Neuroprotectants attenuate hypobaric hypoxia-induced brain injuries in cynomolgus monkeys  

作　　者：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 NCooper Huan-Ming Yang Jian Wang Yu-Qi Gao Wei Yin Guo-Jie Zhang Guang-Mei Yan 

机构地区：[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 CF144XN,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

出　　处：《Zoological Research》2020年第1期3-19,共17页动物学研究（英文）

基　　金：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);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);National Major Scientific and Technological Special Project for “Significant New Drugs Development”(2016ZX09101026)to S.Z.L.;Key Projects of the Military Science and Technology PLA(AWS14C007 and AWS16J023)to Y.Q.G

摘　　要：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.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 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 neuroprotectant5α-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.

关 键 词：Acute hypobaric hypoxia Cynomolgus monkeys Brain injury NEUROPROTECTANT Gene regulatory networks 

分 类 号：R339.5[医药卫生—人体生理学]