Remote ischemic preconditioning improves spatial memory and sleep of young males during acute high-altitude exposure.

OBJECTIVE: The high-altitude hypoxia environment will cause poor acclimatization in a portion of the population. Remote ischemic preconditioning（RIPC）has been demonstrated to prevent cardiovascular and cerebrovascular diseases under ischemic or hypoxic conditions. However, its role in improving acclimatization and preventing acute mountain sickness (AMS) at high altitude has been undetermined. This study aims to estimate the effect of RIPC on acclimatization of individuals exposed to high altitude. METHODS: The project was designed as a randomized controlled trial with 82 healthy young males, who received RIPC training once a day for 7 consecutive days. Then they were transported by aircraft to a high altitude (3680 m) and examined for 6 days. Lake Louise Score(LLS) of AMS, physiological index, self-reported sleep pattern, and Pittsburgh Sleep Quality Index（PSQI）score were applied to assess the acclimatization to the high altitude. Five neurobehavioral tests were conducted to assess cognitive function. RESULTS: The result showed that the RIPC group had a significantly lower AMSscore than the control group (2.43 ± 1.58 vs 3.29 ± 2.03, respectively; adjusted mean difference-0.84, 95% confidence interval-1.61 to -0.06, P = 0.036). and there was no significant difference in AMS incidence between the two groups (25.0% vs 28.57%, P = 0.555). The RIPC group performed better than the control group in spatial memory span score (11[9-12] vs 10[7.5-11], P=0.025) and the passing digit (7[6-7.5] vs 6[5-7], P= 0.001). Spatial memory was significantly higher in the high-altitude RIPC group than in the low-altitude RIPC group (P＜0.01). And the RIPC group obtained significantly lower self-reported sleep quality score (P = 0.024) and PSQI score (P = 0.031). CONCLUSIONS: The RIPC treatment improved spatial memory and sleep quality in subjects exposed to acute hypoxic exposure and this may lead to improved performance at high altitude.

Exposure to Intermittent Environmental Hypoxia Promotes Vascular Remodeling through Angiogenesis in the Liver of Largemouth Bass (Micropterus salmoides).

In this study, we explored the effects of 4 weeks of intermittent hypoxic exposure (IHE) on liver angiogenesis and related regulatory mechanisms in largemouth bass (Micropterus salmoides). The results indicated that the O2 tension for loss of equilibrium (LOE) decreased from 1.17 to 0.66 mg/L after 4 weeks of IHE. Meanwhile, the red blood cell (RBC) and hemoglobin concentrations significantly increased during IHE. Our investigation also found that the observed increase in angiogenesis was correlated with a high expression of related regulators, such as Jagged, phosphoinositide-3-kinase (PI3K), and mitogen-activated protein kinase (MAPK). After 4 weeks of IHE, the overexpression of factors related to angiogenesis processes mediated by HIF-independent pathways (such as nuclear factor kappa-B (NF-κB), NADPH oxidase 1 (NOX1), and interleukin 8 (IL8)) was correlated with the accumulation of lactic acid (LA) in the liver. The addition of cabozantinib, a specific inhibitor of VEGFR2, blocked the phosphorylation of VEGFR2 and downregulated the expression of downstream angiogenesis regulators in largemouth bass hepatocytes exposed to hypoxia for 4 h. These results suggested that IHE promoted liver vascular remodeling by the regulation of angiogenesis factors, presenting a potential mechanism for the improvement of hypoxia tolerance in largemouth bass.

Hypoxic Therapy as a New Therapeutic Modality for Cardiovascular Benefit: A Mini Review.

