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1.  Aerobic Exercise Alleviates Ischemia-Induced Memory Impairment by Enhancing Cell Proliferation and Suppressing Neuronal Apoptosis in Hippocampus 
Neurogenic lower urinary tract dysfunction (NLUTD) is a possible consequence of several neurological disorders. NLUTD may produce debilitating symptoms and serious complications, such as chronic renal failure, and recurrent urinary tract infections. Many animal studies of NLUTD symptoms have focused on animal models of cerebral ischemia. In the present study, we investigated the effects of treadmill exercise on memory function and its relation to cell proliferation and apoptosis in the hippocampus, following transient global ischemia in gerbils.
To induce transient global ischemia in gerbil, both common carotid arteries were occluded for 5 minutes. Gerbils in the exercise groups were forced to run on a treadmill exercise for 30 minutes once a day for 2 weeks. Step-down avoidance task and Y maze task were performed. Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL)-staining, immunohistochemistry for 5-bromo-2'-deoxyridine, doublecortin, caspase-3, and Western blot for brain-derived neurotrophic factor (BDNF), Bax, Bcl-2, cytochrome c, caspase-3 were conducted.
Ischemia caused memory impairment with an increase of cell proliferation, BDNF expression, and apoptosis in the hippocampus. Treadmill exercise improved memory function with further increase of cell proliferation and BDNF expression and a decrease of apoptosis.
The animal model that we have developed and our assessment of the relation between exercise and brain function can be useful tools for future investigations of NLUTD symptoms associated with stroke, particularly ischemic stroke. The present study suggests that treadmill exercise promoted the recovery of brain function after cerebral ischemia.
PMCID: PMC4280438  PMID: 25562035
Ischemia; Cell Proliferation; Brain-Derived Neurotrophic Factor; Apoptosis; Exercise Test
2.  Treadmill exercise reduces spinal cord injury-induced apoptosis by activating the PI3K/Akt pathway in rats 
Apoptosis occurring secondary to spinal cord injury (SCI) causes further neural damage and functional loss. In this study, a rat model was used to investigate the effect of treadmill exercise on SCI-induced apoptosis and expression of neurotrophic factors. To produce SCI, a contusion injury (10 g × 25 mm) was applied subsequent to laminectomy at the T9–T10 level. Following SCI, treadmill exercise was performed for six weeks. Hindlimb motor function was evaluated with a grid-walking test. The expression of neurotrophic factors and the level of apoptosis at the site of SCI were determined by western blotting. SCI reduced hindlimb motor function and suppressed expression of neurotrophin (NT)-3 and insulin-like growth factor (IGF)-1. Expression of phosphatidylinositol 3-kinase (PI3K), the ratio of phosphorylated Akt to Akt (pAkt/Akt) and the ratio of B-cell lymphoma 2 (Bcl-2) to Bax (Bcl-2/Bax) were decreased, and cleaved caspase-3 expression was increased by SCI. Treadmill exercise enhanced hindlimb motor function and increased expression of nerve growth factor (NGF), NT-3 and IGF-1 in the SCI rats. Treadmill exercise increased PI3K expression, the pAkt/Akt and the Bcl-2/Bax ratios, and suppressed cleaved caspase-3 expression in the injured spinal cord. This study demonstrated that treadmill exercise promotes the recovery of motor function by suppressing apoptosis in the injured spinal cord. The beneficial effect of exercise may be attributed to the increase in expression of neurotrophic factors via activation of the PI3K/Akt pathway.
PMCID: PMC3919853  PMID: 24520250
spinal cord injury; treadmill exercise; motor function; apoptosis; neurotrophic factors
3.  The impact of duration of one bout treadmill exercise on cell proliferation and central fatigue in rats 
The purpose of this study was to investigate the impact of the duration-dependence of the one bout treadmill exercise on cell proliferation, stress, and central fatigue in rats. The animals were randomly divided into five groups: the non-exercise group, 1-h exercise group, 2-h exercise group, 4-h exercise group, and 6-h exercise group. The exercise load consisted of running at speed of 13 meters/min with the 0° inclination. Cell proliferation in the hippocampal dentate gyrus was increased in response to one bout moderate treadmill exercise in all exercise groups. But there was no statistical significance between the exercise duration and cell proliferation. The optical density of glucocorticoid (GR)-positive cells in the hippocampal dentate gyrus was not changed by treadmill exercise at any exercise duration. Expressions of serotonin (5-hydroxytryptamine, 5-HT) and tryptophan hyroxylase (TPH) were increased by treadmill exercise only at 6 h duration. It seemed like that there was no additional benefits on cell proliferation over 2 h exercise due to stressful factors with over exercise dose, and there was no change of GR expression due to early assessment point of time. It can be suggested that the one-bout of moderate treadmill exercise increased cell proliferation, but treadmill exercise prolonged to 6 h induced central fatigue in rats.
