One-year Aerobic Interval Training Improves Endothelial Dysfunction in Patients with Atrial Fibrillation: A Randomized Trial.

Objective To evaluate the effects of one-year aerobic interval training on endothelial dysfunction in patients with atrial fibrillation. Methods Seventy-four patients with atrial fibrillation (53 men, 21 women; mean age 63±6 years old) were randomized into a 1-year continuous aerobic interval training (CT), 6-month detraining after 6 months of aerobic interval training (DT), or medical treatment only (MT) group. Aerobic interval training was performed 3 times a week for 1 year or 6 months, with an exercise intensity of 85-95% of the peak heart rate. The primary outcome was a change in biomarkers of endothelial dysfunction from baseline at six months or at the one-year follow-up. Results Six-month aerobic interval training reduced von Willebrand factor (CT: 103.7±30.7 IU/dL and DT: 106±31.2 IU/dL vs. MT: 145±47.7 IU/dL, p=0.044). Improvements were maintained with continuous aerobic interval training; however, the values increased again to the baseline levels upon detraining (CT: 84.3±39.1 IU/dL vs. DT: 122.2±27.5 IU/dL and MT: 135.9±50.4 IU/dL, p=0.002). Interleukin 1 beta levels decreased after 6 months of aerobic interval training (CT: 0.59±0.1 pg/mL and DT: 0.63±0.09 pg/mL vs. MT: 0.82±0.28 pg/mL, p=0.031), and the improvement was maintained with continuous aerobic interval training and even after detraining (CT: 0.58±0.08 pg/mL and DT: 0.62±0.09 pg/mL vs. MT: 0.86±0.28 pg/mL, p=0.015). Conclusion One-year aerobic interval training improves endothelial dysfunction in patients with atrial fibrillation and is primarily associated with the reduction in circulating thrombogenic and pro-inflammatory factors. A definitive way to sustain these improvements is the long-term continuation of aerobic training.

Postnatal treadmill exercise alleviates short-term memory impairment by enhancing cell proliferation and suppressing apoptosis in the hippocampus of rat pups born to diabetic rats.

During pregnancy, diabetes mellitus exerts detrimental effects on the development of the fetus, especially the central nervous system. In the current study, we evaluated the effects of postnatal treadmill exercise on short-term memory in relation with cell proliferation and apoptosis in the hippocampus of rat pups born to streptozotocin (STZ)-induced diabetic maternal rats. Adult female rats were mated with male rats for 24 h. Two weeks after mating, the pregnant female rats were divided into two groups: control group and STZ injection group. The pregnant rats in the STZ injection group were administered 40 mg/kg of STZ intraperitoneally. After birth, the rat pups were divided into the following four groups: control group, control with postnatal exercise group, maternal STZ-injection group, and maternal STZ-injection with postnatal exercise group. The rat pups in the postnatal exercise groups were made to run on a treadmill for 30 min once a day, 5 times per week for 2 weeks beginning 4 weeks after birth. The rat pups born to diabetic rats were shown to have short-term memory impairment with suppressed cell proliferation and increased apoptosis in the hippocampal dentate gyrus. Postnatal treadmill exercise alleviated short-term memory impairment by increased cell proliferation and suppressed apoptosis in the rat pups born to diabetic rats. These findings indicate that postnatal treadmill exercise may be used as a valuable strategy to ameliorate neurodevelopmental problems in children born to diabetics.

Treadmill exercise alleviates prenatal noise stress-induced impairment of spatial learning ability through enhancing hippocampal neurogenesis in rat pups.