Cardiovascular diseases (CVDs) are recognized as one of the major causes of morbidity and mortality worldwide. Generally, most CVDs can be prevented by addressing behavioral risk factors, including smoking, unhealthy diet and obesity, lack of physical activity, and alcohol abuse. Therefore, it is important to have a healthy lifestyle by performing regular physical activity to improve cardiovascular health and diseases. However, a majority of adults worldwide do not meet the minimum recommendations for regular aerobic exercise, and overweight and obesity ratio continues to rise. In addition, obese individuals, with a high prevalence of CVDs, have a lower participation rate for exercise because of the strain on the musculoskeletal system. Hypoxic therapy, including exposure or exercise intervention under hypoxia, has been utilized as a new therapeutic modality for cardiovascular benefit and amelioration of CVDs. Hypoxic therapy shows various physiological and pathophysiological properties, including increased appetite suppression and dietary intake reduction, increased energy consumption, improved glycogen storage, enhanced fatty acid oxidation, improved myocardial angiogenesis or ventricular remodeling, augmentation of blood flow within the skeletal muscle vascular beds, and reduction of the burden on the musculoskeletal system making it applicable to patients with CVDs and obesity with attenuated cardiovascular function. In particular, hypoxic therapy is very effective in improving cardiovascular benefits and preventing CVDs by enhancing arterial function, vascular endothelial function, and hemorheological properties. These observations indicate that hypoxic therapy may be an important and essential strategy for improving cardiovascular health and reducing cardiovascular morbidity and mortality.

Memantine ameliorates cognitive impairment induced by exposure to chronic hypoxia environment at high altitude by inhibiting excitotoxicity.

AIMS: Memantine is a non-competitive antagonist of glutamatergic NMDA receptor that is mainly used in the treatment of Alzheimer's disease. The excitatory toxicity mediated by glutamate via glutamatergic receptor signals is considered to be one of the mechanisms mediating neuronal injury and cognitive impairment after exposure to a hypoxic environment at a high altitude. Therefore, in this study, we hypothesized that inhibiting glutamate signaling using memantine could alleviate neuronal injury and cognitive impairment in rats exposed to chronic hypoxia. MAIN METHODS: we made animal models in the natural environment of the Qinghai-Tibet Plateau at an altitude of 4300 m, and used animal behavior, morphology, molecular biology and other methods to evaluate the impact of chronic hypoxia exposure on cognitive function and the neuroprotective effect of Memantine. KEY FINDINGS: Our results showed that the expression of NMDA receptors increased, while the expression of AMPA receptors decreased, after 4 weeks of chronic hypoxia exposure. Concomitantly, apoptotic neuronal cell death in the hippocampus and frontal cortex was significantly increased, along with levels of oxidative stress, whereas innate ability to inhibit free radicals decreased. Moreover, after 8 weeks of hypoxia exposure, learning, memory, and space exploration abilities were significantly decreased. Notably, after treatment with memantine, apoptotic neuronal cell death, oxidative stress, and free radical levels decreased, and the cognitive function of the animals improved. SIGNIFICANCE: Present study shows that chronic hypoxia can produce the excitatory toxicity leading to neural injury and cognitive impairment that can be suppressed with memantine treatment by inhibiting excitatory toxicity.

Effects of acute mild hypoxia on cerebral blood flow in pilots.

BACKGROUND: Pilots often face and need to overcome a diverse range of unfavorable conditions, of which hypoxic exposure is the most common. Studies have reported that hypoxia can induce a decrease in cerebral blood flow (CBF) in the brains of both humans and animals. Hypoxia and the associated cerebral hemodynamic changes can contribute to cognitive performance deficits that may endanger flight safety and increase the risk of accidents. AIM: In this study, we aimed to identify region-specific alterations in CBF in male pilots after exposure to hypoxia. MATERIAL AND METHODS: We used 3D pseudo-continuous arterial spin labeling sequences in 35 healthy male pilots (mean age: 30.6 ± 4.82 years) under simulated hypoxic conditions with a 3.0-T magnetic resonance imaging scanner. The generated CBF maps were measured and averaged in several regions of interest. RESULTS: Hypoxia decreased CBF in various brain regions, including the right temporal and bilateral occipital lobes, the anterior and posterior lobes of the cerebellum, the culmen and declive, and the inferior semilunar lobule of the cerebellum. CONCLUSION: These changes may impact the functional activity of the brains of pilots experiencing hypoxia in flight, but the related mechanisms require further investigation.

NMDA Receptor-Mediated Excitotoxicity Is Involved in Neuronal Apoptosis and Cognitive Impairment Induced by Chronic Hypobaric Hypoxia Exposure at High Altitude.

