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Zoological Research
Kunming Institute of Zoology, Chinese Academy of Sciences
ISSN: 2095-8137
Vol. 41, No. 1, 2020, pp. 3-19
Bioline Code: zr20002
Full paper language: English
Document type: Research Article
Document available free of charge

Zoological Research, Vol. 41, No. 1, 2020, pp. 3-19

 en Neuroprotectants attenuate hypobaric hypoxia-induced brain injuries in cynomolgus monkeys
Zhang, Pei; Chen, Jie-Si; Li, Qi-Ye; Sheng, Long-Xiang; Gao, Yi-Xing; Lu, Bing-Zheng; Zhu, Wen-Bo; Zhan, Xiao-Yu; Li, Yuan; Yuan, Zhi-Bing; Xu, Gang; Qiu, Bi-Tao; Yan, Min; Guo, Chun-Xue; Wang, You-Qiong; Huang, Yi-Jun; Zhang, Jing-Xia; Liu, Fu-Yu; Tang, Zhong-Wei; Lin, Sui-Zhen; Cooper, David N.; Yang, Huan-Ming; Wang, Jian; Gao, Yu-Qi; Yin, Wei; Zhang, Guo-Jie & Yan, Guang-Mei

Abstract

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 check for this species in other resources ) exposed to acute HH developed humanlike 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.

Keywords
Acute hypobaric hypoxia; Cynomolgus monkeys; Brain injury; Neuroprotectant; Gene regulatory networks

 
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