Stress alters brain cell properties and then disturbs cognitive processes, such as learning and memory. In this study, we investigated the effect of postnatal treadmill exercise on hippocampal neurogenesis and spatial learning ability of rat pups following prenatal noise stress. The impact of exercise intensity (mild-intensity exercise vs heavy-intensity exercise) was also compared. The pregnant rats in the stress-applied group were exposed to a 95 dB supersonic machine sound for 1 h once a day from the 15th day after mating until delivery. After birth, the rat pups in the exercise groups were made to run on a treadmill for 30 min once a day for 7 consecutive days, starting 4 weeks after birth. The spatial learning ability was tested using radial-arm maze task and hippocampal neurogenesis was determined by 5-bromo-2'-deoxyuridine (BrdU) immunohistochemistry. The rat pups born from the stress-applied maternal rats spent more time for the seeking of water and showed higher number of error in the radial-arm maze task compared to the control group. These rat pups showed suppressed neurogenesis in the hippocampus. In contrast, the rat pups performed postnatal treadmill exercise saved time for seeking of water and showed lower number of error compared to the stress-applied group. Postnatal treadmill exercise also enhanced neurogenesis in the hippocampus. The mild-intensity exercise showed more potent impact compared to the heavy-intensity exercise. The present results reveal that postnatal treadmill exercise lessens prenatal stress-induced deterioration of brain function in offspring.

Age-dependent effect of treadmill exercise on hemorrhage-induced neuronal cell death in rats.

Intracerebral hemorrhage (ICH) is a major cause of death and disability in the elderly. In the present study, we examined the age-dependence of the effect of treadmill exercise on the intrastriatal hemorrhage-induced neuronal cell death in rats. Young (8 weeks old) and old (64 weeks old) Sprague-Dawley male rats were used in the present study. Intrastriatal hemorrhage was induced by injection of 0.2 U collagenase (1 µL volume) into the striatum using a stereotaxic instrument. The rats in the exercise groups were forced to run on a treadmill for 30 min daily for 7 days. Lesion size was determined by Nissl staining. Apoptosis was assessed by the terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay. In the present results, induction of hemorrhage increased lesion size and enhanced apoptosis. Treadmill exercise decreased the lesion size with suppressing apoptosis. However, the size of lesion induced by hemorrhage and the number of apoptotic cells were not different between young and old rats. Treadmill exercise significantly reduced the ICH-induced lesion size and the number of apoptotic cells irrespective of age. The data suggest that treadmill exercise may provide therapeutic value against ICH by suppressing neuronal apoptosis regardless of age.

Effects of treadmill exercise on memory and c-Fos expression in the hippocampus of the rats with intracerebroventricular injection of streptozotocin.

Alzheimer's disease is a progressive neurodegenerative disease clinically characterized by dementia and neurobehavioral deterioration. Hippocampal neurons are vulnerable to injury induced by Alzheimer's disease. The immediate early gene c-Fos has been used as a marker of neuronal activity. In the present study, we investigated the effects of treadmill exercise on long-term memory capacity and c-Fos expression in the hippocampus of rats with Alzheimer's disease. The rat model of Alzheimer's disease used in the present study was induced by the intracerebroventricular (ICV) injection of streptozotocin (STZ) using a stereotaxic instrument. The rats in the exercise group were forced to run on a treadmill for 30 min once daily for 14 consecutive days starting at 3 days after the ICV injection of STZ. The results of the present study showed that ICV injection of STZ impaired long-term memory capacity and decreased the number of c-Fos-positive cells in several regions of the rat hippocampus. However, treadmill exercise alleviated long-term memory deficits and enhanced c-Fos expression in the rats with ICV injection of STZ. The results of the present study showed that treadmill exercise could be a useful strategy for treating several neurodegenerative diseases.

Effect of Acanthopanax senticosus on 5-hydroxytryptamine synthesis and tryptophan hydroxylase expression in the dorsal raphe of exercised rats.

Acanthopanax senticosus Harms (AS) is classified into the family of Araliaceae. The plant has been used as an analeptic aid, which improves weakened physical status and strength. Serotonin (5-hydroxytryptamine, 5-HT) is an important neurotransmitter and tryptophan hydroxylase (TPH) catalyzes the rate-f the raphe nuclei. These are associated with "central fatigue hypotheses" in the brain. In the present study, the effects of Acanthopanax senticosus on the time to exhaustion by treadmill exercise and on 5-HT synthesis and TPH expression in the dorsal raphe were investigated by immunohistochemistry. In the present results, Acanthopanax senticosus increased the time to exhaustion by treadmill running and it suppressed the exercise-induced increase of 5-HT synthesis and TPH expression. Acanthopanax senticosus was effective as caffeine for increasing the exhaustion time in treadmill running and for reducing the exercise-induced increase of 5-HT synthesis and TPH expression in the dorsal raphe. The present study shows that Acanthopanax senticosus reduces fatigue during exercise by the inhibition of exercise-induced 5-HT synthesis and TPH expression in the dorsal raphe.

