Hypobaric hypoxia induces oxidative stress in rat brain

High altitude exposure results in decreased partial pressure of oxygen and an increased formation of reactive oxygen and nitrogen species (RONS), which causes oxidative damage to lipids, proteins and DNA. Exposure to high altitude appears to decrease the activity and effectiveness of antioxidant enzyme system. The antioxidant system is very less in brain tissue and is very much susceptible to hypoxic stress. The aim of the present study was to investigate the time dependent and region specific changes in cortex, hippocampus and striatum on oxidative stress markers on chronic exposure to hypobaric hypoxia. The rats were exposed to simulated high altitude equivalent to 6100 m in animal decompression chamber for 3 and 7 days. Results indicate an increase in oxidative stress as seen by increase in free radical production, nitric oxide level, lipid peroxidation and lactate dehydrogenase levels. The magnitude of increase in oxidative stress was more in 7 days exposure group as compared to 3 days exposure group. The antioxidant defence system such as reduced glutathione (GSH), glutathione peroxidase (GPx), glutathione reductase (GR), superoxide dismutase (SOD) and reduced/oxidized glutathione (GSH/GSSG) levels were significantly decreased in all the three regions. The observation suggests that the hippocampus is more susceptible to hypoxia than the cortex and striatum. It may be concluded that hypoxia differentially affects the antioxidant status in the cortex, hippocampus and striatum.     

Huperzine A Ameliorates Cognitive Deficits and Oxidative Stress in the Hippocampus of Rats Exposed to Acute Hypobaric Hypoxia

Acute exposure to high altitudes can cause neurological dysfunction due to decreased oxygen availability to the brain. In this study, the protective effects of Huperzine A on cognitive deficits along with oxidative and apoptotic damage, due to acute hypobaric hypoxia, were investigated in male Sprague–Dawley rats. Rats were exposed to simulated hypobaric hypoxia at 6,000 m in a specially fabricated animal decompression chamber while receiving daily Huperzine A orally at the dose of 0.05 or 0.1 mg/kg body weight. After exposure to hypobaric hypoxia for 5 days, rats were trained in a Morris Water Maze for 5 consecutive days. Subsequent trials revealed Huperzine A supplementation at a dose of 0.1 mg/kg body weight restored spatial memory significantly, as evident from decreased escape latency and path length to reach the hidden platform, and the increase in number of times of crossing the former platform location and time spent in the former platform quadrant. In addition, after exposure to hypobaric hypoxia, animals were sacrificed and biomarkers of oxidative damage, such as reactive oxygen species, lipid peroxidation, lactate dehydrogenase activity, reduced glutathione, oxidized glutathione and superoxide dismutase were studied in the hippocampus. Expression levels of pro-apoptotic proteins (Bax, caspase-3) and anti-apoptotic protein (Bcl-2) of hippocampal tissues were evaluated by Western blotting. There was a significant increase in oxidative stress along with increased expression of apoptotic proteins in hypoxia exposed rats, which was significantly improved by oral Huperzine A at 0.1 mg/kg body weight. These results suggest that supplementation with Huperzine A improves cognitive deficits, reduces oxidative stress and inhibits the apoptotic cascade induced by acute hypobaric hypoxia.     

