title: Inhibition of glucocorticoid receptors ameliorates hypobaric hypoxia induced memory impairment in rat.
abstract: Chronic exposure to hypobaric hypoxia (HH) causes neurodegeneration and loss of memory. The underlying mechanisms of HH induced memory impairment have been attributed to prolonged elevated corticosterone level in hippocampus leading to augmented glutamate excitotoxicity, oxidative stress, alteration of neurotransmitter level or their receptors and calcium mediated signaling. Whether this corticosterone mediated neurodegenerative effect occurs through overstimulation of glucocorticoid receptors (GRs) or is independent of the GRs, is not known. Four groups of rats were taken and GR blocker mifepristone was administered intraperitoneally during exposure to HH from 3rd to 7th days. Our results showed a duration dependent transcriptional upregulation of GRs and MRs following exposure to HH. Prolonged exposure to HH for 7 days augmented the translocation of GRs from cytosol to nucleus. Inhibition of GRs during hypoxic exposure improved the hippocampal ATP level and modulated the apoptotic markers like p53, Bcl(2) and Bax. Decreased expression of L-type calcium channel and NR1 subunit of NMDA receptors were also observed following administration of mifepristone during hypoxic exposure. Morphological studies following mifepristone administration during hypoxic exposure showed decreased number of pyknotic cells in hippocampus and decrease in apoptotic and necrotic cells in the CA3 region of hippocampus. The study indicates that elevated corticosterone level during hypoxic exposure causes neurodegeneration and acts through its binding to GRs indicating that inhibition of GRs may provide therapeutic effect in ameliorating HH induced 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: Dipti
authors.initials: D
authors.lastname: Prasad
authors.forename: G
authors.initials: G
authors.lastname: Ilavazhagan
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D020746:Calcium Channels, L-Type / Q000187:drug effects / Q000378:metabolism; D003345:Corticosterone / Q000502:physiology*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002534:Hypoxia, Brain / Q000150:complications* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008569:Memory Disorders / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D015735:Mifepristone / Q000494:pharmacology*; D009336:Necrosis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000187:drug effects / Q000378:metabolism; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D011965:Receptors, Glucocorticoid / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000187:drug effects / Q000378:metabolism; D015854:Up-Regulation; D051028:bcl-2-Associated X Protein / Q000187:drug effects / Q000378:metabolism
chemical_list: D020746:Calcium Channels, L-Type; C409466:NR1 NMDA receptor; C542344:NR3C1 protein, rat; D019253:Proto-Oncogene Proteins c-bcl-2; D011965:Receptors, Glucocorticoid; D016194:Receptors, N-Methyl-D-Aspartate; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D015735:Mifepristone; D003345:Corticosterone