title: Corticosterone synthesis inhibitor metyrapone ameliorates chronic hypobaric hypoxia induced memory impairment in rat.
abstract: Chronic exposure to hypobaric hypoxia causes oxidative stress and neurodegeneration leading to memory impairment. The present study aimed at investigating the role of corticosterone in hypoxia induced neurodegeneration and effect of metyrapone, a corticosterone synthesis inhibitor that reduces the stress induced elevation of corticosterone without affecting the basal level, in ameliorating chronic hypobaric hypoxia induced cognitive decline. Rats were exposed to simulated altitude of 25,000 ft for 0, 3, 7, 14 and 21 days to determine the temporal alterations in corticosterone and its receptors following exposure to hypobaric hypoxia. Our results showed an elevation of corticosterone in plasma and hippocampal tissue following 7 days of exposure, which declined on prolonged hypoxic exposure for 21 days. A concomitant increase in ROS and lipid peroxidation was observed along with depletion of intracellular antioxidants. Glucocorticoid and mineralocorticoid receptors were upregulated on 3 and 7 days of hypoxic exposure. Though expression of Glut1 and Glut3 were upregulated on 3 days of hypoxic exposure, sharp decline in Glut1 expression following 7 days of hypoxic exposure leads to reduced neuronal glucose uptake. Administration of metyrapone from 3rd to 7th day of hypoxic exposure to suppress hypoxia induced increase in corticosterone levels resulted in reduced oxidative damage, neurodegeneration and improvement of intracellular energy status. The metyrapone treated hypoxic animals performed better in the Morris Water Maze. Further, administration of exogenous corticosterone along with metyrapone during hypoxic exposure blunted the neuroprotective effect of metyrapone indicating a role for corticosterone in mediating hypobaric hypoxia induced neurodegeneration and memory impairment.
authors.affiliation: Defence Institute of Physiology and Allied Sciences, Defence Research Development Organisation, Lucknow Road, Delhi-54, India.
authors.forename: Iswar
authors.initials: I
authors.lastname: Baitharu
authors.forename: Satya Narayan
authors.initials: SN
authors.lastname: Deep
authors.forename: Vishal
authors.initials: V
authors.lastname: Jain
authors.forename: Kalpana
authors.initials: K
authors.lastname: Barhwal
authors.forename: Anand Swaroop
authors.initials: AS
authors.lastname: Malhotra
authors.forename: Sunil Kumar
authors.initials: SK
authors.lastname: Hota
authors.forename: Dipti
authors.initials: D
authors.lastname: Prasad
authors.forename: Govindasamy
authors.initials: G
authors.lastname: Ilavazhagan
mesh_terms: D000532:Altitude Sickness / Q000139:chemically induced / Q000150:complications / Q000188:drug therapy / Q000378:metabolism / Q000523:psychology; D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D003345:Corticosterone / Q000097:blood / Q000378:metabolism / Q000494:pharmacology; D004347:Drug Interactions; D005947:Glucose / Q000378:metabolism; D051272:Glucose Transporter Type 1 / Q000378:metabolism; D051274:Glucose Transporter Type 3 / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D000860:Hypoxia / Q000139:chemically induced / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism / Q000523:psychology; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008569:Memory Disorders / Q000139:chemically induced / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism; D008797:Metyrapone / Q000037:antagonists & inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D018696:Neuroprotective Agents / Q000037:antagonists & inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D018161:Receptors, Mineralocorticoid / Q000378:metabolism; D013252:Steroid 11-beta-Hydroxylase / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000975:Antioxidants; D051272:Glucose Transporter Type 1; D051274:Glucose Transporter Type 3; D018696:Neuroprotective Agents; D017382:Reactive Oxygen Species; D011965:Receptors, Glucocorticoid; D018161:Receptors, Mineralocorticoid; C495679:Slc2a1 protein, rat; C495690:Slc2a3 protein, rat; D013252:Steroid 11-beta-Hydroxylase; D005947:Glucose; D003345:Corticosterone; D008797:Metyrapone