红景天苷对高原缺氧大鼠认知功能障碍的治疗作用及其可能机制

目的:探讨红景天苷(Sal)对高原缺氧大鼠认知功能障碍的治疗作用及其可能机制。方法:将30只成年雄性SD大鼠随机分为健康对照组、模型组(Model组)、Sal[按体重1g/(kg.d)]治疗组(sal组)。采用Morris水迷宫实验方法检测缺氧后大鼠学习记忆功能变化,同时检测脑组织匀浆中超氧化物歧化酶(SOD)、谷胱甘肽过氧化物酶(GSH-PX)、谷胱甘肽(GSH)、丙二醛(MDA)的水平。结果:(1)模型组大鼠寻找平台的潜伏期明显长于对照组,具有统计学意义(P<0.05),Sal组寻找平台的潜伏期相对于模型组显著缩短(P<0.05)。撤离平台后,模型组大鼠在平台所在象限的停留时间明显短于对照组(P<0.05),Sal治疗后大鼠在平台所在象限的停留时间较模型组显著延长(P<0.05)。(2)模型组SOD、GSH-PX、GSH显著下降,MDA明显增高,Sal干预组SOD、GSH-PX、GSH显著增高,而MDA明显下降,具有统计学意义(P<0.05)。结论:Sal可改善高原缺氧大鼠认知功能,其可能机制是通过减轻海马区的氧化应激反应减轻海马区的损伤,从而实现改善认知功能。     

Activity-dependent neuroprotective protein (ADNP)-derived peptide (NAP) ameliorates hypobaric hypoxia induced oxidative stress in rat brain

Hypobaric hypoxia is a socio-economic problem affecting cognitive, memory and behavior functions. Severe oxidative stress caused by hypobaric hypoxia adversely affects brain areas like cortex, hippocampus, basal ganglia, and cerebellum. In the present study, we have investigated the antioxidant and memory protection efficacy of the synthetic NAP peptide (NAPVSIPQ) during long-term chronic hypobaric hypoxia (7, 14, 21 and 28 days, 25,000 ft) in rats. Intranasal supplementation of NAP peptide (2 μg/Kg body weight) improved antioxidant status of brain evaluated by biochemical assays for free radical estimation, lipid peroxidation, GSH and GSSG level. Analysis of expression levels of SOD revealed that NAP significantly activated antioxidant genes as compared to hypoxia exposed rats. We have also observed a significant increased expression of Nrf2, the master regulator of antioxidant defense system and its downstream targets such as HO-1, GST and SOD1 by NAP supplementation, suggesting activation of Nrf2-mediated antioxidant defense response. In corroboration, our results also demonstrate that NAP supplementation improved the memory function assessed with radial arm maze. These cumulative results suggest the therapeutic potential of NAP peptide for ameliorating hypobaric hypoxia-induced oxidative stress.     

Antioxidant responses to chronic hypoxia in the rat cerebellum and pons

Obstructive sleep apnea (OSA) is characterized by chronic intermittent hypoxia (CIH) and sleep fragmentation and deprivation. Exposure to CIH results in oxidative stress in the cortex, hippocampus and basal forebrain of rats and mice. We show that sustained and intermittent hypoxia induces antioxidant responses, an indicator of oxidative stress, in the rat cerebellum and pons. Increased glutathione reductase (GR) activity and thiobarbituric acid reactive substance (TBARS) levels were observed in the pons and cerebellum of rats exposed to CIH or chronic sustained hypoxia (CSH) compared with room air (RA) controls. Exposure to CIH or CSH increased GR activity in the pons, while exposure to CSH increased the level of TBARS in the cerebellum. The level of TBARS was increased to a greater extent after exposure to CSH than to CIH in the cerebellum and pons. Increased superoxide dismutase activity (SOD) and decreased total glutathione (GSHt) levels were observed after exposure to CIH compared with CSH only in the pons. We have previously shown that prolonged sleep deprivation decreased SOD activity in the rat hippocampus and brainstem, without affecting the cerebellum, cortex or hypothalamus. We therefore conclude that sleep deprivation and hypoxia differentially affect antioxidant responses in different brain regions.     

