Hypobaric Hypoxia Induced Memory Impairment Research Articles

Inhibition of 12/15 LOX ameliorates cognitive and cholinergic dysfunction in mouse model of hypobaric hypoxia via. attenuation of oxidative/nitrosative stress

12/15 Lipoxygenase has recently been described as potent propagator of oxidative stress and is closely associated with cognitive decline in neurodegenerative diseases. The mechanism/s behind 12/15 LOX involvement in cognitive deficits remain obscure. The current study has been designed to investigate the underlying role of 12/15LOX and effect of 12/15 LOX inhibition on hypobaric hypoxia-induced memory impairment and cholinergic deficits. Male Balb/c mice subjected to simulated hypobaric hypoxia/reoxygenation condition for 3days showed marked working memory impairment concomitant with hippocampal neuronal damage and malondialdehyde production which were significantly attenuated by baicalein, a specific inhibitor of 12/15LOX. Hypobaric hypoxia-exposed mice had consistently increased expression of 12/15LOX and elevated 12(S) HETE levels in the hippocampus as well as plasma which were significantly mitigated following baicalein treatment. 12/15LOX inhibition also reduced hypobaric hypoxia-mediated upregulation of hippocampal HIF-1α protein expression along with reduction in expression of inflammatory genes. The inhibition of 12/15 LOX resulted in a significant decrease in NO levels in the hippocampal homogenate associated with downregulated iNOS, nNOS transcription but not eNOS speculating that 12/15 LOX is critically involved in HIF-1α, mediated by nitric oxide-induced neurotoxicity. We also observed a similar effect of 12/15 LOX inhibition on hippocampal COX2 expression. 12/15LOX inhibition could effectively modulate central cholinergic indices during hypobaric hypoxia by restoring mAChR-1, α7NAChR expression and AChE, ChAT activity in the hippocampus comparable to normal mice. We report here the mechanistic involvement of 12/15LOX in orchestrating hypoxia-associated neuronal damage and HIF-1α-dependent neuroinflammation resulting in cognitive decline.

Ketogenic diet improves the spatial memory impairment caused by exposure to hypobaric hypoxia through increased acetylation of histones in rats.

Exposure to hypobaric hypoxia causes neuron cell damage, resulting in impaired cognitive function. Effective interventions to antagonize hypobaric hypoxia-induced memory impairment are in urgent need. Ketogenic diet (KD) has been successfully used to treat drug-resistant epilepsy and improves cognitive behaviors in epilepsy patients and other pathophysiological animal models. In the present study, we aimed to explore the potential beneficial effects of a KD on memory impairment caused by hypobaric hypoxia and the underlying possible mechanisms. We showed that the KD recipe used was ketogenic and increased plasma levels of ketone bodies, especially β-hydroxybutyrate. The results of the behavior tests showed that the KD did not affect general locomotor activity but obviously promoted spatial learning. Moreover, the KD significantly improved the spatial memory impairment caused by hypobaric hypoxia (simulated altitude of 6000 m, 24 h). In addition, the improving-effect of KD was mimicked by intraperitoneal injection of BHB. The western blot and immunohistochemistry results showed that KD treatment not only increased the acetylated levels of histone H3 and histone H4 compared to that of the control group but also antagonized the decrease in the acetylated histone H3 and H4 when exposed to hypobaric hypoxia. Furthermore, KD-hypoxia treatment also promoted PKA/CREB activation and BDNF protein expression compared to the effects of hypoxia alone. These results demonstrated that KD is a promising strategy to improve spatial memory impairment caused by hypobaric hypoxia, in which increased modification of histone acetylation plays an important role.