Ji, Weizhong, Yaqing Zhang, Ri-li Ge, Yaqi Wan, and Jie Liu. NMDA receptor-mediated excitotoxicity is involved in neuronal apoptosis and cognitive impairment induced by chronic hypobaric hypoxia exposure at high altitude. High Alt Med Biol. 22:45-57, 2021. Aim: Exposure to chronic hypobaric hypoxia at high altitude can lead to cognitive impairment; however, its underlying mechanism is still unclear. Excessive expression of glutamate and its receptors can induce excitotoxicity and cause neuronal necrosis, which is an important causative factor for the occurrence of various diseases in the nervous system. Therefore, excitotoxicity may also occur after exposure to a chronic hypobaric hypoxic environment. This study concentrates on the action mechanism of glutamate and its receptor-mediated excitotoxicity in cognitive impairment, induced by chronic hypobaric hypoxic exposure. Methods: Sprague-Dawley rats were fed at regions with three different altitudes (4,300, 2,260, and 450 m) for 8 weeks, and had their behavioral changes assessed by the Morris water maze test. Morphological, molecular biological, and biochemical tests were used to determine the role of N-methyl-d-aspartate (NMDA) receptor-mediated excitotoxicity in neuronal injury and cognitive impairment induced by chronic hypobaric hypoxia exposure. Results: We found that exposure to chronic hypobaric hypoxia at high altitudes could cause cognitive impairment, damage the neurons in the hippocampus and cortex, increase apoptosis, and lead to abnormal Caspase-3 protein expression. The expression of NMDA and a-amino-3-hydroxyl-5-methyl-4-isoxazole acid (AMPA) receptors increased significantly, as did the levels of oxidative stress and free radicals as well. However, no change in cognitive function was observed in the chronic hypobaric hypoxia environment at the middle altitude, there were no statistically significant differences in neuronal apoptosis and related protein expression compared with the rats in the flatland environment group. Conclusion: We show that high-altitude chronic hypobaric hypoxic environment could cause obvious cognitive impairments, which is related to the excitotoxicity mediated by glutamate and its receptors, in contrast to the chronic hypobaric hypoxia environment at middle altitude group and flatland environment group.

Central sleep apnea: misunderstood and mistreated!

Central sleep apnea is prevalent in patients with heart failure, healthy individuals at high altitudes, and chronic opiate users and in the initiation of "mixed" (that is, central plus obstructive apneas). This brief review focuses on (a) the causes of repetitive, cyclical central apneas as mediated primarily through enhanced sensitivities in the respiratory control system and (b) treatment of central sleep apnea through modification of key components of neurochemical control as opposed to the current universal use of positive airway pressure.

The effects of a graded increase in chronic hypoxia exposure duration on healthy rats at high-altitude.

To investigate the effects of chronic hypoxia exposure at high altitude on the formation of pulmonary edema in rats, we randomized rats into normoxic control groups and hypoxic 24, 48, and 72-hour exposure groups. In the hypoxic exposure group, the arterial blood gas, wet-dry weight ratio (W/D), lung tissue permeability index (LPI), bronchoalveolar lavage fluid (BALF) and plasma levels of the inflammatory factors were measured after continuous, chronic hypoxic exposure for a corresponding time, and the pathological changes in the lung tissue and the expression of tight junction-associated protein occludin were observed. We found that the contents of arterial blood gas, W/D, LPI, BALF and plasma IL-6, TNF-α, and IL-10 in the hypoxic exposure group were significantly different from the contents of arterial blood gas in the normoxic control group. H&E staining showed tissue effusion, a marked thickening of the pulmonary septum, interstitial inflammatory cells, and erythrocytic infiltration. Compared with the normoxic control group, the pulmonary edema score was significantly increased in the hypoxic 48-hour group. Toluidine blue staining showed that the mast cell count and degranulation rate were significantly increased in the hypoxic 48-hour and 72-hour groups, but massone staining showed no significant pulmonary interstitial fibrosis in the 4 groups. Occludin expression was significantly higher in the normoxic control group than it was in the hypoxic exposure group. These results indicated that different chronic hypoxic exposure durations at the plateau all caused high-altitude pulmonary edema in rats, but there was no significant difference in some indicators among the groups.

