While a growing body of
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.
Materials and methods
Discussion Systemic responses to HH are multifaceted, and they function to restore homeostasis to allow survival and PyBOP kinase under normal conditions. However, excessive and frequent HH stress results in deleterious health consequences, such as impaired cerebral auto-regulation, glio-vascular deficit, oxidative stress, and neuroinflammation, ultimately translating into cognitive deficit (Wilson et al., 2009). The duration of HH exposure determines the clinical manifestations. For example, AMS occurs with acute exposure, whereas high altitude cerebral oedema and high altitude pulmonary oedema occur with chronic exposure. These manifestations most likely occur through temporal molecular orchestrations (Yan, 2014). To understand how initial disease triggers, translate into inflammatory responses and neurodegeneration, it is essential to decipher the specific pathways and cell types that are involved. The AA pathway was investigated in this study, since its metabolites are well known neuroimmunomodulators. Notably, hypoxia increases AA metabolism and AA metabolites are known to affect brain physiology. AA metabolites affect synaptic plasticity, excitotoxicity, cerebrovascular regulation, oxidative stress, neurodegeneration, and neuroinflammation, all of which are also implicated in the pathogenesis of HH (Attwell et al., 2010, Choi et al., 2009, Hoda et al., 2009, Kaizaki et al., 2013, Yang and Chen, 2008). In this study, we reported that HH exposure increases the concentration of AA and PLA2, which then triggers the metabolic pathway. Similar studies on human subjects have also shown that AA metabolism increases after ascending to an altitude of 5300 m (Liao et al., 2016, Liu et al., 2018). In this study, we have illuminated the temporal dynamics of COX-1 and COX-2 expression in the hippocampus during HH exposure. Changes in COX expression were found to depend on the number of days of exposure to HH. COX-2 was up regulated after 1 day of exposure and reached a maximum level at day 3, while COX-1 expression showed a progressive increase. The changes in COX expression shown to follow similar trend with PGE2 levels in the hippocampus. PGE2 concentration increased in both the hippocampus and plasma. This agrees with previous studies reporting higher plasma PGE2 levels at day 3 and day 4 of HH exposure in humans and rodents (Richalet et al., 1991). Cognitive deficits are a prominent consequence of HH, reported in many previous studies (Kauser et al., 2014, Kumar et al., 2016, Kumari et al., 2018). Notably, cognitive deficits due to HH exposure restored with prolonged stay until cerebral oedema develops. Previous studies using same model reported that HH induced maximum effect on hippocampus based memory occurs at 7th day which gets restored with continued exposure of 14 and 21 days as system attain homeostasis (Kumari et al., 2018, Maiti et al., 2008). However, chronic exposure which occurs at real life mountaineering or long term habitation can sometimes lead to irreversible neuronal damage and cognitive deficits even after long acclimatization (Yan, 2014).