Hypoxia induced cognitive impairment modulating activity of Cyperus rotundus

Hypobaric hypoxia leads to decrease in cellular oxygen content which subsequently damages the hippocampus with an increase in brain oxidative stress and impairs the memory of the individual. In the present study, we have evaluated the cognitive impairment modulating activity of total oligomeric flavonoids fraction of Cyperus rotundus (TOF) in Sprague Dawley rats. The rats were trained for memory activity for a period of 7days followed by 7days exposure to 25,000ft. altitude and the spatial reference memory was evaluated. Behavioral analysis of the rats by Morris water maze experiment showed that TOF supplementation enhanced the spatial reference memory activity of the rats exposed to hypobaric hypoxia. The decrease in antioxidant status of the animals exposed to hypoxia was restored with TOF supplementation. The increase in ROS, lipid peroxidation products and protein carbonyls of the hippocampus was significantly decreased in animals with TOF administration. The histological assessment of the pyramidal cells of the hippocampus of hypoxia-exposed animals showed nuclear damage and TOF supplementation prevented nuclear damage. TOF administration suppressed hypoxia-induced increase in serotonin, dopamine, and norepinephrine. GABA and Ach levels were decreased by hypoxia which was prevented by TOF supplementation. The increase in GFAP, HIF-1α and VEGF expression in CA3 region of the hippocampus in hypoxia-exposed rats was decreased in TOF administered rats. Taken together, TOF extract ameliorates hypobaric hypoxia induced memory impairment and neurodegeneration in hippocampus through its anti-stress effects.

Erratum to: Dihydromyricetin Improves Hypobaric Hypoxia-Induced Memory Impairment via Modulation of SIRT3 Signaling.

Inadequate oxygen availability-for instance at high altitudes-leads to hippocampal neurodegeneration and memory impairment. Although oxidative stress is one factor, the mechanism underlying the effects of hypobaric hypoxia (HH) are unclear, and effective strategies for preventing the resultant damage to the brain are limited. In the present study, we demonstrate that ingesting dihydromyricetin (DM) protects against memory impairment in adult rats subjected to HH for 7 days, equivalent to an altitude of 5000 m above sea level. Moreover, DM treatment stimulated mitochondrial biogenesis and improved mitochondrial morphology and function, suppressed the generation of reactive oxygen species, and reduced lipid peroxidation in the hippocampus. In HT-22 cells exposed to hypoxic conditions, the neuroprotective effects of DM were shown to be exerted via attenuation of oxidative stress through sirtuin 3-induced forkhead box O3 deacetylation.

Hypobaric hypoxia-induced neurodegeneration and memory impairment is glucocorticoid receptor dependent

Hypobaric hypoxia-induced neurodegeneration and memory impairment is glucocorticoid receptor dependent

