TY - JOUR

T1 - Neuroprotectants attenuate hypobaric hypoxia-induced brain injuries in cynomolgus monkeys

AU - Zhang, Pei

AU - Chen, Jie-Si

AU - Li, Qi-Ye

AU - Sheng, Long-Xiang

AU - Gao, Yi-Xing

AU - Lu, Bing-Zheng

AU - Zhu, Wen-Bo

AU - Zhan, Xiao-Yu

AU - Li, Yuan

AU - Yuan, Zhi-Bing

AU - Xu, Gang

AU - Qiu, Bi-Tao

AU - Yan, Min

AU - Guo, Chun-Xue

AU - Wang, You-Qiong

AU - Huang, Yi-Jun

AU - Zhang, Jing-Xia

AU - Liu, Fu-Yu

AU - Tang, Zhong-Wei

AU - Lin, Sui-Zhen

AU - Cooper, David N

AU - Yang, Huan-Ming

AU - Wang, Jian

AU - Gao, Yu-Qi

AU - Yin, Wei

AU - Zhang, Guo-Jie

AU - Yan, Guang-Mei

PY - 2019/12/13

Y1 - 2019/12/13

N2 - 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 ( Macacafascicularis) 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.

AB - 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 ( Macacafascicularis) 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.

KW - Acute hypobaric hypoxia

KW - Brain injury

KW - Cynomolgus monkeys

KW - Gene regulatory networks

KW - Neuroprotectant

U2 - 10.24272/j.issn.2095-8137.2020.012

DO - 10.24272/j.issn.2095-8137.2020.012

M3 - Review

C2 - 31840949

VL - 41

SP - 3

EP - 19

JO - Zoological research

JF - Zoological research

SN - 2095-8137

IS - 1

ER -