Inhibition of glucocorticoid receptors ameliorates hypobaric hypoxia induced memory impairment in rat

Baitharu, Iswar; Deep, Satya Narayan; Jain, Vishal; Prasad, Dipti; Ilavazhagan, G.

doi:10.1016/j.bbr.2012.11.005

Cited by 22 publications

(8 citation statements)

References 57 publications

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“…In line with the previous reports, the present finding support the corticosterone hypothesis of depression which reports that persistent elevated corticosterone play a major role in induction of depression [48]. Recent observations from our laboratory also showed that persistent elevated corticosterone level in the hippocampal region of the brain aggravates HH induced neurodegeneration and memory impairment and optimal maintenance of corticosterone level in hippocampus resulted in improved memory function [15]. Moreover, neuronal loss and reduction in hippocampal volume in depressed patient may be correlated the elevated level of corticosterone in hippocampus.…”

supporting

confidence: 92%

“…Hypothalamic corticosteroid releasing factor overexpression contributes to HPA axis hyperactivity in psychiatric patients [13]. Persistent elevation in corticosterone level following prolonged exposure to HH leads to augmented neurodegeneration and memory impairment [14,15]. Apart from HPA axis hyperactivity, altered glutamatergic neurotransmission has been a major pathological factor in depression and glutamatergic agents have demonstrated rapid and robust antidepressant activity in humans.…”

Section: Introductionmentioning

confidence: 99%

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Exposure to Hypobaric Hypoxia and Reoxygenation Induces Transient Anxiety-Like Behavior in Rat

Baitharu¹,

Jain²,

Deep³

et al. 2013

JBBS

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Chronic exposure to hypobaric hypoxia (HH) causes memory impairment and prolonged state of mental confusion. However, effect of high altitude exposure on mood state and its underlying mechanisms have been poorly studied. Present study was undertaken to investigate the mood state alteration following chronic exposure to HH. Male Sprague Dawley rats were divided into five groups and exposed to hypoxia for 3, 7, 14 and 21 days in an animal decompression chamber at an altitude of 25,000ft. Anxiety-and depression-like behaviors were assessed by using various mazes along with changes in serotonin and glutamate level. Our study revealed a decrease in exploratory, grooming and rearing behavior in open field test following initial exposure to HH for 7 days without affecting the locomotory behavior. Initial exposure to HH-decreased time spent in open arm of elevated plus maze indicating induction of anxiety-like behavior which normalized on prolonged hypoxic exposure for 21 days. Hypoxic exposure for 7 days induced anhedonia and increased despair behavior in rat while there was steady improvement in these behaviors when exposed for 21 days. Decrease in serotonin level was noted in hippocampus along with elevated corticosterone and glutamate level which gradually decreased on prolonged exposure to HH. These findings suggest that initial exposure to HH increases transient anxiety-like behavior in rats followed by gradual improvement in mood state on prolonged exposure. Further, the study also indicates the involvement of serotonergic system in mood state alteration at high altitude following chronic exposure and reoxygenation.

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supporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Exposure to Hypobaric Hypoxia and Reoxygenation Induces Transient Anxiety-Like Behavior in Rat

Baitharu¹,

Jain²,

Deep³

et al. 2013

JBBS

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“…Exposure to hypobaric hypoxia in rats induces glutamate excitotoxicity and increases influx of calcium ion by NR1 subunit of NMDA receptor and L-type calcium channel upregulation. 21,22,26 It also induces oxidative stress 18,[20][21][22]34 via apoptotic signalling pathways leading to hippocampal cell apoptosis. 26,27,32 Hypobaric hypoxia exposure also impairs cholinergic 28,29 and adrenergic 37,38 systems and lowers BDNF level which are important for memory function.…”

Section: Resultsmentioning

confidence: 99%

Insight into potential mechanisms of hypobaric hypoxia–induced learning and memory deficit – Lessons from rat studies

et al. 2017

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Impairment of memory is one of the most frequently reported symptoms during sudden hypoxia exposure in human. Cortical atrophy has been linked to the impaired memory function and is suggested to occur with chronic high-altitude exposure. However, the precise molecular mechanism(s) of hypoxia-induced memory impairment remains an enigma. In this work, we review hypoxia-induced learning and memory deficit in human and rat studies. Based on data from rat studies using different protocols of continuous hypoxia, we try to elicit potential mechanisms of hypobaric hypoxia–induced memory deficit.

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“…Hypobaric hypoxia induced prolonged elevation of corticosterone in hippocampus have been shown to cause enhanced oxidative stress, neurodegeneration and impairment of memory consolidation and retrieval. Inhibition of corticosterone synthesis or blockade of glucocorticoid receptor during hypoxic exposure reduced neurodegeneration and ameliorated memory impairment [28] , [40] . However, use of synthetic inhibitors as prophylactic to prevent high altitude maladies may not be preferable because of their possible negative side effects.…”

Section: Discussionmentioning

confidence: 99%

Withanolide A Prevents Neurodegeneration by Modulating Hippocampal Glutathione Biosynthesis during Hypoxia

et al. 2014

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Withania somnifera root extract has been used traditionally in ayurvedic system of medicine as a memory enhancer. Present study explores the ameliorative effect of withanolide A, a major component of withania root extract and its molecular mechanism against hypoxia induced memory impairment. Withanolide A was administered to male Sprague Dawley rats before a period of 21 days pre-exposure and during 07 days of exposure to a simulated altitude of 25,000 ft. Glutathione level and glutathione dependent free radicals scavenging enzyme system, ATP, NADPH level, γ-glutamylcysteinyl ligase (GCLC) activity and oxidative stress markers were assessed in the hippocampus. Expression of apoptotic marker caspase 3 in hippocampus was investigated by immunohistochemistry. Transcriptional alteration and expression of GCLC and Nuclear factor (erythroid-derived 2)–related factor 2 (Nrf2) were investigated by real time PCR and immunoblotting respectively. Exposure to hypobaric hypoxia decreased reduced glutathione (GSH) level and impaired reduced gluatathione dependent free radical scavenging system in hippocampus resulting in elevated oxidative stress. Supplementation of withanolide A during hypoxic exposure increased GSH level, augmented GSH dependent free radicals scavenging system and decreased the number of caspase and hoescht positive cells in hippocampus. While withanolide A reversed hypoxia mediated neurodegeneration, administration of buthionine sulfoximine along with withanolide A blunted its neuroprotective effects. Exogenous administration of corticosterone suppressed Nrf2 and GCLC expression whereas inhibition of corticosterone synthesis upregulated Nrf2 as well as GCLC. Thus present study infers that withanolide A reduces neurodegeneration by restoring hypoxia induced glutathione depletion in hippocampus. Further, Withanolide A increases glutathione biosynthesis in neuronal cells by upregulating GCLC level through Nrf2 pathway in a corticosterone dependenet manner.

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Inhibition of glucocorticoid receptors ameliorates hypobaric hypoxia induced memory impairment in rat

Cited by 22 publications

References 57 publications

Exposure to Hypobaric Hypoxia and Reoxygenation Induces Transient Anxiety-Like Behavior in Rat

Exposure to Hypobaric Hypoxia and Reoxygenation Induces Transient Anxiety-Like Behavior in Rat

Insight into potential mechanisms of hypobaric hypoxia–induced learning and memory deficit – Lessons from rat studies

Withanolide A Prevents Neurodegeneration by Modulating Hippocampal Glutathione Biosynthesis during Hypoxia

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