Role of epigenetic modulation in hypobaric hypoxia induced memory impairment

Event Abstract Back to Event Role of epigenetic modulation in hypobaric hypoxia induced memory impairment Rahul Kumar1, Vishal Jain2, Neetu Kushwah1, Aastha Dheer1, Dipti Prasad1 and Shashi B. Singh1* 1 Defense Institute of Physiology and Allied Sciences (DIPAS) DRDO, Neurobiology Department, India 2 Defense Institute of Physiology and Allied Sciences (DIPAS) DRDO, Neurophysiology Department, India Long term memory formation requires a series of cellular as well as molecular adaptation that control the gene expression at the transcription level. However, epigenetic mechanisms such as histone acetylation, methylation, phosphorylation and DNA methylation have emerge critical regulators of transcription during memory consolidation process. Epigenetic mechanism controls gene expression bidirectional i.e. either enhance or repress gene expression. In addition, histone acetylation has been the main mechanism of epigenetics and play important role in memory formation as well as reconsolidation. Stressful environmental conditions such as hypobaric hypoxia (HH) leads to change in learning and memory. Present study is designed to explore global as well as specific histone modifications, mainly acetylation in different brain regions during different duration of HH exposure. Sprague Dawley rats (220 to 230 gm) were exposed to different duration of HH i.e. 1, 3, 7 and 14 days in an animal decompression chamber at an altitude of 25,000 feet. After exposure, rats were sacrificed and hippocampus and cortex were isolated. Activity of histone acetylase (HAT), histone deacetylase (HDAC) and DNA methyl transferase (DNMT) was analyzed using kits. Further specific histone acetylation sites i.e. H2BK5Acetylation, H3K9Acetylation and H4K14Acetylation were also studied in different brain regions. Results from the present study revealed the correlation between expressions of HDAC and HIF-1 alpha which further control other hypoxia responsive genes in both the brain regions. Gradual increased expression of HDAC on HH exposure causes repression of learning and memory related genes. In addition, the decline in H2BK5Ac expression may also account for inactivation of transcription of memory responsive gene leading to decline in memory. In brief, it can be concluded that epigenetic modification at histone acetylation sites may account for HH mediated memory impairment. Keywords: Memory, epigenetic, in vivo, histone acetylation, hypobaric hypoxia Conference: 14th Meeting of the Asian-Pacific Society for Neurochemistry, Kuala Lumpur, Malaysia, 27 Aug - 30 Aug, 2016. Presentation Type: Poster Presentation Session Topic: 14th Meeting of the Asian-Pacific Society for Neurochemistry Citation: Kumar R, Jain V, Kushwah N, Dheer A, Prasad D and Singh SB (2016). Role of epigenetic modulation in hypobaric hypoxia induced memory impairment. Conference Abstract: 14th Meeting of the Asian-Pacific Society for Neurochemistry. doi: 10.3389/conf.fncel.2016.36.00191 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 04 Aug 2016; Published Online: 11 Aug 2016. * Correspondence: Dr. Shashi B Singh, Defense Institute of Physiology and Allied Sciences (DIPAS) DRDO, Neurobiology Department, New Delhi, North Delhi, India, drshashisingh@gmail.com Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Rahul Kumar Vishal Jain Neetu Kushwah Aastha Dheer Dipti Prasad Shashi B Singh Google Rahul Kumar Vishal Jain Neetu Kushwah Aastha Dheer Dipti Prasad Shashi B Singh Google Scholar Rahul Kumar Vishal Jain Neetu Kushwah Aastha Dheer Dipti Prasad Shashi B Singh PubMed Rahul Kumar Vishal Jain Neetu Kushwah Aastha Dheer Dipti Prasad Shashi B Singh Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Dihydromyricetin Improves Hypobaric Hypoxia-Induced Memory Impairment via Modulation of SIRT3 Signaling.

Inadequate oxygen availability-for instance at high altitudes-leads to hippocampal neurodegeneration and memory impairment. Although oxidative stress is one factor, the mechanism underlying the effects of hypobaric hypoxia (HH) are unclear, and effective strategies for preventing the resultant damage to the brain are limited. In the present study, we demonstrate that ingesting dihydromyricetin (DM) protects against memory impairment in adult rats subjected to HH for 7days, equivalent to an altitude of 5000m above sea level. Moreover, DM treatment stimulated mitochondrial biogenesis and improved mitochondrial morphology and function, suppressed the generation of reactive oxygen species, and reduced lipid peroxidation in the hippocampus. In HT-22 cells exposed to hypoxic conditions, the neuroprotective effects of DM were shown to be exerted via attenuation of oxidative stress through sirtuin 3-induced forkhead box O3 deacetylation.

REMOVED: Enriched environment prevents hypobaric hypoxia induced memory impairment through modulating hippocampal synaptic strength and plasticity

This article has been removed: please see Elsevier Policy on Article Withdrawal (https://www.elsevier.com/about/our‐business/policies/article‐withdrawal)This meeting abstract has been removed by the Publisher. Due to an administrative error, abstracts that were not presented at the ISDN 2014 meeting were inadvertently published in the meeting's abstract supplement. The Publisher apologizes to the authors and readers for this error.

Quercetin ameliorates hypobaric hypoxia-induced memory impairment through mitochondrial and neuron function adaptation via the PGC-1α pathway.

