Volume 41 Issue 1
Jan.  2020
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Pei Zhang, Jie-Si Chen, Qi-Ye Li, Long-Xiang Sheng, Yi-Xing Gao, Bing-Zheng Lu, Wen-Bo Zhu, Xiao-Yu Zhan, Yuan Li, Zhi-Bing Yuan, Gang Xu, Bi-Tao Qiu, Min Yan, Chun-Xue Guo, You-Qiong Wang, Yi-Jun Huang, Jing-Xia Zhang, Fu-Yu Liu, Zhong-Wei Tang, Sui-Zhen Lin, David N. Cooper, Huan-Ming Yang, Jian Wang, Yu-Qi Gao, Wei Yin, Guo-Jie Zhang, Guang-Mei Yan. Neuroprotectants attenuate hypobaric hypoxia-induced brain injuries in cynomolgus monkeys. Zoological Research, 2020, 41(1): 3-19. doi: 10.24272/j.issn.2095-8137.2020.012
Citation: Pei Zhang, Jie-Si Chen, Qi-Ye Li, Long-Xiang Sheng, Yi-Xing Gao, Bing-Zheng Lu, Wen-Bo Zhu, Xiao-Yu Zhan, Yuan Li, Zhi-Bing Yuan, Gang Xu, Bi-Tao Qiu, Min Yan, Chun-Xue Guo, You-Qiong Wang, Yi-Jun Huang, Jing-Xia Zhang, Fu-Yu Liu, Zhong-Wei Tang, Sui-Zhen Lin, David N. Cooper, Huan-Ming Yang, Jian Wang, Yu-Qi Gao, Wei Yin, Guo-Jie Zhang, Guang-Mei Yan. Neuroprotectants attenuate hypobaric hypoxia-induced brain injuries in cynomolgus monkeys. Zoological Research, 2020, 41(1): 3-19. doi: 10.24272/j.issn.2095-8137.2020.012

Neuroprotectants attenuate hypobaric hypoxia-induced brain injuries in cynomolgus monkeys

doi: 10.24272/j.issn.2095-8137.2020.012
Funds:  This study was supported by the National Natural Science Foundation of China (81773711) to W. Y., Strategic Priority Research Program of the Chinese Academy of Sciences (XDB13000000), Lundbeck Foundation Grant (R190-2014-2827), and Carlsberg Foundation Grant (CF16-0663) to G. J. Z., Science and Technology Program of Guangzhou, China (201704020103) to W. Y., Introduction of Innovative R&D Team Program of Guangdong Province (2013Y104), Leading Talent Project in Science and Technology of Guangzhou Development District (2019-L002), and National Major Scientific and Technological Special Project for“Significant New Drugs Development” (2016ZX09101026) to S.Z.L., and Key Projects of the Military Science and Technology PLA (AWS14C007 and AWS16J023) to Y.Q.G
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  • Hypobaric hypoxia (HH) exposure can cause serious brain injury as well as life-threatening cerebral edema in severe cases. Previous studies on the mechanisms of HH-induced brain injury have been conducted primarily using non-primate animal models that are genetically distant to humans, thus hindering the development of disease treatment. Here, we report that cynomolgus monkeys (Macaca fascicularis) exposed to acute HH developed human-like HH syndrome involving severe brain injury and abnormal behavior. Transcriptome profiling of white blood cells and brain tissue from monkeys exposed to increasing altitude revealed the central role of the HIF-1 and other novel signaling pathways, such as the vitamin D receptor (VDR) signaling pathway, in co-regulating HH-induced inflammation processes. We also observed profound transcriptomic alterations in brains after exposure to acute HH, including the activation of angiogenesis and impairment of aerobic respiration and protein folding processes, which likely underlie the pathological effects of HH-induced brain injury. Administration of progesterone (PROG) and steroid neuroprotectant 5α-androst-3β,5,6β-triol (TRIOL) significantly attenuated brain injuries and rescued the transcriptomic changes induced by acute HH. Functional investigation of the affected genes suggested that these two neuroprotectants protect the brain by targeting different pathways, with PROG enhancing erythropoiesis and TRIOL suppressing glutamate-induced excitotoxicity. Thus, this study advances our understanding of the pathology induced by acute HH and provides potential compounds for the development of neuroprotectant drugs for therapeutic treatment.

  • #Authors contributed equally to this work
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