Neuroprotective effect of cobalt chloride on hypobaric hypoxia-induced oxidative stress

Hypobaric hypoxia, characteristic of high altitude is known to increase the formation of reactive oxygen and nitrogen species (RONS), and decrease effectiveness of antioxidant enzymes. RONS are involved and may even play a causative role in high altitude related ailments. Brain is highly susceptible to hypoxic stress and is involved in physiological responses that follow. Exposure of rats to hypobaric hypoxia (7619 m) resulted in increased oxidation of lipids and proteins due to increased RONS and decreased reduced to oxidized glutathione (GSH/GSSG) ratio. Further, there was a significant increase in superoxide dismutase (SOD), glutathione peroxidase (GPx), and glutathione-S-transferase (GST) levels. Increase in heme oxygenase 1 (HO-1) and heat shock protein 70 (HSP70) was also noticed along with metallothionein (MT) II and III. Administration of cobalt appreciably attenuated the RONS generation, oxidation of lipids and proteins and maintained GSH/GSSH ratio similar to that of control cells via induction of HO-1 and MT offering efficient neuroprotection. It can be concluded that cobalt reduces hypoxia oxidative stress by maintaining higher cellular HO-1 and MT levels via hypoxia inducible factor 1alpha (HIF-1alpha) signaling mechanisms. These findings provide a basis for possible use of cobalt for prevention of hypoxia-induced oxidative stress.     

Effect of Ca2EDTA on Zinc Mediated Inflammation and Neuronal Apoptosis in Hippocampus of an In Vivo Mouse Model of Hypobaric Hypoxia

Background

Calcium overload has been implicated as a critical event in glutamate excitotoxicity associated neurodegeneration. Recently, zinc accumulation and its neurotoxic role similar to calcium has been proposed. Earlier, we reported that free chelatable zinc released during hypobaric hypoxia mediates neuronal damage and memory impairment. The molecular mechanism behind hypobaric hypoxia mediated neuronal damage is obscure. The role of free zinc in such neuropathological condition has not been elucidated. In the present study, we investigated the underlying role of free chelatable zinc in hypobaric hypoxia-induced neuronal inflammation and apoptosis resulting in hippocampal damage.

Methods

Adult male Balb/c mice were exposed to hypobaric hypoxia and treated with saline or Ca₂EDTA (1.25 mM/kg i.p) daily for four days. The effects of Ca₂EDTA on apoptosis (caspases activity and DNA fragmentation), pro-inflammatory markers (iNOS, TNF-α and COX-2), NADPH oxidase activity, poly(ADP ribose) polymerase (PARP) activity and expressions of Bax, Bcl-2, HIF-1α, metallothionein-3, ZnT-1 and ZIP-6 were examined in the hippocampal region of brain.

Results

Hypobaric hypoxia resulted in increased expression of metallothionein-3 and zinc transporters (ZnT-1 and ZIP-6). Hypobaric hypoxia elicited an oxidative stress and inflammatory response characterized by elevated NADPH oxidase activity and up-regulation of iNOS, COX-2 and TNF-α. Furthermore, hypobaric hypoxia induced HIF-1α protein expression, PARP activation and apoptosis in the hippocampus. Administration of Ca₂EDTA significantly attenuated the hypobaric hypoxia induced oxidative stress, inflammation and apoptosis in the hippocampus.

Conclusion

We propose that hypobaric hypoxia/reperfusion instigates free chelatable zinc imbalance in brain associated with neuroinflammation and neuronal apoptosis. Therefore, zinc chelating strategies which block zinc mediated neuronal damage linked with cerebral hypoxia and other neurodegenerative conditions can be designed in future.     