Acute hypobaric hypoxia (HH) causes persistent cognitive impairment, affecting memory function specifically. Mitochondrial dysfunction and synaptic morphological change were the prominent pathological features of HH exposure on brain. Quercetin, a flavonoid found in fruits, vegetables, leaves and grains, is reported to prevent ischemia induced by neuronal injury. This study investigated the efficacy of quercetin to ameliorate HH-induced memory deficit. Rats were exposed to HH equivalent to 5000 m for 7 days in a decompression chamber and received quercetin daily (50, 75 or 100 mg/kg·bw) via gavage during the period of exposure. Cognitive performance was assessed by the Morris water maze test. In vitro, the effect of quercetin was tested in hippocampus tissue. Quercetin, especially at 100 mg/kg·bw, significantly reduced HH-induced memory decline. Meanwhile, HH-induced hippocampus mitochondrial and synaptic lesions were ameliorated by quercetin. Furthermore, quercetin regulated the expression of sirtuin 1(Sirt1), PGC-1α, and the proteins related with mitochondrial biogenesis and dynamics. Moreover, quercetin increased expression of fibronectin type III domain-containing protein 5 (FNDC5) and brain-derived neurotrophic factor (BDNF), showing the PGC-1α/FNDC5/BNDF pathways might be involved in neuronal adaptation. The results suggest quercetin has prophylactic potential for amelioration of HH-induced memory impairment, which is associated with the mitochondrial and neuronal adaptation in hippocampus.

Quercetin Reverses Hypobaric Hypoxia-Induced Hippocampal Neurodegeneration and Improves Memory Function in the Rat

Inadequate oxygen availability at high altitude causes elevated oxidative stress, resulting in hippocampal neurodegeneration and memory impairment. Though oxidative stress is known to be a major cause of neurodegeneration in hypobaric hypoxia, neuroprotective and ameliorative potential of quercetin, a flavonoid with strong antioxidant properties in reversing hypobaric hypoxia-induced memory impairment has not been studied. Four groups of male adult Sprague Dawley rats were exposed to hypobaric hypoxia for 7 days in an animal decompression chamber at an altitude of 7600 meters. Rats were supplemented with quercetin orally by gavage during 7 days of hypoxic exposure. Spatial working memory was assessed by a Morris Water Maze before and after exposure to hypobaric hypoxia. Changes in oxidative stress markers and apoptotic marker caspase 3 expression in hippocampus were assessed. Histological assessment of neurodegeneration was performed by cresyl violet and fluoro Jade B staining. Our results showed that quercetin supplementation during exposure to hypobaric hypoxia decreased reactive oxygen species levels and consequent lipid peroxidation in the hippocampus by elevating antioxidant status and free radical scavenging enzyme system. There was reduction in caspase 3 expression, and decrease in the number of pyknotic and fluoro Jade B-positive neurons in hippocampus after quercetin supplementation during hypoxic exposure. Behavioral studies showed that quercetin reversed the hypobaric hypoxia-induced memory impairment. These findings suggest that quercetin provides neuroprotection to hippocampal neurons during exposure to hypobaric hypoxia through antioxidative and anti-apoptotic mechanisms, and possesses promising therapeutic potential to ameliorate hypoxia-induced memory dysfunction.

Enriched Environment Prevents Hypobaric Hypoxia Induced Memory Impairment and Neurodegeneration: Role of BDNF/PI3K/GSK3β Pathway Coupled with CREB Activation