PMCID: PMC3836548  PMID: 24282806
Treadmill exercise; Exercise duration; Cell proliferation; Glucocorticoid receptor; 5-hydroxytryptamine; Tryptophan hyroxylase
4.  Treadmill exercise alleviates short-term memory impairment in 6-hydroxydopamine-induced Parkinson’s rats 
Progressive loss of dopaminergic neurons in substantia nigra is a key pathogenesis of Parkinson’s disease. In the present study, we investigated the effects of treadmill exercise on short-term memory, apoptotic dopaminergic neuronal cell death and fiber loss in the nigrostriatum, and cell proliferation in the hippocampal dentate gyrus of Parkinson’s rats. Parkinson’s rats were made by injection of 6-hydroxydopamine (6-OHDA) into the striatum using stereotaxic instrument. Four weeks after 6-OHDA injection, the rats in the 6-OHDA-injection group exhibited significant rotational asymmetry following apomorphine challenge. The rats in the exercise groups were put on the treadmill to run for 30 min once a day for 14 consecutive days starting 4 weeks after 6-OHDA injection. In the present results, extensive degeneration of the dopaminergic neurons in the substantia nigra with loss of dopaminergic fibers in the striatum were produced in the rats without treadmill running, which resulted in short-term memory impairment. However, the rats performing treadmill running for 2 weeks alleviated nigrostriatal dopaminergic cell loss and alleviated short-term memory impairment with increasing cell proliferation in the hippocampal dentate gyrus of Parkinson’s rats. The present results show that treadmill exercise may provide therapeutic value for the Parkinson’s disease.
PMCID: PMC3836534  PMID: 24278884
Parkinson’s rats; 6-Hydroxydopamine; Treadmill exercise; Cell proliferation; Apoptosis
5.  Neuroprotective effects of tadalafil on gerbil dopaminergic neurons following cerebral ischemia☆ 
Neural Regeneration Research  2013;8(8):693-701.
Impairment of dopamine function, which is known to have major effects on behaviors and cognition, is one of the main problems associated with cerebral ischemia. Tadalafil, a long-acting phosphodiesterase type-5 inhibitor, is known to ameliorate neurologic impairment induced by brain injury, but not in dopaminergic regions. We investigated the neuroprotective effects of treatment with tadalafil on cyclic guanosine monophosphate level and dopamine function following cerebral ischemia. Forty adult Mongolian gerbils were randomly and evenly divided into five groups (n = 8 in each group): Sham-operation group, cerebral ischemia-induced and 0, 0.1, 1, and 10 mg/kg tadalafil-treated groups, respectively. Tadalafil dissolved in distilled water was administered orally for 7 consecutive days, starting 1 day after surgery. Cyclic guanosine monophosphate assay and immunohistochemistry were performed for thyrosine hydroxylase expression and western blot analysis for dopamine D2 receptor expression. A decrease in cyclic guanosine monophosphate level following cerebral ischemia was found with an increase in thyrosine hydroxylase activity and a decrease in dopamine D2 receptor expression in the striatum and substantia nigra region. However, treatment with tadalafil increased cyclic guanosine monophosphate expression, suppressed thyrosine hydroxylase expression and increased dopamine D2 receptor expression in the striatum and substantia nigra region in a dose-dependent manner. Tadalafil might ameliorate cerebral ischemia-induced dopaminergic neuron injury. Therefore, tadalafil has the potential as a new neuroprotective treatment strategy for cerebral ischemic injury.
PMCID: PMC4146079  PMID: 25206715
neural regeneration; brain injury; cerebral ischemia; Tadalafil; phosphodiesterase type-5 inhibitor; dopamine; dopamine D2 receptor; cyclic guanosine monophosphate; grants-supported paper; photographs-containing paper; neuroregneration
6.  Neuroprotective effects of bovine colostrum on intracerebral hemorrhage-induced apoptotic neuronal cell death in rats☆ 
Neural Regeneration Research  2012;7(22):1715-1721.