红景天苷对高原缺氧大鼠认知功能障碍的治疗作用及其可能机制

目的：探讨红景天苷（Sal）对高原缺氧大鼠认知功能障碍的治疗作用及其可能机制。方法：将30只成年雄性SD大鼠随机分为健康对照组、模型组（Model组）、Sal[按体重1g／（kg·d）]治疗组（sal组）。采用Morris水迷宫实验方法捡测缺氧后大鼠学习记忆功能变化,同时检测脑组织匀浆中超氧化物歧化酶（SOD）、谷胱甘肽过氧化物酶（GSH—PX）、谷胱甘）lk（GSH）、丙二醛（MDA）的水平。结果：（1）模型组大鼠寻找平台的潜伏期明显长于对照组,具有统计学意义（P〈0．05）,Sal组寻找平台的潜伏期相对于模型组显著缩短（P〈0．05）。撤离平台后,模型组大鼠在平台所在象限的停留时间明显短于对照组（P〈0．05）,Sal治疗后大鼠在平台所在象限的停留时间较模型组显著延长（P〈0．05）。（2）模型组SOD、GSH—PX、GSH显著下降,MDA明显增高,Sal干预组SOD、GSH．PX、GSH显著增高,而MDA明显下降,具有统计学意义（P〈O．05）。结论：Sal可改善高原缺氧大鼠认知功能,其可能机制是通过减轻海马区的氧化应激反应减轻海马区的损伤,从而实现改善认知功能。     

Omega-3 supplementation can restore glutathione levels and prevent oxidative damage caused by prenatal ethanol exposure

Prenatal ethanol exposure (PNEE) causes long-lasting deficits in brain structure and function. In this study, we have examined the effect of PNEE on antioxidant capacity and oxidative stress in the adult brain with particular focus on four brain regions known to be affected by ethanol: cerebellum, prefrontal cortex and hippocampus (cornu ammonis and dentate gyrus subregions). We have utilized a liquid diet model of fetal alcohol spectrum disorders that is supplied to pregnant Sprague-Dawley rats throughout gestation. To examine the therapeutic potential of omega-3 fatty acid supplementation, a subset of animals were provided with an omega-3-enriched diet from birth until adulthood to examine whether these fatty acids could ameliorate any deficits in antioxidant capacity that occurred due to PNEE. Our results showed that PNEE caused a long-lasting decrease in glutathione levels in all four brain regions analyzed that was accompanied by an increase in lipid peroxidation, a marker of oxidative damage. These results indicate that PNEE induces long-lasting changes in the antioxidant capacity of the brain, and this can lead to a state of oxidative stress. Postnatal omega-3 supplementation was able to increase glutathione levels and reduce lipid peroxidation in PNEE animals, partially reversing the effects of alcohol exposure, particularly in the dentate gyrus and the cerebellum. This is the first study where omega-3 supplementation has been shown to have a beneficial effect in PNEE, reducing oxidative stress and enhancing antioxidant capacity.     

Regional vulnerability to oxidative stress in a model of experimental epilepsy

We evaluated oxidative stress associated with a model of experimental epilepsy. Male Wistar rats were injected i.p. with 150 mg/kg convulsant 3-mercaptopropionic acid and decapitated in two stages: during seizures or in the post-seizure period. Spontaneous chemiluminescence, levels of thiobarbituric acid reactive substances, total antioxidant capacity and antioxidant enzyme activities were measured in cerebellum, hippocampus, cerebral cortex and striatum. In animals killed at seizure, increases of 42% and 90% were observed in spontaneous chemiluminescence of cerebellum and cerebral cortex homogenates, respectively, accompanied by a 25% increase in cerebral cortex levels of thiobarbituric acid reactive substances. In the post-seizure stage, emission completely returned to control levels in cerebral cortex and partly in cerebellum, thus showing oxidative stress reversibility in time. Hippocampus and striatum seemed less vulnerable areas to oxidative damage. A 30% decrease in glutathione peroxidase activity was only observed in cerebral cortex during seizures, while catalase and superoxide dismutase remained unchanged in all four areas during either stage. Likewise, total antioxidant capacity was unaffected in any of the studied areas. It is suggested that oxidative stress in this model of epilepsy arises from an increase in oxidant species rather than from depletion of antioxidant defences.     