Treadmill exercise suppresses nigrostriatal dopaminergic neuronal loss in 6-hydroxydopamine-induced Parkinson's rats.

In Parkinson's disease, the progressive loss of dopaminergic neurons in the pars compacta of the substantia nigra leads to debilitating motor dysfunction. In the present study, we investigated the effects of treadmill exercise on the dopaminergic neuronal cell death in the substantia nigra and on the dopaminergic fiber loss in the striatum of Parkinson's rats. Parkinson's rats were made by injecting 6-hydroxydopamine into the striatum with using a stereotaxic instrument. The rats in the exercise groups were put on the treadmill to run for 30 min once a day for 14 consecutive days after 6-hydroxydopamine administration into the striatum. Two weeks after the intrastriatal injection of 6-hydroxydopamine, the rats without treadmill exercise displayed rotational asymmetry following injection of apomorphine (0.5 mg/kg, s.c.). In contrast, the rats undergoing treadmill exercise showed a significant reduction of rotational asymmetry. Analysis via immunohistochemistry for the tyrosine hydroxylase expression revealed a substantial loss of cell bodies in the substantia nigra and their projected fibers in the striatum ipsilateral to the lesion following 6-hydroxydapamine injection into the striatum. However, treadmill running enhanced the survival of dopaminergic neurons in the substantia nigra and also their fibers projecting into the striatum. The results of the present study show that treadmill exercise may provide therapeutic value for the treatment of Parkinson's disease patients.

Influence of prenatal noise and music on the spatial memory and neurogenesis in the hippocampus of developing rats.

During the prenatal period, the development of individual is influenced by the environmental factors. In the present study, the influence of prenatal noise and music on the spatial memory and neurogenesis in the hippocampus of developing rats was investigated. The exposure to the noise during pregnancy caused growth retardation, decreased neurogenesis in the hippocampus, and impaired spatial learning ability in pups. The exposure to music during pregnancy, on the other hand, caused increased neurogenesis in the hippocampus and enhanced spatial learning ability in pups. The present study has shown the importance of the prenatal environmental conditions for the cognition and brain development.

Maternal swimming during pregnancy enhances short-term memory and neurogenesis in the hippocampus of rat pups.

In the present study, the effects of maternal swimming during pregnancy on the short-term memory ability, hippocampal neurogenesis, and brain-derived neurotrophic factor (BDNF) mRNA expression of rat pups were investigated. After confirming their pregnancy, the pregnant rats were divided into two groups: the control group and the swimming group. From the 15th day of pregnancy until delivery, pregnant rats were subcutaneously injected with 100mg/kg of 5-bromo-2'-deoxyuridine (BrdU) once a day at 30min before the starting of swimming exercise. Pregnant rats in the swimming group were forced to swim for 10min once a day until delivery. On the 21 days after birth, the rat pups were trained in a step-down avoidance test. The latency time of the step-down avoidance task was determined on the 28 days after birth in order to evaluate the short-term memory ability of pups. On the 29 days after birth, the rat pups' brains were removed, and BrdU immunohistochemistry for the detection of neurogenesis and reverse transcription-polymerase chain reaction (RT-PCR) for the detection of BDNF mRNA expression were then performed. The rat pups born from the maternal rats that performed swimming during pregnancy showed significantly increased BDNF mRNA expression, enhanced hippocampal neurogenesis, and improved short-term memory capability. The present results have clearly shown that maternal swimming by rats during pregnancy enhances the memory of the rats' offspring by increasing neurogenesis. Our present study provides the evidence that maternal exercise during the gestational period may enhance the brain functions of the mothers' offspring.