ACUTE ANTIOXIDATIVE RESPONSE TO SHORT-TERM NORMOBARIC HYPOXIA IN HUMANS —ANALYSIS BASED ON THE CHANGES IN HEME-OXYGENASE-1 mRNA EXPRESSION AND SERUM BILIRUBIN CONCENTRATION— / 体力科学

The purpose of this study was to investigate heme oxygenase-1 (HO-1) mRNA expression and bilirubin concentration alteration in humans exposed to acute hypoxia. Fourteen healthy adult males were randomly assigned to a sea level group and a hypoxia group, and then exposed to normoxia (400 m, 20.0 %O₂) and hypoxia (3,000 m, 14.5 %O₂) respectively, in a hypoxic chamber for 3 hours. SpO₂ during hypoxia were significantly lower than those at sea level (P＜0.05). Indirect bilirubin levels after hypoxia were significantly higher than those at sea level (P＜0.05). However, HO-1 mRNA expression was unaltered by hypoxia. In conclusion, our data indicate that an acute exposure to hypoxia at resting state for 3 hours might lead to antioxidative cytoprotective response without any increase in HO-1 gene expression.

Relation of CAG Repeat Polymorphism of AR Gene in Men of Han Nationality from Northern China to the Effectiveness of Hypoxic Training / 中国运动医学杂志

Objective To investigate the distribution characteristics of (CAG)n polymorphism in the exonl of the androgen receptor (AR) gene and its relation to the sensitivity of hypoxic training in men of Han nationality from northern China. Methods Sixty five healthy young men of Han nationality completed HiHiLo training under simulated normobaric hypoxic environment for 4 weeks. They stayed under the condition of 14.3-14.8% O_2 (simulating 2800～3000m) during nighttime and carried out hypoxic training under the condition of 14.8-15.4% O_2 (simulating 2500～2800m) 3 times per week at the intensity of 75% individual VO_2max. VO_2max and body weight of the subjects were measured. GeneScan method was used to identify the repeat alleles (genotypes) of CAG polymorphism. Results (1) Fifteen alleles (CAG)12,(CAG)16-28,(CAG)30 repeat alleles (genotypes) were observed in the subjects, in which (CAG)22 was the most common allele; (2) When 21 and 22 alleles were used as the cut point, the baseline of body weight in those carrying shorter genotypes was significantly lower than that in those carrying longer genotypes; (3) △VO_2max and △rVO_2max in men carrying shorter genotypes were significantly higher than that in men carrying longer genotypes after hypoxic training. Conclusion The result reveals that AR (CAG)n polymorphism is associated with the sensitivity of simulated normobaric hypoxic HiHiLo training in men of Han nationality from northern China, especially in those carrying shorter genotypes of AR CAG.

Changes of expression levels of 12S rRNA and COXⅠ mRNA encoded by mtDNA in rat brain during hypoxic exposure / 第三军医大学学报

Objective To explore the changes of expression levels of 12S rRNA and cytochrome oxidase subunit Ⅰ (COXⅠ) mRNA encoded by mtDNA in rat cerebral cortex after rat exposure to hypobaric hypoxia for different days. Methods Healthy male Wistar rats were exposed to hypobaric chamber simulating 5 000 m above sea level (23 5 h/day) for 2, 5, 15 and 30 d. Rats in the control group were not exposed to hypoxia. Rats were sacrificed by decapitation. Total RNA in cerebral cortex was extracted using a standard program. Transcriptional levels of 12S rRNA and COXⅠ mRNA were determined by reverse transcription polymerase chain reaction (RT PCR). Results Compared with that in the control, the expression of 12S rRNA increased by 57% after hypoxic exposure for 2 d ( P 0 05). Compared with that in the control group, the expression of COXⅠ mRNA increased significantly by 55% and 106% after hypoxic exposure for 2 and 5 d ( P 0 05). Conclusion Hypoxic exposure may have effect on both protein gene and ribosome gene expression encoded by mtDNA, and the expression changes in a hypoxic exposure time dependent manner. This suggests that hypoxia can have effect on mitochondrial oxidative phosphorylation gene expression at both mitochondrial transcriptional and translational levels.