The present study aimed to investigate the effects of a short period of normobaric hypoxic exposure on spatial learning and memory, and brain-derived neurotrophic factor (BDNF) levels in the rat hippocampus. Hypoxic conditions were set at 12.5% O2. We compared all variables between normoxic trials (Norm), after 24 h (Hypo-24 h), and after 72 h of hypoxic exposure (Hypo-72 h). Spatial learning and memory were evaluated by using a water-finding task in an open field. Time to find water drinking fountains was significantly extended in Hypo 24 h (36.2 ± 21.9 s) compared to those in Norm (17.9 ± 12.8 s; P < 0.05), whereas no statistical differences between Norm and Hypo-72 h (22.7 ± 12.3 s). Moreover, hippocampal BDNF level in Hypo-24 h was significantly lower compared to Norm (189.4 ± 28.4 vs. 224.9 ± 47.7 ng/g wet tissue, P < 0.05), whereas no statistically differences in those between Norm and Hypo-72 h (228.1 ± 39.8 ng/g wet tissue). No significant differences in the changes in corticosterone and adrenocorticotropic hormone levels were observed across the three conditions. When data from Hypo-24 h and Hypo-72 h of hypoxia were pooled, there was a marginal negative relationship between the time to find drinking fountains and BDNF (P < 0.1), and was a significant negative relationship between the locomotor activities and BDNF (P < 0.05). These results suggest that acute hypoxic exposure (24 h) may impair spatial learning and memory; however, it recovered after 72 h of hypoxic exposure. These changes in spatial learning and memory may be associated with changes in the hippocampal BDNF levels in rats.

Abstract Background Several factors have been shown to contribute to hypoxic-induced declined in aerobic capacity. In the present study, we investigated the effects of resting hypoxic ventilatory and cardiac responses (HVR and HCR) on hypoxic-induced declines in peak oxygen uptake ( $$\dot{\mathrm V}$$ V ˙ O2peak). Methods Peak oxygen uptakes was measured in normobaric normoxia (room air) and hypoxia (14.1% O2) for 10 young healthy men. The resting HVR and HCR were evaluated at multiple steps of hypoxia (1 h at each of 21, 18, 15 and 12% O2). Arterial desaturation (ΔSaO2) was calculate by the difference between SaO2 at normoxia—at each level of hypoxia (%). HVR was calculate by differences in pulmonary ventilation between normoxia and each level of hypoxia against ΔSaO2 (L min−1 %−1 kg−1). Similarly, HCR was calculated by differences in heart rate between normoxia and each level of hypoxia against ΔSaO2 (beats min−1 %−1). Results $$\dot{\mathrm V}$$ V ˙ O2peak significantly decreased in hypoxia by 21% on average (P < 0.001). HVR was not associated with changes in $$\dot{\mathrm V}$$ V ˙ O2peak. ΔSaO2 from normoxia to 18% or 15% O2 and HCR between normoxia and 12% O2 were associated with changes in $$\dot{\mathrm V}$$ V ˙ O2peak (P < 0.05, respectively). The most optimal model using multiple linear regression analysis found that ΔHCR at 12% O2 and ΔSaO2 at 15% O2 were explanatory variables (adjusted R 2 = 0.580, P = 0.02). Conclusion These results suggest that arterial desaturation at moderate hypoxia and heart rate responses at severe hypoxia may account for hypoxic-induced declines in peak aerobic capacity, but ventilatory responses may be unrelated.

A relationship between Bifidobacterium and defecation has previously been reported. Our hypothesis on the effectiveness of alkaline electrolyzed water (AEW) proposes that ingestion of AEW, considered possessing antioxidative properties, increases the number of Bifidobacteria and improves stool hardness and gastrointestinal symptoms. A double-blind, randomized study was conducted to evaluate the connection between stool consistency and change in gut microbiota composition induced by drinking hydrogen-dissolved AEW. The participants drank 500 mL of purified tap water or AEW every day for 2 weeks. In this study, drinking AEW did not drastically change gut microbiota, but it appeared to act on a specific bacterial species. Drinking AEW was confirmed to cause an increase in Bifidobacterium. The AEW group also saw stool consistency significantly converge to Bristol stool scale Type 4 (“normal”). Therefore, it is highly likely that the gut microbiota will be changed by drinking AEW. This study was retrospectively registered in University Hospital Medical Information Network (UMIN) Clinical Trials Registry (UMIN ID: UMIN000039507) on February 18, 2020, and was approved by the Ethics Committee of University of Yamanashi (approval No. H30-25) on January 9, 2018.