Early treadmill exercise decreases intrastriatal hemorrhage-induced neuronal cell death and increases cell proliferation in the dentate gyrus of streptozotocin-induced hyperglycemic rats.

Intracerebral hemorrhage (ICH) is a severe complication in diabetic patients. Currently, physical exercise is recommended as a behavioral intervention to promote functional recovery in brain diseases, including ICH. Recently, hyperglycemia is known to aggravate brain injury in experimental ICH. Here, we examined the effect of treadmill exercise on the intrastriatal hemorrhage-induced neuronal cell death and cell proliferation in the dentate gyrus of hyperglycemic rats. Hyperglycemia was induced by the intraperitoneal injection of 50 mg/kg streptozotocin (STZ). Intrastriatal hemorrhage was induced by the infusion of 0.2 U collagenase into the striatum using stereotaxic instrument. Rats in the exercise groups were forced to run on a treadmill for 30 min daily for 10 days. Apoptosis was assessed by the terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay. Cell proliferation was assessed by the 5-bromo-2'-deoxyuridine (BrdU) immunohistochemistry. Our data showed that in rats started treadmill exercise 24 h after ICH induction, the size of lesion induced by hemorrhage and the number of apoptotic cells were decreased significantly. The number of proliferating cells in the dentate gyrus was significantly decreased in hyperglycemic rats. Treadmill exercise markedly enhanced cell proliferation in the dentate gyrus of hyperglycemic rats. The data suggest that treadmill exercise may provide therapeutic value to ICH patients with hyperglycemia by suppressing neuronal apoptosis and increasing cell proliferation.

Maternal ethanol administration inhibits 5-hydroxytryptamine synthesis and tryptophan hydroxylase expression in the dorsal raphe of rat offspring.

Maternal ethanol consumption during pregnancy has a detrimental effect on the central nervous system (CNS) development of fetus. 5-Hydroxytryptamine (5-HT) is an important neurotransmitter and/or neuromodulator in the mammalian CNS. Tryptophan hydroxylase (TPH) is the rate limiting enzyme of 5-HT synthesis. Ethanol is known to induce neuropsychiatric disorders by alteration of the central serotonergic system. In the present study, the effects of maternal ethanol intake on the 5-HT synthesis and the TPH expression in the dorsal raphe of rat offspring were investigated. The present results show that the synthesis of 5-HT and the expression of TPH in the dorsal raphe of rat offspring were suppressed by maternal ethanol intake and that the suppressive effect of alcohol was more potent in the 5 weeks old rat pups compared to the 3 weeks old rat pups. Based on the present study, it can be suggested that the pathogenesis of ethanol-induced neuropsychological disorders involves ethanol-induced suppression on the 5-HT synthesis and the TPH expression in the dorsal raphe of offspring.

Long-term treadmill exercise overcomes ischemia-induced apoptotic neuronal cell death in gerbils.

It has been suggested that exercise may ameliorate neurologic impairment by impeding neuronal loss following various brain insults. In the present study, the effect of long-term treadmill exercise on short-term memory and apoptotic neuronal cell death in the hippocampus following transient global ischemia in gerbils was investigated. A step-down inhibitory avoidance task, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay, and immunohistochemistry for caspase-3 were used for this study. Ischemia was induced by occlusion of both the common carotid arteries of gerbils for 5 min. Gerbils in the exercise groups were forced to run on a treadmill for 30 min once a day for 4 consecutive weeks. The present results reveal that treadmill exercise for 4 weeks improved short-term memory by suppressing the ischemia-induced apoptotic neuronal cell death in the hippocampus. Here in this study, we show that long-term treadmill exercise for 4 weeks overcomes the ischemia-induced apoptotic neuronal cell death and thus facilitates the recovery of short-term memory impairment induced by ischemic cerebral injury.

Effect of acupuncture on 6-hydroxydopamine-induced nigrostratal dopaminergic neuronal cell death in rats.