Ketogenic Diet Increases Glutathione Peroxidase Activity in Rat Hippocampus

Ketogenic diets have been used in the treatment of refractory childhood epilepsy for almost 80 years; however, we know little about the underlying biochemical basis of their action. In this study, we evaluate oxidative stress in different brain regions from Wistar rats fed a ketogenic diet. Cerebral cortex appears to have not been affected by this diet, and cerebellum presented a decrease in antioxidant capacity measured by a luminol oxidation assay without changes in antioxidant enzyme activities—glutathione peroxidase, catalase, and superoxide dismutase. In the hippocampus, however, we observed an increase in antioxidant activity accompanied by an increase of glutathione peroxidase (about 4 times) and no changes in lipoperoxidation levels. We suggest that the higher activity of this enzyme induced by ketogenic diet in hippocampus might contribute to protect this structure from neurodegenerative sequelae of convulsive disorders.     

Influence of intermittent hypoxia and pyrimidinic nucleosides on cerebral enzymatic activities related to energy transduction

The effect of intermittent normobaric hypoxia and of biological pyrimidines (uridine and cytidine) on the specific activities of some enzymes related to cerebral energy metabolism were studied. Measurement were carried out on the following: (a) homogenate in toto; (b) purified mitochondrial fraction; (c) crude synaptosomal fraction, in different areas of rat brain: cerebral cortex, hippocampus, corpus striatum, hypothalamus, cerebellum, and medulla oblongata. Intermittent normobaric hypoxia (12 hours daily for 5 days) caused modifications of the enzyme activities in the homogenate in toto (decrease of hexokinase in cerebellum; increase of pyruvate kinase in medulla oblongata), in the purified mitochondrial fraction (increase of succinate dehydrogenase in the corpus striatum) and in the crude synaptosomal fraction (decrease of cytochrome oxidase activity in cerebral cortex, hippocampus, and cerebellum; decrease of malate dehydrogenase in hippocampus and cerebellum; decrease of lactate dehydrogenase in cerebellum). Daily treatment with cytidine or uridine altered some enzyme activities either affected or unaffected by intermittent hypoxia.     

Sleep deprivation under sustained hypoxia protects against oxidative stress

We previously showed that total sleep deprivation increased antioxidant responses in several rat brain regions. We also reported that chronic hypoxia enhanced antioxidant responses and increased oxidative stress in rat cerebellum and pons, relative to normoxic conditions. In the current study, we examined the interaction between these two parameters (sleep and hypoxia). We exposed rats to total sleep deprivation under sustained hypoxia (SDSH) and compared changes in antioxidant responses and oxidative stress markers in the neocortex, hippocampus, brainstem, and cerebellum to those in control animals left undisturbed under either sustained hypoxia (UCSH) or normoxia (UCN). We measured changes in total nitrite levels as an indicator of nitric oxide (NO) production, superoxide dismutase (SOD) activity and total glutathione (GSHt) levels as markers of antioxidant responses, and levels of thiobarbituric acid-reactive substances (TBARS) and protein carbonyls as signs of lipid and protein oxidation products, respectively. We found that acute (6h) SDSH increased NO production in the hippocampus and increased GSHt levels in the neocortex, brainstem, and cerebellum while decreasing hippocampal lipid oxidation. Additionally, we observed increased hexokinase activity in the neocortex of SDSH rats compared to UCSH rats, suggesting that elevated glucose metabolism may be one potential source of the enhanced free radicals produced in this brain region. We conclude that short-term insomnia under hypoxia may serve as an adaptive response to prevent oxidative stress.     

Activity of Lactate Dehydrogenase in Serum and Cerebral Cortex of Immature and Mature Rats after Hypobaric Hypoxia

In our previous studies we have found both an increase of lipid peroxidation damage (expressed as levels of thiobarbituric acid-reactive substances) in brain and plasma lactate concentration in 21-day-old rats after a 30-min exposure to hypobaric hypoxia. Pretreatment of rats with l-carnitine decreased both parameters. The aim of our present study was to determine if the l-carnitine-dependent decrease of plasma lactate could be due to a modification of lactate dehydrogenase (LDH) activity. We followed brain and blood serum LDH activity of 14-, 21- and 90-day-old Wistar rats. We found an increase of brain LDH activity with age. However, we did not observe any significant differences in LDH activity after exposure to hypobaric hypoxia or l-carnitine pretreatment. In contrast to brain, serum LDH activity did not show any clear age-dependence. The hypoxia exposure increased LDH activity of 21-day-old rats only. Pretreatment of rats with l-carnitine decreased serum LDH activity of 21- and 90-day-old rats probably due to membrane stabilizing role of l-carnitine. In conclusions, acute hypobaric hypoxia and/or l-carnitine pretreatment modified serum but not brain LDH activity.     

