here we investigate the causal contribution of oxidative stress in the brain cortex to neuropathological alterations in a mouse model of sleep apnea. Wild-type (WT) and the NADPH-oxidase-2 (gp91-phox/NOX2) knock-out adult male C57BL/6J mice were exposed to intermittent hypoxia (IH) or standard room air in the same chamber. In vivo we determined the impact (1) of IH exposures on NOX2 expression, (2) of genetic gp91-phox/NOX2 knock-out and (3) of pharmacological NOX2 inhibition on IH-induced neuropathological alterations in adult mice. Endpoints were oxidative stress, PV-IN and neurobehavioral alterations. The results showed IH exposures increased NOX2 expression in the prefrontal cortex of WT mice, which was accompanied with elevations of indirect markers of oxidative stress (HNE, HIF-1α, 8-OHDG). WT mice showed loss of PV-IN in the prefrontal cortex and increased locomotion activity and anxiety levels after exposed to IH, while no change emerged in NOX2 knock-out mice. Treatment of WT mice with the antioxidant/NOX inhibitor apocynin prevented the neuropathological and neurobehavioral alterations induced by IH exposures. Our data suggest that NOX2-derived oxidative stress is involved in the loss of PV-IN in the prefrontal cortex and development of neurobehavioral alterations for adult mice exposed to IH. These results provide a molecular mechanism for the coupling between sleep apnea and brain oxidative stress as well as potential new therapeutic avenues.

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Acknowledgments

This work was supported by the Grants 81172094 and 8110186 from the National Science Foundation of China, Grant 2011-WS-005 from the Six Talents Peak Foundation of Jiangsu Province.

Conflict of interest

We declare that we have no competing interests.

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    Authors and Affiliations

    1. Department of Anaesthesiology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, People’s Republic of China

      Liang Yuan, Jing Wu & Guowei Li

    2. Comprehensive Cancer Center of Drum-Tower Hospital, School of Medicine, Nanjing University, Nanjing, People’s Republic of China

      Jiang Liu

    3. Department of Emergency, Ruijin Hospital North, School of Medicine, Shanghai Jiaotong University, 999 Xiwang Road, Jiading District, Shanghai, 201801, People’s Republic of China

      Dong Liang

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    1. Liang Yuan
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    Correspondence to Dong Liang.

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    Liang Yuan and Jing Wu have equally contributed to this work.

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    Yuan, L., Wu, J., Liu, J. et al. Intermittent Hypoxia-Induced Parvalbumin-Immunoreactive Interneurons Loss and Neurobehavioral Impairment is Mediated by NADPH-Oxidase-2. Neurochem Res 40, 1232–1242 (2015). https://doi.org/10.1007/s11064-015-1586-1

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