In this study, we investigated the effect of acupuncture at the Zusanli acupoint (ST36) on the nigrostriatal dopaminergic neuronal cell death in the rats with Parkinson's disease. Two weeks after unilateral injection of 6-hydroxydopamine (6-OHDA) into the striatum, an apomorphine-induced rotational behavior test showed significant rotational asymmetry in the rats with Parkinson's disease. Immunostaining for tyrosine hydroxylase demonstrated a dopaminergic neuronal loss in the substantia nigra and dopaminergic fiber loss in the striatum. Acupuncture at the ST36 for 14 days significantly inhibited rotational asymmetry in the rats with Parkinson's disease, and also protected against 6-OHDA-induced nigrostriatal dopaminergic neuronal loss. These effects of acupuncture were not observed for the non-acupoint (hip) acupuncture. The present study shows that acupuncture at the ST36 acupoint can be used as a useful strategy for the treatment of Parkinson's disease.

Influence of maternal alcohol administration on c-Fos expression in the hippocampus of infant rats.

Maternal alcohol consumption during pregnancy is known to have a detrimental effect on the development of the fetus and its central nervous system (CNS) in particular. In the present study, the dose-dependence of the effect of maternal alcohol on hippocampal c-Fos expression, which is a marker of hippocampal neuronal activity and which is induced by a variety of stimuli, was examined in infant rats. In the present study, it was shown that expression of c-Fos in the hippocampus is decreased following treatment with alcohol in a dose-dependent fashion. Based on the results of the present study and the findings of other studies, it can be suggested that suppression of c-Fos expression in the hippocampus of infant rats with maternal alcohol administration mediates the associated developmental retardation and/or anomalies.

Age-dependence of the effect of treadmill exercise on cell proliferation in the dentate gyrus of rats.

The impact of age on the effect of treadmill exercise on cell proliferation in the dentate gyrus of rats was investigated via 5-bromo-2'-deoxyuridine immunohistochemistry. Animals of different ages were used: 4-week-old, 8-week-old, and 62-week-old. Based upon the present study, the most prominent cell proliferation in the dentate gyrus was observed in the 4-week-old rats, and decreased in direct relation to the age of the animals. In addition, although treadmill exercise increased cell proliferation in the dentate gyrus of animals in all age groups, the most potent enhancing effect appeared in the 8-week-old rats. The present results demonstrate that age is an important factor in the regulation of cell proliferation in the dentate gyrus and that the enhancing effect of the treadmill exercise on cell proliferation also depends on age status.

Treadmill exercise decreases intrastriatal hemorrhage-induced neuronal cell death via suppression on caspase-3 expression in rats.

Intracerebral hemorrhage is one of the most devastating types of stroke. This disease is known to cause severe neurological damage and also has a very high mortality rate. In this study, the effect of treadmill exercise on intrastriatal hemorrhage-induced neuronal cell death was investigated. Intrastriatal hemorrhage was caused by injection of collagenase into the striatum using a stereotaxic instrument. Animals of the exercise group were made to run on a treadmill for 30 min once a day during 10 consecutive days. In the present results, treadmill exercise was shown to suppress the increase in the size of hemorrhage-induced lesions and the increase in caspase-3 expression in the striatum. Based on these results, it is possible that treadmill exercise aids in the recovery from central nervous system sequelae following intracerebral hemorrhage.

Treadmill exercise suppresses diabetes-induced increment of neuropeptide Y expression in the hypothalamus of rats.

Diabetes mellitus is a metabolic disorder with serious sequelae in humans. Hyperphagia is a characteristic symptom of diabetes and is a central nervous system-mediated disorder. Neuropeptide Y (NPY) is a 36-amino-acid peptide and is concentrated in the hypothalamus which is an appetite-regulating area. NPY is known to stimulate appetite and decrease energy expenditure. In the present study, the effect of treadmill exercise on the hypothalamic NPY expression in rats with streptozotocin (STZ)-induced diabetes was investigated via immunohistochemistry. Enhanced NPY expression in the paraventricular nucleus and arcuate nucleus was observed in the STZ-induced diabetic rats. Treadmill exercise suppressed a diabetes-induced increase of NPY expression. The present results suggest the possibility that treadmill exercise inhibits diabetes-induced increment of the desire for food.