Hypobaric hypoxia, an environmental condition arising due to the reduced partial pressure of oxygen on ascent to high altitude, is known to cause memory impairment. The mechanism underlying the cognitive dysfunction has been attributed to oxidative stress, glutamate excitotoxicity and Ca2+ mediated death cascade. Though the role of corticosterone in higher order brain function including cognition has been well documented in restrained stress, social stress and other moderate stress, its impact in hypobaric hypoxia induced cognitive dysfunction still remains to be investigated. To determine the effect, five groups of rat were exposed in a simulated decompression chamber at an altitude of 25 000 ft for 0, 3, 7, 14 and 21 days. Corticosterone synthesis was blocked using metyrapone (75 mg/kg BW) on the day showing maximum corticosterone level and neuronal damage. Our study revealed a duration dependent elevation in corticosterone level in plasma and hippocampus. There was increased ROS generation, decreased antioxidant defence system and compromised neuronal energy status. Exposure to hypobaric hypoxia upregulated the expression of glucocorticoid and mineralocorticoid receptor in a duration dependent manner. Neuronal glucose transporter Glut3 and bloodbrain barrier glucose transporter Glut1 was found to be upregulated during initial period of exposure to hypobaric hypoxia. There was decreased citrate synthase activity and increased glutamate dehydrogenase activity along with altered expression of proteins (MDR1apG and HSD1) regulating the corticosterone bioavailability in hippocampus. These findings suggest that chronic elevation in corticosterone level may lead to induction of glutamate excitotoxicity, perturbance in neuronal energy status and enhanced oxidative stress leading to neuronal damage and ultimately to memory impairment following exposure to hypobaric hypoxia as shown by behaviour studies. Maintenance of optimal corticosterone level by metyrapone administration however reduced oxidative damage, improved energy status, reduced caspase 3 expression in CA3 region of the hippocampus indicating reduced neurodegeneration and improved memory functions.
Key words: Glut1, hypobaric hypoxia, metyrapone, hippocampus, corticosterone, citrate synthase.