Zoological Research ›› 2020, Vol. 41 ›› Issue (1): 3-19.doi: 10.24272/j.issn.2095-8137.2020.012

Special Issue: Animal models Primates Neuroscience

• Articles • Previous Articles     Next Articles

Neuroprotectants attenuate hypobaric hypoxia-induced brain injuries in cynomolgus monkeys

Pei Zhang1,2,3, Jie-Si Chen4, Qi-Ye Li2, Long-Xiang Sheng4, Yi-Xing Gao5,6,7, Bing-Zheng Lu4, Wen-Bo Zhu4, Xiao-Yu Zhan2, Yuan Li4, Zhi-Bing Yuan5,6,7, Gang Xu5,6,7, Bi-Tao Qiu3, Min Yan4, Chun-Xue Guo2, You-Qiong Wang4, Yi-Jun Huang4, Jing-Xia Zhang8, Fu-Yu Liu5,6,7, Zhong-Wei Tang5,6,7, Sui-Zhen Lin9, David N. Cooper10, Huan-Ming Yang2,11, Jian Wang2,11, Yu-Qi Gao5,6,7,*(), Wei Yin12,*(), Guo-Jie Zhang1,3,13,14,*(), Guang-Mei Yan4,*()   

  1. 1 State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650223, China
    2 BGI-Shenzhen, Shenzhen, Guangdong 518083, China
    3 Section for Ecology and Evolution, Department of Biology, University of Copenhagen, Copenhagen DK-2100, Denmark
    4 Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, Guangdong 510080, China
    5 Institute of Medicine and Hygienic Equipment for High Altitude Region, College of High Altitude Military Medicine, Third Military Medical University, Chongqing 400038, China
    6 Key Laboratory of High Altitude Medicine of People's Liberation Army, Chongqing 400038, China
    7 Key Laboratory of High Altitude Environmental Medicine, Third Military Medical University, Ministry of Education, Chongqing 400038, China
    8 School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, Guangdong 510006, China
    9 Guangzhou Cellprotek Pharmaceutical Co. Ltd., Guangzhou, Guangdong 510663, China
    10 Institute of Medical Genetics, School of Medicine, Cardiff University, Cardiff CF14 4XN, UK
    11 James D. Watson Institute of Genome Sciences, Hangzhou, Zhejiang 310058, China
    12 Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, Guangdong 510080, China
    13 Center for Excellence in Animal Evolution and Genetics, Chinese Academy of Sciences, Kunming, Yunnan 650223, China
    14 China National Genebank, BGI-Shenzhen, Shenzhen, Guangdong 518120, China
  • Received:2019-12-02 Accepted:2019-12-11 Online:2020-01-18 Published:2020-01-09
  • Contact: Yu-Qi Gao,Wei Yin,Guo-Jie Zhang,Guang-Mei Yan E-mail:gaoy66@yahoo.com;yinwei@mail.sysu.edu.cn;guojie.zhang@bio.ku.dk;ygm@mail.sysu.edu.cn
  • Supported by:
    the National Natural Science Foundation of China(81773711);Strategic Priority Research Program of the Chinese Academy of Sciences(XDB13000000);Lundbeck Foundation Grant(R190-2014-2827);Carlsberg Foundation Grant(CF16-0663);Science and Technology Program of Guangzhou, China(201704020103);Introduction of Innovative R&D Team Program of Guangdong Province(2013Y104);Leading Talent Project in Science and Technology of Guangzhou Development District(2019-L002);National Major Scientific and Technological Special Project for“Significant New Drugs Development”(2016ZX09101026);Key Projects of the Military Science and Technology PLA(AWS14C007);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

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) 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.

Key words: Acute hypobaric hypoxia, Cynomolgus monkeys, Brain injury, Neuroprotectant, Gene regulatory networks