Brain cell death after intracerebral hemorrhage may be mediated in part by an apoptotic mechanism. Colostrum is the first milk produced by mammals for their young. It plays an important role in protection and development by providing various antibodies, growth factors and nutrients, and has been used for various diseases in many countries. In the present study, we investigated the anti-apoptotic effects of bovine colostrum using organotypic hippocampal slice cultures and an intracerebral hemorrhage animal model. We performed densitometric measurements of propidium iodide uptake, a step-down avoidance task, Nissl staining, and caspase-3 immunohistochemistry. The present results revealed that colostrum treatment significantly suppressed N-methyl-D-aspartic acid-induced neuronal cell death in the rat hippocampus. Moreover, colostrum treatment improved short-term memory by suppressing hemorrhage-induced apoptotic neuronal cell death and decreasing the volume of the lesion induced by intracerebral hemorrhage in the rat hippocampus. These results suggest that colostrum may have a beneficial role in recovering brain function following hemorrhagic stroke by suppressing apoptotic cell death.
PMCID: PMC4302452  PMID: 25624793
intracerebral hemorrhage; organotypic hippocampal slice culture; bovine colostrum; apoptotic cell death; N-methyl-D-aspartic acid; caspase-3; hippocampus; memory
7.  2,4-Di-tert-butylphenol from Sweet Potato Protects Against Oxidative Stress in PC12 Cells and in Mice 
Journal of Medicinal Food  2013;16(11):977-983.
In this study, the protective effect of sweet potato extract against hydrogen peroxide-induced oxidative stress and cytotoxicity on the pheochromocytoma cell line (PC12) was investigated. The active component of the sweet potato extract was purified and determined to be 2,4-di-tert-butylphenol. The antioxidant capacity of 2,4-di-tert-butylphenol was measured by using 2,2′-azino-bis(3-ethylbenzthiazoline-6-sulfonic acid (ABTS) radical. To examine the effects of 2,4-di-tert-butylphenol on amyloid-beta peptide (Aβ1-42)-induced learning and memory impairment in mice, in vivo behavioral tests were performed. Administration of 2,4-di-tert-butylphenol increased alternation behavior in mice injected with Aβ1-42. These results suggest that sweet potato extract could be protective against Aβ-induced neurotoxicity, possibly due to the antioxidative capacity of its constituent, 2,4-di-tert-butylphenol.
PMCID: PMC3833388  PMID: 24074359
Alzheimer's disease; amyloid beta peptide; oxidative stress; PC12 cells
8.  Treadmill exercise improves motor coordination through ameliorating Purkinje cell loss in amyloid beta23-35-induced Alzheimer’s disease rats 
Alzheimer’s disease (AD) is a most common age-related neurodegenerative disease. AD is characterized by a progressive loss of neurons causing cognitive dysfunction. The cerebellum is closely associated with integration of movement, including motor coordination, control, and equilibrium. In the present study, we evaluated the effect of tread-mill exercise on the survival of Purkinje neurons in relation with reactive astrocyte in the cerebellum using Aβ25–35–induced AD rats. AD was induced by a bilateral intracerebroventricular (ICV) injection of Aβ25–35. The rats in the exercise groups were forced to run on a motorized treadmill for 30 min once a day for 4 weeks, starting 2 days after Aβ25–35 injection. In the present results, ICV injection of Aβ25–35 deteriorated motor coordination and balance. The number of calbindin-positive cells in the cerebellar vermis was decreased and glial fibrillary acidic protein (GFAP) expression in the cerebellar vermis was increased in the Aβ25–35-induced AD rats. Treadmill exercise improved motor coordination and balance. Treadmill exercise increased the number of Purkinje neurons and suppressed GFAP expression in the cerebellar vermis. The present study demonstrated that treadmill exercises alleviated dysfunction of motor coordination and balance by reduction of Purkinje cell loss through suppressing reactive astrocytes in the cerebellum of AD rats. The present study provides the possibility that treadmill exercise might be an important therapeutic strategy for the symptom improvement of AD patients.
PMCID: PMC4237839  PMID: 25426461
Alzheimer’s disease; Treadmill exercise; Cerebellum; Motor coordination and balance; Purkinje neurons; Reactive astrocytes
9.  Effect of Atomoxetine on Hyperactivity in an Animal Model of Attention-Deficit/Hyperactivity Disorder (ADHD) 
PLoS ONE  2014;9(10):e108918.
