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Nitronyl Nitroxide Ameliorates Hypobaric Hypoxia-Induced Cognitive Impairment in Mice by Suppressing the Oxidative Stress, Inflammatory Response and Apoptosis

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Abstract

Abundant investigations have shown that hypobaric hypoxia (HH) causes cognitive impairment, mostly attributed to oxidative stress, inflammation, and apoptosis. HPN (4′-hydroxyl-2-subsitiuted phenylnitronyl nitroxide) is an excellent free radical scavenger with anti-inflammatory and anti-apoptotic activities. Our previous study has found that HPN exhibited neuroprotective effect on HH induced brain injury. In the present study, we examined the protective effect and potential mechanism of HPN on HH-induced cognitive impairment. Male mice were exposed to HH at 8000 m for 3 days with and without HPN treatment. Cognitive performance was assessed by the eight-arm radical maze. The histological changes were assayed by Nissle staining. The hippocampus cell apoptosis was detected by Tunnel staining. The levels of inflammatory cytokines and oxidative stress markers were detected. The expression of oxidative stress, inflammation-related and apoptosis-related proteins was determined by western blot. HPN administration significantly and mitigated HH induced histological damages and spatial memory loss with the evidence of decreased working memory error (WME), reference memory error (RME), total errors (TE) and total time (TT). In addition, HPN treatment significantly decreased the content of H2O2 and MDA, increased the levels of SOD, CAT, GSH-Px and GSH, and inhibited the synthesis of TNF-α, IL-1β and IL-6. Moreover, HPN administration could down-regulate the expression of NF-κB, TNF-α, Bax, and cleaved caspase-3 and up-regulate the expression of Nrf2, HO-1 and Bcl-2. The number of apoptotic cells was also significantly decreased in the hippocampus of mice in the HPN group. There results indicate that HPN improve HH-induced cognitive impairment by alleviating oxidative stress damage, suppressing inflammatory response and apoptosis and may be a powerful candidate compound for alleviating memory loss induced by HH.

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Funding

This work was supported by the National Natural Science Foundation of China (81872796, 81202458, 81303097), Natural Science Foundation of Gansu Province (18JR3RA408) and Guizhou Province Science and Technology Plan Project (Qian ke He support [2020] 4Y128).

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Authors and Affiliations

  1. Department of Pharmacy, The First Affiliated Hospital of Xi’an Jiaotong University, NO.277 Yanta West Road, Yanta District, Xi’an, 710061, Shaanxi, People’s Republic of China

    Linlin Jing, Qingyue Da & Shuyu Zhang

  2. Department of Pharmacy, The 940th Hospital of Joint Logistics Support force of PLA, Lanzhou, 730050, Gansu, People’s Republic of China

    Linlin Jing, Qingyue Da, Shuyu Zhang, Jie Zhang & Huiping Ma

  3. Department of Neurology, The Fifth Affiliated Hospital of Zunyi Medical University, NO.1439 Zhufeng Road, Doumen District, Zhuhai, 519000, Guangdong, People’s Republic of China

    Hongbo Luo

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Contributions

LLJ and HBL: conceived and supervised the study; LLJ and HPM: designed experiments; QYD, JZ, SYZ and HPM: performed experiments; QYD and JZ: analyzed data; LLJ and QYD: wrote the manuscript; LLJ, HPM and HBL: revised manuscript. All authors read and approved the final manuscript.

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Correspondence to Linlin Jing or Hongbo Luo.

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The current study was conducted strictly according to the principles and procedures approved by Animal Care and Use of the 940th Hospital of Joint Logistic Support Force of PLA (2018kyll015). All efforts were made to minimize the number of mice used and their suffering.

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Jing, L., Da, Q., Zhang, S. et al. Nitronyl Nitroxide Ameliorates Hypobaric Hypoxia-Induced Cognitive Impairment in Mice by Suppressing the Oxidative Stress, Inflammatory Response and Apoptosis. Neurochem Res 49, 785–799 (2024). https://doi.org/10.1007/s11064-023-04080-x

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