人参皂甙Rb1对大鼠慢性缺氧性认知功能障碍的治疗作用

目的：目前尚无特效的防治慢性缺氧性认知功能障碍措施,前人的研究提示人参皂甙Rb1可能有上述功效,故本实验拟研究人参皂甙Rb1对大鼠慢性缺氧性认知功能障碍的治疗作用及其可能机制。方法：取雄性成年SD大鼠30只,随机分为对照组、模型组、人参皂甙Rb1（2 mg/kg·d）治疗组。采用Morris水迷宫行为学实验检测大鼠学习记忆功能,运用膜片钳技术在脑片水平检测海马的突出可塑性。结果：（1）模型组大鼠寻找平台潜伏期较对照组显著延长（P〈0.05）,在目标象限的停留时间较对照组明显缩短（P〈0.05）,人参皂甙Rb1治疗后,大鼠寻找平台潜伏期较模型组缩短（P〈0.05）,在目标象限的停留时间较模型组延长（P〈0.05）;（2）在高频强直刺激（HFS）作用下,各组均有长时程增强（LTP）现象,但模型组LTP较对照组明显减弱（P〈0.05）,人参皂甙Rb1治疗后LTP明显增强（P〈0.05）。结论：人参皂甙Rbl减轻了慢性缺氧大鼠在水迷宫实验中的行为学改变,并增强了慢性缺氧大鼠海马LTP,证实人参皂甙Rbl可明显减轻大鼠慢性缺氧性认知功能障碍,该作用与其减轻海马LTP抑制有关,为高原缺氧性认知功能障碍的防治提供了新思路,但其具体机制尚有待于进一步研究,本室将在此基础上进一步深入研究人参皂甙Rbl改善慢性缺氧性认知功能障碍的机制。     

Evidence of a decrease in nitric oxide-storage molecules following acute hypoxia and/or hypobaria, by means of chemiluminescence analysis.

Nitrate, nitrite, and other nitroso compounds (NOxs) had been proposed as possible nitric oxide (NO) storage molecules. The present work examines, by means of chemiluminescence analysis, changes in NOx serum levels in rats 1 h before and 24, 48, and 72 h after exposure to acute hypobaric hypoxia (HH; barometric pressure [P(B)] 225 mmHg, oxygen partial pressure [PO2] 48 mmHg), normobaric hypoxia (NH; P(B) 716 mmHg [Jaén city], PO2 48 mmHg), hypobaric normoxia (HN; P(B) 225 mmHg, PO2 150 mmHg), and normobaric normoxia (NN; P(B) 716 mmHg, PO2 150 mmHg) the latter as a control group. Results show a decrease in NOx levels, which reached significance 24 h after exposure in HH animals, 4 h after exposure in the HN and NH groups, and persisted after 48 h of exposure in the HN group. NOx determinations were also performed in brain (cerebral cortex, hippocampus, decorticated brain [basal ganglia-brainstem] and cerebellum), liver, kidney, lung, and heart homogenates, 72 h after the experiment, to detect persistent effects when serum NOx levels had returned to basal values. Only in cerebellum (HN group) and hippocampus (HN and NH groups) were NOx levels significantly lower than in controls. We conclude that not only acute hypobaric hypoxia but also either hypobaria or hypoxia alone induce changes in NOx serum levels. Moreover, all three episodes involve a decrease in NOxs, greater and longer-lasting in hypoxia alone than in hypobaria and hypoxia together. The exhaustion of these NO-storage molecules could be critical when, as during a hypoxic episode, the L-arginine/NOS pathway is impaired.     

