Neuroprotectants attenuate hypobaric hypoxia-induced brain injuries in cynomolgus monkeys

作者：Pei Zhang, Jie-Si Chen, Qiye Li, Longxiang Sheng, Gao Yi-Xing, Bingzheng Lu, Wenbo Zhu, Zhan Xiao-Yu, Li Yuan, Zhi-Bing Yuan, Gang Xu, Bitao Qiu, Yan Min, Chunxue Guo, Wang You-Qiong, Yijun Huang, Jingxia Zhang, Liu Fu-Yu, Zhong-wei Tang, Lin Sui-Zhen, Nelson David, Huanming Yang, Jian Wang, Yuqi Gao, Wei Yin, Zhang Guo-Jie, Yan Guang-Mei · 发表于：动物学研究 · 年份：2020 · DOI：10.24272/j.issn.2095-8137.2020.012 · 被引用次数：24 · 研究领域：High Altitude and Hypoxia、Cancer, Hypoxia, and Metabolism、Neuroscience of respiration and sleep

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 excitotox...