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  • br Conclusion br Acknowledgement The

    2019-12-13


    Conclusion
    Acknowledgement The project was supported by National Natural Science Foundation of China, China (No. 31872535); Natural Science Foundation of Shandong Province, China (ZR2018MC027, ZR2016CQ29); and Funds of Shandong \"Double Tops\" Program, China.
    Introduction High-altitude hypoxia (HH) Etoricoxib is a public health risk for a diverse population, including travelers, mountaineers, military personnel, miners, and skiers. It occurs due to a low partial pressure of oxygen, which translates into decreases in tissue oxygen availability, eventually disrupting tissue homeostasis (Gallagher and Hackett, 2004, Netzer et al., 2013, Wilson et al., 2009). The extent and severity of cognitive impairment at high altitude is determined by the duration of exposure. Acute exposure prevails in the early days of HH, subacute exposure occurs as an intermediate stage, and chronic exposure occurs with weeks to years of HH (Yan, 2014). Physiological responses tend to restore homeostasis to allow survival and adaptation. However, chronic HH stress results in a spectrum of symptoms, including impaired cerebral auto-regulation, gliovascular deficit, oxidative stress, inflammation, and cognitive deficit (Bailey et al., 2009, MacInnis et al., 2010, Rodway et al., 2003). The cognitive deficits produced by HH are known to be caused by early-phase responses, such as gliovascular dysfunction, formation of oxygen-derived free radicals, and inflammation (Kumar et al., 2016, Zhou et al., 2017). Moreover, the hypoxic brain is vulnerable to these early events due to the presence of high concentrations of polyunsaturated fatty acids (PUFA), such as arachidonic Etoricoxib (AA), which are prone to oxidation (Rink and Khanna, 2011). Oxidation of AA leads to the formation of various biologically active metabolites, including prostaglandins (PGs). PGs are significantly elevated in subjects after four days at high altitude (Liao et al., 2016). AA, produced from membrane phospholipids by phospholipase A2 activity, is the main substrate for COX-1 and COX-2 enzymes, which catalyse the formation of an intermediate, prostaglandin H2 (PGH2). PGH2 is subsequently converted into PGE2 by PGE2 synthase enzymes (Jiang and Dingledine, 2013). AA metabolites like PGE2 upon acute HH exposure may contribute to clinical manifestation of acute mountain sickness (AMS) with symptoms including headaches (Sun et al., 2017). However, Phospholipase A2 release AA metabolites produce oxygen free radicals that upon chronic hypoxia exposure can directly damage vessel basement membranes, may trigger vasogenic oedema in some cases (Tanaka et al., 2003, Wilson et al., 2009). A significant elevation in the concentration of PGs, especially PGE2, has been observed in the plasma of acute mountain sickness (AMS) subjects after three and four days of HH exposure (Richalet et al., 1991). Alterations in AA metabolism and an increase in the production of PGs significantly contribute to HH-induced conditions (Benedetti et al., 2014, Liao et al., 2016). In addition, numerous studies have shown that non-steroidal anti-inflammatory drugs (NSAIDs), like indomethacin, naproxen, aspirin, and ibuprofen, which act by impeding PG synthesis, are effective at reducing HH-induced maladies (Burtscher, 1999, Burtscher et al., 2001, Goswami et al., 2012). However, the mechanism by which hypoxia-induced PGE2 production is temporally regulated by inducible COX-2 or constitutively expressed COX-1 and then exerts its downstream effect on neurophysiology during HH, remains unknown. Moreover, there are evidences about association between inflammation and cognitive impairment in many conditions, such as acute mountain sickness (AMS) and high altitude cerebral oedema (HACE). A recent study showed a significant increase in plasma TNF-α, IL-1β, and IL-6 levels when volunteers were exposed to an altitude of 3860 m (Song et al., 2016). Acute exposure of mice to HH in combination with LPS results in augmented levels of proinflammatory cytokines in the plasma, which contribute to brain oedema (Zhou et al., 2017).