We investigated the effects of 4-day dietary beetroot (BR) juice supplementation on executive function assessed by color-word Stroop task (CWST) in hypoxia (fraction of inspired oxygen [FiO2] = 0.1395). Eight healthy young men performed 25-minute leg cycling exercise (target heart rate, 140 bpm) randomly with placebo (PL) juice or BR supplementation. The CWST was evaluated at resting hypoxic condition (after 30 minutes of hypoxic exposure) and at 15 minutes during exercise. During exercise, the correct response time in the CWST was significantly shortened compared with those at rest with no differences between PL and BR. The response accuracy in the CWST with BR was marginally lower than that with PL during exercise (p = 0.066). There were no significant differences in all physiological values, including pulmonary ventilation, arterial oxygen saturation, partial pressure of end-tidal carbon dioxide output, and tissue oxygenation in the left frontal lobe, assessed by near-infrared spectroscopy during exercise conditions involving PL and BR supplementation. These results suggest that moderate exercise in hypoxia partially improved executive function; however, 4-day dietary BR supplementation did not improve executive function during hypoxic exercise.

Both exercise training and chronic caloric restriction contribute to brain health through enhanced expression of brain-derived neurotrophic factor (BDNF). This study investigated the synergistic effects between 12-week low-intensity exercise training and caloric restriction on hippocampal BDNF expression with redox status in rats. Twenty-six, 7-week-old male Wistar rats were randomly divided into the following 4 groups: (1) sedentary control (Con, n = 7), (2) exercise (Ex, n = 6), (3) caloric restriction (CR, n = 7), and (4) caloric restriction and exercise training (ExCR, n = 6). Although Con and Ex rats were fed ad libitum over time, CR and ExCR rats consumed 40% less food compared to Con rats. Ex and ExCR rats underwent low-intensity treadmill running (30 min/day, 5 days/week). Forty-eight hours after the termination of the 12-week intervention, rats were sacrificed and the hippocampus was quickly dissected for measuring BDNF expression and markers of oxidative stress, including 4-hydroxy-2-nonenal (4-HNE). Hippocampal BDNF expression was significantly increased in Ex compared to Con rats (p = 0.007), whereas the exercise-induced increase in BDNF was completely suppressed by a combination with caloric restriction. Furthermore, we observed a significant relationship between hippocampal BDNF and 4-HNE expression (r = 0.725, p < 0.001). Our findings indicate that exercise training combined with caloric restriction might not have a synergistic effect on hippocampal BDNF expression in young rats. Moreover, exercise-induced oxidative stress can trigger BDNF expression in the hippocampus.

Whether dietary nitrate supplementation improves exercise performance or not is still controversial. While redistribution of sufficient oxygen from inactive to active muscles is essential for optimal exercise performance, no study investigated the effects of nitrate supplementation on muscle oxygenation profiles between active and inactive muscles. Nine healthy males performed 25 min of submaximal (heart rate similar to 140 bpm; EXsub) and incremental cycling (EXmax) until exhaustion under three conditions: (A) normoxia without drink; (B) hypoxia (FiO(2) = 13.95%) with placebo (PL); and (c) hypoxia with beetroot juice (BR). PL and BR were provided for 4 days. Oxygenated and deoxygenated hemoglobin (HbO(2) and HHb) were measured in vastus lateralis (active) and biceps brachii (inactive) muscles, and the oxygen saturation of skeletal muscle (StO(2); HbO(2)/total Hb) were calculated. During EXsub, BR suppressed the HHb increases in active muscles during the last 5 min of exercise. During EXmax, time to exhaustion with BR (513 +/- 24 sec) was significantly longer than with PL (490 +/- 39 sec, P < 0.05). In active muscles, BR suppressed the HHb increases at moderate work rates during EXmax compared to PL (P < 0.05). In addition, BR supplementation was associated with greater reductions in HbO(2) and StO(2) at higher work rates in inactive muscles during EXmax. Collectively, these findings indicate that short-term dietary nitrate supplementation improved hypoxic exercise tolerance, perhaps, due to suppressed increases in HHb in active muscles at moderate work rates. Moreover, nitrate supplementation caused greater reductions in oxygenation in inactive muscle at higher work rates during hypoxic exercise.

What is the central question of this study? Acute hypoxia reduces dynamic cerebral autoregulation (dCA); however, it is unclear what level of hypoxia is necessary to exert this effect. We sought to investigate whether dCA would be reduced during progressive periods of normobaric hypoxia using a duplex Doppler ultrasound technique to evaluate the volumetric blood flow. What is the main finding and its importance? We showed that dCA decreased linearly as inspired O2 decreased from 21 to 12%. Additionally, symptoms of acute mountain sickness were related to changes in dCA. Our results may provide a sensitive and clinically relevant test to evaluate the risk of acute mountain sickness.