Hyperactivity related behaviors as well as inattention and impulsivity are regarded as the nuclear symptoms of attention-deficit/hyperactivity disorder (ADHD).
To investigate the therapeutic effects of atomoxetine on the motor activity in relation to the expression of the dopamine (DA) D2 receptor based on the hypothesis that DA system hypofunction causes ADHD symptoms, which would correlate with extensive D2 receptor overproduction and a lack of DA synthesis in specific brain regions: prefrontal cortex (PFC), striatum, and hypothalamus.
Young male spontaneously hypertensive rats (SHR), animal models of ADHD, were randomly divided into four groups according to the daily dosage of atomoxetine and treated for 21 consecutive days. The animals were assessed using an open-field test, and the DA D2 receptor expression was examined.
The motor activity improved continuously in the group treated with atomoxetine at a dose of 1 mg/Kg/day than in the groups treated with atomoxetine at a dose of 0.25 mg/Kg/day or 0.5 mg/Kg/day. With respect to DA D2 receptor immunohistochemistry, we observed significantly increased DA D2 receptor expression in the PFC, striatum, and hypothalamus of the SHRs as compared to the WKY rats. Treatment with atomoxetine significantly decreased DA D2 expression in the PFC, striatum, and hypothalamus of the SHRs, in a dose-dependent manner.
Hyperactivity in young SHRs can be improved by treatment with atomoxetine via the DA D2 pathway.
PMCID: PMC4182750  PMID: 25271814
10.  Comparison of Spatiotemporal Gait Parameters between Children with Normal Development and Children with Diplegic Cerebral Palsy 
Journal of Physical Therapy Science  2014;26(9):1317-1319.
[Purpose] The purpose of this study was to determine the differences in spatiotemporal gait parameters between children with spastic diplegic CP and children with normal development (ND). [Subjects and Methods] Sixteen children (eight children with spastic diplegic CP and eight ND children) were recruited for participation as volunteers in this study. The children with CP had a Gross Motor Function Classification (GMFC) System level of between I and II. [Results] Walking velocity, cadence, stride length, and step width of children with CP with a GMFC of between I and II were a level of 60%, 77%, 73%, and 160%, respectively, of those of ND children. The percentages of right and left double-limb support were 188% and 179% higher, respectively, and the proportion of single limb support was shorter by 83% and 82%. [Conclusion] Our results provide objective evidence of distinct differences in spatiotemporal gait parameters between children with spastic diplegic CP with a GMFC level I or II and ND children and would be helpful to persons involved in the care of these children.
PMCID: PMC4175228  PMID: 25276007
Cerebral palsy; Spatiotemporal gait parameter; Gait pattern
11.  Comparison of Children with Joint Angles in Spastic Diplegia with Those of Normal Children 
Journal of Physical Therapy Science  2014;26(9):1475-1479.
[Purpose] The purpose of this study was to compare joint angles between normal children and those with spastic diplegia using three-dimensional gait analysis. [Subjects and Methods] The study subjects were eight patients with spastic diplegia and eight normal children. Three-dimensional gait analysis was used for the survey. The measured gait variables were the joints of the lower extremity in the sagittal plane, frontal plane, and transverse planes and the maximum and minimum angles of their stance phase and swing phases. [Results] In the sagittal plane, the maximum angles of both the right and left pelvis and hip joint in the stance phase and swing phases were significantly greater for children with spastic diplegia than for normal children. In the stance phase of the right side of the hip joint, the maximum angles of the hip in the swing phase and the knee joint’s minimum angles in the stance phase differed significantly. In the transverse plane, there were a significant differences on the left side of the pelvis in the maximum angles in the swing and stance phases. There were also significant differences on the right side pelvis, in the maximum and minimum angles in the stance phase and minimum angles in the swing phase. [Conclusion] Children with spastic diplegia employ a different gait strategy and pattern from normal children.