Adverse environmental conditions such as hypobaric hypoxia (HH) cause memory impairment by affecting cellular machinery leading to neurodegeneration. Providing enriched environment (EE) is found to be beneficial for curing several neurodegenerative disorders. The protective role of EE in preventing HH induced neuronal death has been reported previously but the involved mechanism is still not clearly understood. The present study is an attempt to verify the impact of EE on spatial memory during HH and also to explore the possible role of neurotrophin in EE mediated neuroprotection. Signaling mechanism involved in neuroprotection was also explored. Male Sprague Dawley rats were simulated to HH condition in an Animal Decompression Chamber at an altitude of 25000 feet in standard and enriched cages for 7 days. Spatial memory was assessed through Morris Water Maze. Role of different neurotrophins was explored by gene silencing and inhibitors for their respective receptors. Further, using different blockers signaling pathway was also explored. Finding of the present study suggested that EE prevents HH mediated memory impairment and neurodegeneration. Also brain-derived neurotrophic factor (BDNF) plays a major role in EE mediated neuroprotection and it effectively prevented neurodegeneration by activating PI3K/AKT pathway resulting in GSK3β inactivation which further inhibits apoptosis. Moreover GSK3β phosphorylation and hence its inactivation upregulates CREB phosphorylation which may also accounts for activation of survival machinery in cells and provides neuroprotection. From these observations it can be postulated that EE has a therapeutic potential in amelioration of HH induced memory impairment and neurodegeneration. Hence it may be used as a non invasive and non pharmacological intervention against various neurological disorders.

Withania somnifera root extract ameliorates hypobaric hypoxia induced memory impairment in rats

Ethnopharmacological relevanceWithania somnifera (WS) root extract has been used traditionally in ayurvedic system of medicine as a memory enhancer and anti-stress agent. Aim of the studyTo evaluate the neuroprotective and prophylactic potential of WS root extract in ameliorating hypobaric hypoxia (HH) induced memory impairment and to explore the underlying molecular mechanism. Materials and methodsWS root extract was administered to male Sprague Dawley rats during a period of 21 days pre-exposure and 07 days exposure to a simulated altitude of 25,000ft. Spatial memory was assessed by Morris Water Maze. Neurodegeneration, corticosterone, acetylcholine (Ach) levels, acetylcholine esterase (AchE) activity, oxidative stress markers and nitric oxide (NO) concentration were assessed in the hippocampus. Synaptic and apoptotic markers were also investigated by immunoblotting. To study the role of NO in regulating corticosterone mediated signaling, the neuronal nitric oxide synthase (n-NOS) inhibitor, l-Nitro-arginine methyl ester (l-Name) and NO agonist sodium nitroprusside (SNP) were administered from 3rd to 7th day of hypoxic exposure. ResultsAdministration of WS root extract prevented HH induced memory impairment and neurodegeneration along with decreased NO, corticosterone, oxidative stress and AchE activity in hippocampal region. Inhibition of NO synthesis by administration of l-Name reduced corticosterone levels in hippocampus during hypoxic exposure while co-administration of corticosterone increased neurodegeneration. Administration of sodium nitroprusside (SNP) along with WS root extract supplementation during hypoxic exposure increased corticosterone levels and increased the number of pyknotic cells. ConclusionWS root extract ameliorated HH induced memory impairment and neurodegeneration in hippocampus through NO mediated modulation of corticosterone levels.

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

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, Bcl2 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.

Corticosterone synthesis inhibitor metyrapone ameliorates chronic hypobaric hypoxia induced memory impairment in rat

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.

Free chelatable zinc modulates the cholinergic function during hypobaric hypoxia-induced neuronal damage: an in vivo study