Aims] Skyrunning (SR) is an extreme sport of mountain running above 2,000 meters, and the number of participants in SR is rapidly increasing in Europe.In Japan, the sport has been growing in popularity since the establishment of the Japan Skyrunning Association (JSA) in 2013.However, the physical loads during SR remain unknown.The purpose of this study was to examine the effects of SR on runners.[Methods] 7 healthy males and females performed skyrunning (from 1,500 m to 2700 m in altitude) followed by a pre-test (20 m shuttle-run, weight bearing index, vertical jump, muscle hardness and blood, saliva and urine sampling).The data was analyzed as the trained group (TR: n=4, 2 males & 2 females) and the untrained group (n=3, 2 males & 1 female).[Results] There was no significant difference in mean HR during SR, however %V ・ O 2max indicated a high value in TR (p<0.05).And there were no significant differences in vertical jump, muscle hardness and oxidative stress markers, however WBI was high in TR compared with in the untrained group (p<0.05).[Conclusion] Compared with the untrained group, TRs performed continuously high intensity exercise with an equal HR level in a hypoxic environment.

[Aims] Skyrunning (SR) is an extreme sport of mountain running above 2,000 meters, and the number of participants in SR is rapidly increasing in Europe. In Japan, the sport has been growing in popularity since the establishment of the Japan Skyrunning Association (JSA) in 2013. However, the physical loads during SR remain unknown. The purpose of this study was to examine the effects of SR on runners. [Methods] 7 healthy males and females performed skyrunning (from 1,500 m to 2700 m in altitude) followed by a pre-test (20 m shuttle-run, weight bearing index, vertical jump, muscle hardness and blood, saliva and urine sampling). The data was analyzed as the trained group (TR: n=4, 2 males & 2 females) and the untrained group (n=3, 2 males & 1 female). [Results] There was no significant difference in mean HR during SR, however %V・O2max indicated a high value in TR (p<0.05). And there were no significant differences in vertical jump, muscle hardness and oxidative stress markers, however WBI was high in TR compared with in the untrained group (p<0.05). [Conclusion] Compared with the untrained group, TRs performed continuously high intensity exercise with an equal HR level in a hypoxic environment.

We investigated the relation between blood pressure and cerebral oxygenation (COX) immediately after exercise in ten healthy males. Subjects completed an exercise and recovery protocol while breathing either 21% (normoxia) or 14.1% (hypoxia) O2 in a randomized order. Each exercise session included four sets of cycling (30 min/set, 15 min rest) at 50% of altitude-adjusted peak oxygen uptake, followed by 60 min of recovery. After exercise, mean arterial pressure (MAP; 87±1 vs. 84±1 mmHg, average values across the recovery period) and COX (68±1% vs. 58±1%) were lower in hypoxia compared to normoxia (P<0.001). Changes in MAP and COX were correlated during the recovery period in hypoxia (r=0.568, P<0.001) but not during normoxia (r=0.028, not significant). These results demonstrate that reductions in blood pressure following exercise in hypoxia are (1) more pronounced than in normoxia, and (2) associated with reductions in COX. Together, these results suggest an impairment in cerebral autoregulation as COX followed changes in MAP more passively in hypoxia than in normoxia. These findings could help explain the increased risk for postexercise syncope at high altitude.

The oxidant and antioxidant equilibrium is known to play an important role in equine medicine and equine exercise physiology. There are abundant findings in this field; however, not many studies have been conducted for reference ranges of oxidative stress biomarkers in horses. This study was conducted to determine the reference values of reactive oxygen metabolites (d-ROMs) and biological antioxidant potential (BAP) using blood samples from 372 (191 males, 181 females) Thoroughbred racehorse aged 2 to 5 (3.43 ± 1.10 (mean ± SD)) years old. There were obvious gender differences in oxidative biomarkers, and growth/age-related changes were observed especially in females. Gender and age must be considered when interpreting obtained oxidative stress biomarkers for diagnosis of disease or fitness alterations in Thoroughbred racehorses.