PMCID: PMC4175261  PMID: 25276040
Spastic diplegia; Joint angle
12.  Inhibitory Effects of Isoquinoline Alkaloid Berberine on Ischemia-Induced Apoptosis via Activation of Phosphoinositide 3-Kinase/Protein Kinase B Signaling Pathway 
Berberine is a type of isoquinoline alkaloid that has been used to treat various diseases. A neuroprotective effect of berberine against cerebral ischemia has been reported; however, the effects of berberine on apoptosis in relation to reactive astrogliosis and microglia activation under ischemic conditions have not yet been fully evaluated. In the present study, we investigated the effects of berberine on global ischemia-induced apoptosis, and focused on the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) signaling pathway in the hippocampus using gerbils.
Gerbils received berberine orally once a day for 14 consecutive days, starting one day after surgery. In this study, a step-down avoidance task was used to assess short-term memory. Furthermore, we employed the terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay to evaluate DNA fragmentation, immunohistochemistry to investigate glial fibriallary acidic protein, CD11b, and caspase-3, and western blot to assess PI3K, Akt, Bax, Bcl-2, and cytochrome c.
Our results revealed that berberine treatment alleviated ischemia-induced short-term memory impairment. Treatment with berbeine also attenuated ischemia-induced apoptosis and inhibited reactive astrogliosis and microglia activation. Furthermore, berberine enhanced phospho-PI3K and phospho-Akt expression in the hippocampus of ischemic gerbils.
Berberine exerted a neuroprotective effect against ischemic insult by inhibiting neuronal apoptosis via activation of the PI3K/Akt signaling pathway. The antiapoptotic effect of berberine was achieved through inhibition of reactive astrogliosis and microglia activation. Berberine may therefore serve as a therapeutic agent for stroke-induced neurourological problems.
PMCID: PMC4180161  PMID: 25279238
Berberine; Brain ischemia; Short-term memory; Apoptosis; Phosphatidylinositol 3-kinases
14.  Treadmill exercise inhibits hippocampal apoptosis through enhancing N-methyl-D-aspartate receptor expression in the MK-801-induced schizophrenic mice 
Schizophrenia is a severe mental disorder characterized by abnormal mental functioning and disruptive behaviors. Abnormal expression of N-methyl-D-aspartate (NMDA) receptor, one of the glutamate receptor subtypes, has also been suggested to contribute to the symptoms of schizophrenia. The effect of treadmill exercise on schizophrenia-induced apoptosis in relation with NMDA receptor has not been evaluated. In the present study, we investigated the effect of treadmill exercise on neuronal apoptosis in the hippocampus using MK-801-induced schizophrenic mice. MK-801 was intraperitoneally injected once a day for 2 weeks. The mice in the exercise groups were forced to run on a treadmill exercise for 60 min, once a day for 2 weeks. In the present results, repeated injection of the NMDA receptor antagonist MK-801 reduced expression of NMDA receptor in hippocampal CA2-3 regions. MK-801 injection increased casapse-3 expression and enhanced cytochrome c release in the hippocampus. The ratio of Bax to Bcl-2 was higher in the MK-801-induced schizophrenia mice than the normal mice. In contrast, treadmill exercise enhanced NMDA receptor expression, suppressed caspae-3 activation and cytochrome c release, and inhibited the ratio of Bax to Bcl-2. Based on present finding, we concluded that NMDA receptor hypofunctioning induced neuronal apoptosis in MK-801-induced schizophrenic mice. Treadmill exercise suppressed neuronal apoptosis through enhancing NMDA receptor expression in schizophrenic mice.
PMCID: PMC4157928  PMID: 25210696
Schizophrenia; Treadmill exercise; N-methyl-D-aspartate receptor; Apoptosis; Mice
15.  Anti-apoptotic effect of exercise on neuropsychiatric disorders 
PMCID: PMC4106766  PMID: 25061591
16.  Influence of mild traumatic brain injury during pediatric stage on short-term memory and hippocampal apoptosis in adult rats 
Traumatic brain injury (TBI) is a leading cause of neurological deficit in the brain, which induces short- and long-term brain damage, cognitive impairment with/without structural alteration, motor deficits, emotional problems, and death both in children and adults. In the present study, we evaluated whether mild TBI in childhood causes persisting memory impairment until adulthood. Moreover, we investigated the influence of mild TBI on memory impairment in relation with hippocampal apoptosis. For this, step-down avoidance task, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay, and immunohistochemistry for caspase-3 were performed. Male Sprague-Dawley rats were used in the experiments. The animals were randomly divided into two groups: sham-operation group and TBI-induction group. The mild TBI model was created with an electromagnetic contusion device activated at a velocity of 3.0 m/sec. The results showed that mild TBI during the pediatric stage significantly decreased memory retention. The numbers of TUNEL-positive and caspase-3-positive cells were increased in the TBI-induction group compared to those in the sham-operation group. Defective memory retention and apoptosis sustained up to the adult stage. The present results shows that mild TBI induces long-lasting cognitive impairment from pediatric to adult stages in rats through the high level of apoptosis. The finding of this study suggests that children with mild TBI may need intensive treatments for the reduction of long-lasting cognitive impairment by secondary neuronal damage.