The deregulation of cholinergic system and associated neuronal damage is thought to be a major contributor to the pathophysiologic sequelae of hypobaric hypoxia-induced memory impairment. Uniquely, the muscarinic receptors also play a role in zinc uptake. Despite the potential role of muscarinic receptors in the development of post hypoxia cognitive deficits, no studies to date have evaluated the mechanistic relationship between memory dysfunction and zinc homeostasis in brain. In the present study, we evaluated the effect of Ca2EDTA, a specific zinc chelator in the spatial working and associative memory deficits following hypobaric hypoxia. Our results demonstrate that accumulation of intracellular free chelatable zinc in the hippocampal CA3 pyramidal neurons is accompanied with neuronal loss and memory impairment in hypobaric hypoxic condition. Chelation of this free zinc with Ca2EDTA (1.25 mM/kg) ameliorated the hippocampus-dependent spatial as well as associative memory dysfunction and neuronal damage observed on exposure to hypobaric hypoxia. The zinc chelator significantly alleviated the downregulation in expression of choline acetyltransferase, muscarinic receptor 1 and 4, and acetylcholinesterase activity due to hypobaric hypoxia. Our data suggest that the free chelatable zinc released during hypobaric hypoxia might play a critical role in the neuronal damage and the alteration in cholinergic function associated with hypobaric hypoxia-induced memory impairment. We speculate that zinc chelation might be a potential therapy for hypobaric hypoxia-induced cognitive impairment.

Role of cholinergic markers on memory function of rats exposed to hypobaric hypoxia

Hypobaric hypoxia is encountered at high altitude. It has a deleterious effect on cognitive functions. An important cause of memory impairment at high altitude is the impairment of neurotransmission. The present study investigates the role of cholinergic markers in hypobaric hypoxia-induced memory impairment. Rats were exposed to hypobaric hypoxia at 6100 m for 7 days in a simulated-decompression chamber. Memory performance was assessed using the Morris water maze task. Cholinergic markers such as acetylcholine, acetylcholinesterase, choline acetyltransferase, α-7-nicotinic acetylcholine receptor and M 1 muscarinic acetylcholine receptor were also evaluated along with neuronal morphology and DNA fragmentation. We found impairment in memory function along with a decrease in acetylcholine levels, increase in acetylcholinesterase activity, down regulation of choline acetyltransferase, α-7-nicotinic acetylcholine receptor and M 1 muscarinic acetylcholine receptor. We also found that cellular damage is associated with a significant increase in DNA fragmentation. However, administration of acetylcholinesterase inhibitors, such as physostigmine and galantamine, resulted in amelioration of the hypobaric hypoxia induced deleterious effects. It improved acetylcholine level, decreased acetylcholinesterase activity and increased the synthesis of acetylcholine by increasing choline acetyltransferase activity. Also, the acetylcholinesterase inhibitors improved neuronal morphology, perhaps by increasing the expression of α-7-nicotinic acetylcholine receptor and by reducing the acetylcholinesterase level in the cortex and the hippocampus. Therefore, our results suggest cholinergic dysfunction is one of the mechanisms involved in hypobaric hypoxia-induced memory impairment and that acetylcholinesterase inhibitors were able to restore cholinergic function and thus improve memory function.

Acetyl-l-carnitine (ALCAR) prevents hypobaric hypoxia–induced spatial memory impairment through extracellular related kinase–mediated nuclear factor erythroid 2-related factor 2 phosphorylation

Exposure to hypobaric hypoxia, a condition involving decreased availability of oxygen is known to be associated with oxidative stress, neurodegeneration and memory impairment. The multifactorial response of the brain and the complex signaling pathways involved therewith limits the therapeutic efficacy of several antioxidants in ameliorating hypobaric hypoxia–induced memory impairment. The present study was therefore aimed at investigating the potential of acetyl-l-carnitine (ALCAR), a known antioxidant that has been reported to augment neurotrophin-mediated survival mechanisms, in ameliorating hypoxia-induced neurodegeneration and memory impairment. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a key transcription factor involved in the cellular defense mechanism against oxidative stress related to brain injury and neurological disorders. The study was designed to understand the mechanisms involving Nrf2 stabilization following exposure to hypobaric hypoxia. The results displayed reference memory impairment in Sprague–Dawley rats exposed to hypobaric hypoxia (7620 m) for 14 consecutive days which however improved on administration of ALCAR during hypoxic exposure. The study also revealed Nrf2 regulated augmented antioxidant response on administration of ALCAR which was through a novel tyrosine kinase A (TrkA) receptor-mediated mechanism. A decrease in free radical generation, lipid peroxidation and protein oxidation was also observed along with a concomitant increase in thioredoxin and reduced glutathione levels on administration of ALCAR during exposure to hypobaric hypoxia. The present study therefore reveals the therapeutic potential of ALCAR under conditions of hypobaric hypoxia and elucidates a novel mechanism of action of the drug.