PURPOSE: Recent studies have suggested that exercise training and caloric restriction have beneficial effects on brain function, including the improvements of cognitive function by the promotion of brain-derived neurotrophic factor (BDNF) expression in the hippocampus. In addition, the level of oxidative stress might be involved in the mechanism to explain these effects. The purpose of this study was to investigate the synergy effects between 12-week low-intensity exercise training and caloric restriction on BDNF expression and the level of oxidative stress in rat hippocampus. METHODS: Twenty-six, 7 week-old male Wistar rats were randomly divided into the following 4 groups: 1) sedentary control (Con, n=7); 2) exercise (Ex, n=6); 3) caloric restriction (CR, n=7); and 4) exercise training and caloric restriction (ExCR, n=6). Ex and ExCR underwent treadmill running at 10 m/min, 5° slope, 30 min/day, 5 days/week. Although Con and Ex were fed ad libitum over time, CR and ExCR consumed 40 % less food compared with Con. Forty-eight hours after the termination of the 12-week intervention, rats were sacrificed and the hippocampus was quickly dissected for measurement of BDNF and 4-hydroxy-2-nonenal (4-HNE) contents, and serum total antioxidant capacity (TAC) were also assessed. RESULTS: 4-HNE contents in Ex and CR were significantly increased compared with Con (p<0.05, respectively). However, these elevation was not observed in ExCR. On the other hand, no changes were observed in the alteration of serum TAC among 4 groups. Hippocampal BDNF contents was significantly increased in Ex compared with Con (p<0.05), whereas the exercise-induced elevation in BDNF was completely suppressed by a combination with caloric restriction. Furthermore, we found a significant relationship between hippocampal BDNF and 4-HNE contents (p<0.05), suggesting the hypothesis that oxidative stress is essential for the expression of BDNF in the hippocampus. CONCLUSION: Our findings indicate that optimal stimulus of oxidative stress induced by low-intensity exercise training contributes to BDNF expression in hippocampus. However, it is conceivable that exercise training combined with caloric restriction might not have a synergy effect on hippocampal BDNF expression.

Dobashi, Shohei, Masahiro Horiuchi, Junko Endo, Masataka Kiuchi, and Katsuhiro Koyama. Cognitive function and cerebral oxygenation during prolonged exercise under hypoxia in healthy young males. High Alt Med Biol. 17:214-221, 2016.-The present study examined the effect of prolonged hypoxic exercise on cognitive function. Eight healthy male volunteers were required to complete exercise trials (four 30-minute cycling sessions with a 15-minute rest interval) at an intensity corresponding to 50% of their altitude-adjusted peak oxygen uptake under two different conditions: normoxia (room air at 400 m) and hypoxia (fraction of inspired oxygen: 0.141). Cognitive function was evaluated before, during, and 60 minutes after completion of the exercise trial. The color-word Stroop task (CWST) was used to assess cognitive function, with regard to the number of achievements, accuracy rate, and the number of correct responses made within 60 seconds. Cerebral oxygenation was monitored throughout the experimental period using near-infrared spectroscopy. The accuracy rate did not significantly differ between the two trials. A significant reduction in the number of correct responses during simple CWST tasks was detected in the hypoxic condition 60 minutes after exercise (p < 0.05), wherein a significant correlation was identified between reduced task performance on simple CWST and cerebral oxygenation (p < 0.01). These results demonstrate that prolonged exercise under hypoxic conditions induces a reduction in cerebral oxygenation partly associated with impairment of cognitive function.

PURPOSE: Many previous researches have already investigated the effects of short-term hypoxic exercise on cognitive function. However, the influences of prolonged exercise under hypoxic condition on cognitive function were still unknown.The purpose of this study was to examine whether prolonged exercise in hypoxia causes change in cognitive function, and to evaluate the relationships between changes in cognitive function and cerebral oxygenation or degree of acute mountain sickness during hypoxic exposure. METHODS: Eight healthy male volunteers completed two exercise trials consisting of 4 sets of 30-min cycling, at the intensity corresponding to their 50% of peak oxygen uptake in both normoxia (FiO2: 0.200) and hypoxia (FiO2: 0.141). Before, during (immediately after 2nd and 4th set of exercise), and 60 min after exercise trial, cognitive function was evaluated by color-word Stroop task (CWST) that was composed of two tasks including the Stroop and reverse-Stroop task with their control and interference task. Results of CWST were interpreted by the number of correct answers per unit of time and ratio of the interference. The degree of acute mountain sickness was assessed by Lake Louise score (LLS) at the same time point of experiment. Cerebral oxygenation was monitored through the experimental period by near-infrared spectroscopy (NIRS). All results were expressed as differences relative to those before exercise trials. RESULTS: Delta numbers of correct answers of control tasks in CWST during hypoxia were significantly lower than those during normoxia (p < 0.05), whereas the changes in ratio of cognitive interference were not affected by hypoxic exposure. We found significant relationships between changes in score of control tasks in CWST and that in cerebral oxygenation or LLS (p < 0.05, respectively). CONCLUSION: Our results demonstrate that prolonged hypoxic exercise induces the reduction of cerebral oxygenation and increased degree of acute mountain sickness. These changes were closely associated with a reduction in simple cognitive function. However, the underlying mechanism of reduced score of simple tasks in CWST during hypoxia remains unclear.