PMCID: PMC4106768  PMID: 25061593
Traumatic brain injury; Hippocampus; Apoptosis; Pediatric stage; Short-term memory
17.  Aerobic Exercise Affects Myostatin Expression in Aged Rat Skeletal Muscles: A Possibility of Antiaging Effects of Aerobic Exercise Related With Pelvic Floor Muscle and Urethral Rhabdosphincter 
Aging-induced loss of muscle mass and subsequent reduction of strength is a fundamental cause of frailty, functional decline, and disability. And this may lead to muscular dysfunction, voiding dysfunction, or urinary incontinence due to pelvic muscle weakness induced by aging. Physical exercise has been recommended for the prevention and the treatment of these age-related frail states. We investigated the effects of treadmill exercise on muscle strength, myostatin mRNA and protein expression, and gastrocnemius myocytes proliferation in aged rats to investigate the possible antiaging effects of aerobic exercise on skeletal muscles such as pelvic floor muscles and urethral rhabdosphincter muscle.
In this study, 5-month-old male Sprague-Dawley rats were used as the young-age group (n=20) and 24-month-old rats were used as the old-age group (n=20). Each group was randomly divided into two groups (n=10 in each group): the sedentary and the treadmill exercise group. The rats in the exercise groups were forced to run on a motorized treadmill for 30 minutes, once a day, for 6 weeks. For this study, a weight load test, hematoxylin and eosin staining, real-time and reverse transcription polymerase chain reaction for myostatin mRNA, myostatin western blot, and 5-bromo-2'-deoxyuridine immunohistochemistry were performed in the gastrocnemius muscle.
The age-induced reduction of muscle mass and strength was associated with a decrease in myocyte proliferation and an increase in myostatin mRNA and protein expression in the gastrocnemius. However, treadmill exercise improved muscle mass and strength through suppression of myostatin mRNA and protein expression, and myocyte proliferation increase in the gastrocnemius against the aging process.
Aerobic exercise is a useful strategy for enhancing muscle function against aging-induced loss of skeletal muscle mass and functions.
PMCID: PMC4076484  PMID: 24987560
Aging; Exercise; Myostatin; Skeletal muscle; Muscle cell
18.  Oral mucosa stem cells alleviates spinal cord injury-induced neurogenic bladder symptoms in rats 
Spinal cord injury (SCI) deteriorates various physical functions, in particular, bladder problems occur as a result of damage to the spinal cord. Stem cell therapy for SCI has been focused as the new strategy to treat the injuries and to restore the lost functions. The oral mucosa cells are considered as the stem cells-like progenitor cells. In the present study, we investigated the effects of oral mucosa stem cells on the SCI-induced neurogenic bladder in relation with apoptotic neuronal cell death and cell proliferation.
The contraction pressure and the contraction time in the urinary bladder were increased after induction of SCI, in contrast, transplantation of the oral mucosa stem cells decreased the contraction pressure and the contraction time in the SCI-induced rats. Induction of SCI initiated apoptosis in the spinal cord tissues, whereas treatment with the oral mucosa stem cells suppressed the SCI-induced apoptosis. Disrupted spinal cord by SCI was improved by transplantation of the oral mucosa stem cells, and new tissues were increased around the damaged tissues. In addition, transplantation of the oral mucosa stem cells suppressed SCI-induced neuronal activation in the voiding centers.
Transplantation of oral mucosa stem cells ameliorates the SCI-induced neurogenic bladder symptoms by inhibiting apoptosis and by enhancing cell proliferation. As the results, SCI-induced neuronal activation in the neuronal voiding centers was suppressed, showing the normalization of voiding function.
