Hypobaric Hypoxia Induces Deficits in Adult Neurogenesis and Social Interaction via Cyclooxygenase-1/ EP1 Receptor Pathway Activating NLRP3 Inflammasome.

Low oxygen environments, like hypobaric hypoxia (HH), are common nodes in a number of diseases characterized by neuroinflammation, which is detrimental to the structural and functional aspects of hippocampal circuitry. Hypoxic conditions lead to elevation of inflammasome-mediated inflammation that may contribute to cognitive deficits. However, a systematic investigation of the impact of inflammasome-mediated neuroinflammation on the components of neurogenic niche during HH remains to be elusive. Cerebral hypoxia was induced in adult male Sprague Dawley rats via decreasing partial pressure of oxygen. The effect of HH (1, 3, and 7 days at 25,000 ft) on social memory, anxiety, adult neurogenesis, and NLRP3- (NLR family pyrin domain containing 3) mediated neuroinflammation in the dentate gyrus (DG) was explored in detail. Furthermore, we explored the therapeutic efficacy of cyclooxygenase-1 inhibitor (valeryl salicylate, 5 mg/kg/day, i.p.) and EP1 receptor (EP1R) antagonist (SC19220, 1 mg/kg/day, i.p.) on HH-induced deficits. Seven days of HH exposure induced alteration in social and anxiety-like behavior along with perturbation in adult neurogenesis. Elevation in NLRP3, caspase-1, and IL-1β levels was observed during HH from day 1. A notable increase in the COX-1/EP1R pathway in activated glial cells in DG was evident during HH. COX-1 inhibitor and EP1R antagonist mitigated the detrimental effects of HH on social memory, adult neurogenesis via blunting NLRP3-mediated inflammation. Our data showed induction of the COX-1/EP1R pathway in the glial cells, which is detrimental to neurogenesis and social memory, opening up the possibility that the COX-1/EP1R pathway is a plausible target for inflammasome-related neurogenesis impairments.