Moreover the hypoxic brain is vulnerable to these

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 p2y inhibitor (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). While a growing body of knowledge demonstrates the importance of COX-1 and COX-2 accompanied with neuroinflammation in altitude related conditions. In fact, PGE2 has been widely thought to promote the neuronal inflammation and degeneration in many neurological maladies (Griffin et al., 2013, Jiang and Dingledine, 2013). As COX-1 is predominantly present in microglia, can secrete PGE2 and proinflammatory cytokines in response to inflammatory stimuli. However, COX-2 which is mostly expressed in pyramidal neurons, contributes predominantly to elevation in PG levels in response to insults that directly challenge neurons (Choi et al., 2009) However, it is still unresolved how hypoxia induced PGE2 production is temporally regulated by inducible COX-2 versus constitutively expressed COX-1 isoform and exerts its downstream effect on neurophysiology in HH condition. Nevertheless, it is unknown how COXs isoform are expressed in brain cell type and acts in a time resolved manner in response to HH. Here we have selected three-time point named, 1HH (acute), 3HH (sub acute), 7HH (short term) determined by chronicity of HH exposure (Maiti et al., 2008). Keeping in view of this, we hypothesize that COX isoform have differential role on cognition, neuroinflammation and neurodegeneration during acute HH exposure. The findings of the study could lead to revisiting current therapeutic strategies and open new approaches for the treatment of HH induced neuropathological conditions.