Neuroprotectants attenuate hypobaric hypoxia-induced brain injuries in cynomolgus monkeys
Neuroprotectants attenuate hypobaric hypoxia-induced brain injuries in cynomolgus monkeys
复制标题
神经保护剂可减轻食蟹猴低压缺氧引起的脑损伤。
DOI：
10.24272/j.issn.2095-8137.2020.012
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发表时间：
2020-01-18
影响因子：
4.9
通讯作者：
Yan, Guang-Mei
中科院分区：
文献类型：
--
作者：
Zhang, Pei;Chen, Jie-Si;Yan, Guang-Mei
低压缺氧（HH）暴露可导致严重的脑损伤，严重时还会引发危及生命的脑水肿。以往关于HH诱导脑损伤机制的研究主要使用与人类基因差异较大的非灵长类动物模型，这阻碍了疾病治疗方法的开发。在此，我们报告称，暴露于急性HH环境下的食蟹猴（食蟹猕猴）出现了类似人类的HH综合征，包括严重的脑损伤和行为异常。对暴露于不同海拔高度的猴子的白细胞和脑组织进行转录组分析后发现，缺氧诱导因子 - 1（HIF - 1）以及其他新的信号通路，如维生素D受体（VDR）信号通路，在共同调节HH诱导的炎症过程中发挥核心作用。我们还观察到，急性HH暴露后，猴子大脑发生了显著的转录组改变，包括血管生成的激活以及有氧呼吸和蛋白质折叠过程的受损，这些很可能是HH诱导脑损伤病理效应的基础。给予黄体酮（PROG）和类固醇神经保护剂5α - 雄甾 - 3β,5,6β - 三醇（TRIOL）可显著减轻脑损伤，并挽救急性HH诱导的转录组变化。对受影响基因的功能研究表明，这两种神经保护剂通过靶向不同的途径来保护大脑，PROG增强红细胞生成，而TRIOL抑制谷氨酸诱导的兴奋性毒性。因此，本研究增进了我们对急性HH所致病理的理解，并为开发用于治疗的神经保护药物提供了潜在的化合物。
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 5 alpha-androst-3 beta,5,6 beta-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.