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.
Highlights
High altitude, which represents one of the most extreme environments on Earth, creates hypobaric hypoxia (HH) conditions to which only a small proportion of people can adapt
Monkeys develop severe brain injuries under acute HH conditions that can be significantly alleviated by PROG and TRIOL Twenty-four healthy, adult male cynomolgus monkeys were classified into four groups (n=6): i. e., normobaric normoxia (NN), HH, HH+PROG, and HH+TRIOL
To characterize the behavioral and pathological changes caused by acute HH and to assess the drug effects, animals from the HH, HH+PROG, and HH+TRIOL groups were placed in a hypobaric chamber, which mimicked ascending altitudes from 320 to 7 500 m at a velocity of 2–3 m/s (HH group)
Summary
High altitude, which represents one of the most extreme environments on Earth, creates hypobaric hypoxia (HH) conditions to which only a small proportion of people can adapt. As the brain is the most hypoxia-intolerant organ, most people who ascend too rapidly to high altitudes cannot acclimatize to the HH environment and frequently suffer from a range of symptoms caused by acute hypoxia (Wilson et al, 2009). With over 35 million people around the world traveling to high-altitude regions annually for tourism, sport, or work (Martin & Windsor, 2008), brain damage caused by HH has become a health hazard for lowland people who move to high altitudes. The main mechanisms underlying brain damage include metabolic disturbance of neural cells, increased permeability of brain microvasculature, and oxidative stress (Basnyat & Murdoch, 2003; Wilson et al, 2009). Details on the cascades and gene regulatory networks through which brain damage is induced by HH have not yet been determined
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