Bacopa monniera leaf extract ameliorates hypobaric hypoxia induced spatial memory impairment

Hypobaric hypoxia induced memory impairment has been attributed to several factors including increased oxidative stress, depleted mitochondrial bioenergetics, altered neurotransmission and apoptosis. This multifactorial response of the brain to hypobaric hypoxia limits the use of therapeutic agents that target individual pathways for ameliorating hypobaric hypoxia induced memory impairment. The present study aimed at exploring the therapeutic potential of a bacoside rich leaf extract of Bacopa monniera in improving the memory functions in hypobaric conditions. The learning ability was evaluated in male Sprague Dawley rats along with memory retrieval following exposure to hypobaric conditions simulating an altitude of 25,000 ft for different durations. The effect of bacoside administration on apoptosis, cytochrome c oxidase activity, ATP levels, and oxidative stress markers and on plasma corticosterone levels was investigated. Expression of NR1 subunit of N-methyl- d-aspartate receptors, neuronal cell adhesion molecules and was also studied along with CREB phosphorylation to elucidate the molecular mechanisms of bacoside action. Bacoside administration was seen to enhance learning ability in rats along with augmentation in memory retrieval and prevention of dendritic atrophy following hypoxic exposure. In addition, it decreased oxidative stress, plasma corticosterone levels and neuronal degeneration. Bacoside administration also increased cytochrome c oxidase activity along with a concomitant increase in ATP levels. Hence, administration of bacosides could be a useful therapeutic strategy in ameliorating hypobaric hypoxia induced cognitive dysfunctions and other related neurological disorders.

Ceftriaxone rescues hippocampal neurons from excitotoxicity and enhances memory retrieval in chronic hypobaric hypoxia

Exposure to high altitude is known to cause impairment in cognitive functions in sojourners. The molecular events leading to this behavioral manifestation, however, still remain an enigma. The present study aims at exploring the nature of memory impairment occurring on chronic exposure to hypobaric hypoxia and the possible role of glutamate in mediating it. Increased ionotropic receptor stimulation by glutamate under hypobaric hypoxic conditions could lead to calcium mediated excitotoxic cell death resulting in impaired cognitive functions. Since glutamate is cleared from the synapse by the Glial Glutamate Transporter, upregulation of the transporter can be a good strategy in preventing excitotoxic cell death. Considering previous reports on upregulation of the expression of Glial Glutamate Transporter on ceftriaxone administration, the therapeutic potential of ceftriaxone in ameliorating hypobaric hypoxia induced memory impairment was investigated in male Sprague Dawley rats. Exposure to hypobaric hypoxia equivalent to an altitude of 7600 m for 14 days lead to oxidative stress, chromatin condensation and neuronal degeneration in the hippocampus. This was accompanied by delayed memory retrieval as evident from increased latency and pathlength in Morris Water Maze. Administration of ceftriaxone at a dose of 200 mg/kg for 7 days and 14 days during the exposure on the other hand improved the performance of rats in the water maze along with decreased oxidative stress and enhanced neuronal survival when compared to hypoxic group without drug administration. An increased expression of Glial Glutamate Transporter was also observed following drug administration indicating faster clearance of glutamate from the synapse. The present study not only brings to light the effect of longer duration of exposure to hypobaric hypoxia on the memory functions, but also indicates the pivotal role played by glutamate in mediating excitotoxic neuronal degeneration at high altitude. The therapeutic potential of ceftriaxone in providing neuroprotection in excitotoxic conditions by increasing Glial Glutamate Transporter expression and thereby enhancing glutamate uptake from the synapse has also been explored.