Upon intensive, exhaustive exercise, exercise-induced reactive oxygen species may exceed the antioxidant defence threshold, consequently resulting in muscular damage or late-onset chronic inflammation. Recently, the therapeutic antioxidant and anti-inflammatory effects of molecular hydrogen (H2) for human rheumatoid arthritis have been demonstrated. However, it is also important to clarify the effects of administrating H2 in large animals other than humans, as H2 is thought to reach the target organ by passive diffusion upon delivery from the blood flow, indicating that the distance from the administration point to the target is critical. However, data on the effects of H2 on oxidative stress in real-life exhaustive exercise in large animals are currently lacking. We here investigated 13 Thoroughbred horses administered intravenous 2-L saline with or without 0.6-ppm H2 (placebo, N = 6; H2, N = 7) before participating in a high-intensity simulation race. Intravenous H2-saline significantly suppressed oxidative stress immediately, 3 h, and 24 h after the race, although the antioxidant capability was not affected throughout the study. The serum creatine kinase, lactate, and uric acid levels were increased in both groups. Taken together, these results indicate that intravenous H2-saline can significantly and specifically suppress oxidative stress induced after exhaustive racing in Thoroughbred horses.

Irisin is mainly released from skeletal muscle (myocytes) and promotes thermogenesis by browning of the white adipose tissue. Although exercise has been shown to increase irisin concentration in blood and myocytes via up-regulation peroxisome proliferator receptor γ coactivator-1α (PGC-1α) expression, the influence of exercise intensity on irisin secretion remains unclear. Therefore, we determined circulating irisin responses following a single bout of running at different intensities. Six sedentary males underwent treadmill running under two different conditions: a low-intensity (40% of VO2max) exercise trial (LIE) or a high-intensity (80% of VO2max) exercise trial (HIE). The exercises in LIE and HIE were lasted for 20 and 40 min, respectively. All subjects underwent the two trials on separate days, and a randomized cross-over design was used. Blood samples were collected before (Pre) and immediately after exercise, at 3, 6, and 19 h after exercise. Energy consumption during exercise did not significantly differ between the two trials. HIE significantly increased blood lactate and serum lactate dehydrogenase levels (P < 0.05). Compared with pre-exercise levels, the irisin concentrations were elevated at 6 h (18% increase) and 19 h (23% increase) after HIE, but significantly decreased after LIE. The relative irisin concentrations (compared with pre-exercise levels) were significantly greater in HIE than in LIE immediately after exercise, and at 6 and 19 h after exercise (P < 0.05). These findings suggest that irisin secretion after acute running exercise is affected by exercise intensity, independent of energy consumption.

The purpose of this study was to investigate the effect of attenuation of exercise-induced oxidative stress by antioxidant administration on brain-derived neurotrophic factor (BDNF) expression in the rat hippocampus. Wistar rats were assigned to four groups: non-exercise (Cont), exercise (Ex), or the combination of exercise with antioxidant administration (small dose: SP, large dose: LP) group. Exercise groups were subjected to treadmill running for 10 consecutive days. The exercise load increased gradually by 5 m/min per day for the first 5 days (10 m/min-30 m/min), and maintained at 30 m/min for the last 5 days. In addition, SP and LP were injected with N-tert butyl-a-phenyl nitrone (PBN) 1h prior to exercise. High-intensity exercise resulted in increased hippocampal 4-hydroxy-2-nonenal (4-HNE) contents compared with Cont. But this elevation was completely suppressed by a large dose of PBN. In Ex and SP, serum total antioxidative power were significantly decreased compared with Cont, whereas no changes were observed in LP. There was a significant negative correlation between hippocampal 4-HNE contents and serum total antioxidative power in SP and LP, suggesting the hypothesis that exercise-induced reduction in total antioxidant power might lead hippocampal 4-HNE accumulation. Furthermore, there was a significant increase of hippocampal BDNF level in LP compared with Cont and Ex. These findings indicate that an increase of oxidative stress might not have a beneficial effect on hippocampal BDNF expression. Our results of this study also suggest that attenuation of exercise-induced oxidative stress by some antioxidants contributes to BDNF expression in the hippocampus.