Effect of chlorpyrifos on thiobarbituric acid reactive substances, scavenging enzymes and glutathione in rat tissues

The present study showed that exposure of chlorpyrifos, O,O'-diethyl-O-3,5,6-trichloro-2-pyridyl phosphorothionate (CPF), a widely used pesticide in rats caused significant inhibition of acetylcholinesterase (AChE) activity in different tissues viz., liver, kidney and spleen. CPF exposure also generated oxidative stress in the body, as evidenced by increase in thiobarbituric acid reactive substances (TBARS), decrease in the levels of superoxide scavenging enzymes viz., superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx) in liver, kidney and spleen at all doses. Malondialdehyde levels were increased by 14%, 31% and 76% in liver, 11%, 31% and 64% in kidney and 32%, 75% and 99.9% in spleen when 50 mg, 100 mg and 200 mg/kg body wt. CPF was administered for three days. SOD and CAT activities were decreased in liver, kidney and spleen, while GPx activity showed slight increase in kidney at 50 mg and 100 mg dose, and decreased on further increase in dose of CPF. Liver and spleen showed dose-dependent decrease in GPx activity. The levels of reduced glutathione (GSH) was decreased, while oxidized glutathione (GSSG) was increased, thus a marked fall in GSH/GSSG ratio was observed in all tissues. A maximum decrease of 83% was observed in liver, followed by kidney and spleen, which showed 78% and 57% decrease, respectively in group given 200 mg/kg CPF. The levels of glucose-6-phosphate dehydrogenase (G6PDH) and glutathione reductase (GR) were also decreased in liver and kidney, while spleen showed increase at lower doses, but decrease at high dose of CPF. The data provide evidence for induction of oxidative stress on CPF exposure.     

Hypobaric hypoxia modulates brain biogenic amines and disturbs sleep architecture

Sojourners to high altitude experience poor-quality of sleep due to hypobaric hypoxia (HH). Brain neurotransmitters are the key regulators of sleep wakefulness. Scientific literature has limited information on the role of brain neurotransmitters involved in sleep disturbance in HH. The present study aimed to investigate the time dependent changes in neurotransmitter levels and enzymes involved in the biosynthesis of brain neurotransmitters in frontal cortex, brain stem, cerebellum, pons and medulla and the effect of these alterations on sleep architecture in HH. Thirty adult Sprague-Dawley rats, body weight of 230-250 g were exposed to simulated altitude ～7620 m, 282 mm Hg, partial pressure of O(2) 59 mm Hg for 7 and 14 days continuously in an animal decompression chamber. After 7 and 14 days of HH, brain nor-epinephrine and dopamine levels were significantly increased in frontal cortex, brain stem, cerebellum and pons and medulla whereas serotonin level was significantly reduced in frontal cortex and pons and medulla after 14 days of HH. Tyrosine hydroxylase level in locus coeruleus (LC) was significantly increased whereas Choline Acetyl Transferase and Glutamic Acid Decarboxylase (GAD) levels were significantly reduced in laterodorsal-tegmentum and pedunculopontine-tegmentum after 7 days of HH. GAD was also reduced in LC after 7 days HH. Alteration in these neurotransmitters and enzyme levels was accompanied with reduction in quality and quantity of sleep. There was a significant increase in sleep latency, rapid eye movement (REM) latency, duration of active awake, quiet awake, quiet sleep and a significant decrease in duration of REM sleep and deep sleep on day 7 and 14 of HH. It was concluded that HH alters the expression of enzymes linked to sleep neurotransmitter synthesis pathway and subsequent loss of homeostasis at neurotransmitter level disrupts the sleep pattern in hypobaric hypoxia.