PMCID: PMC4028106  PMID: 24884998
Spinal cord injury; Oral mucosa stem cells; Cystometry; Apoptosis; Nerve growth factor; c-Fos
19.  Duration-dependence of the effect of treadmill exercise on hyperactivity in attention deficit hyperactivity disorder rats 
Attention-deficit hyperactivity disorder (ADHD) is a common neurobehavioral disorder, and its symptoms are hyperactivity and deficits in learning and memory. Physical exercise increases dopamine synthesis and neuronal activity in various brain regions. In the present study, we investigate the duration-dependence of the treadmill exercise on hyperactivity in relation with dopamine expression in ADHD. Spontaneously hypertensive rats were used for the ADHD rats and Wistar-Kyoto rats were used for the control rats. The rats in the exercise groups were forced to run on a treadmill for 10 min, 30 min, and 60 min once daily for 28 consecutive days. For this experiment, open field test and immunohistochemistry for tyrosine hydroxylase were conducted. The present results revealed that ADHD rats showed hyperactivity, and tyrosine hydroxylase expression in the striatum and substantia nigra were decreased in ADHD rats. Treadmill exercise alleviated hyperactivity and also increased TH expression in ADHD rats. Treadmill exercise for 30 min per day showed most potent suppressing effect on hyperactivity, and this dose of treadmill exercise also most potently inhibited tyrosine hydroxylase expression. The present study suggests that treadmill exercise for 30 min once a day is the most effective therapeutic intervention for ADHD patients.
PMCID: PMC4025553  PMID: 24877041
Attention-deficit hyperactivity disorder; Treadmill exercise; Duration-dependence; Hyperactivity; Dopamine
20.  Presence of multiple peripheral circadian oscillators in the tissues controlling voiding function in mice 
Circadian clocks are the endogenous oscillators that harmonize a variety of physiological processes within the body. Although many urinary functions exhibit clear daily or circadian variation in diurnal humans and nocturnal rodents, the precise mechanisms of these variations are as yet unclear. In the present study, we demonstrate that Per2 promoter activity clearly oscillates in neonate and adult bladders cultured ex vivo from Per2::Luc knock-in mice. In subsequent experiments, we show that multiple local oscillators are operating in all the bladder tissues (detrusor, sphincter and urothelim) and the lumbar spinal cord (L4–5) but not in the pontine micturition center or the ventrolateral periaqueductal gray of the brain. Accordingly, the water intake and urine volume exhibited daily and circadian variations in young adult wild-type mice but not in Per1−/−Per2−/− mice, suggesting a functional clock-dependent nature of the micturition rhythm. Particularly in PDK mice, the water intake and urinary excretion displayed an arrhythmic pattern under constant darkness, and the amount of water consumed and excreted significantly increased compared with those of WT mice. These results suggest that local circadian clocks reside in three types of bladder tissue and the lumbar spinal cord and may have important roles in the circadian control of micturition function.
PMCID: PMC3972783  PMID: 24603368
bladder; circadian clock; lumbar spinal cord; peripheral oscillator; voiding; water intake
21.  Treadmill Exercise Ameliorates Short-Term Memory Disturbance in Scopolamine-Induced Amnesia Rats 
Scopolamine is a nonselective muscarinic cholinergic receptor antagonist, which induces impairment of learning ability and memory function. Exercise is known to ameliorate brain disturbance induced by brain injuries. In the present study, we investigated the effect of treadmill exercise on short-term memory in relation to acetylcholinesterase (AChE) expression in the hippocampus, using a scopolamine-induced amnesia model in mice.
To induce amnesia, 1 mg/kg scopolamine hydrobromide was administered intraperitoneally once per day for 14 days. A step-down avoidance test for short-term memory was conducted. AChE histochemistry, immunohistochemistry for collagen IV, and doublecortin were performed.
Short-term memory deteriorated in the mice with scopolamine-induced amnesia, concomitant with enhanced AChE expression and suppression of angiogenesis in the hippocampus. Critically, treadmill exercise ameliorated short-term memory impairment, suppressed AChE expression, and enhanced angiogenesis in the mice with scopolamine-induced amnesia.
Overexpression of AChE is implicated in both brain and renal disease. The findings of our study indicate that treadmill exercise may be of therapeutic value in neurodegenerative and renal diseases by suppressing the effects of AChE expression.
PMCID: PMC3983504  PMID: 24729923
Amnesia; Exercise test; Short-term memory; Acetylcholinesterase
22.  Treadmill exercise improves short-term memory by enhancing neurogenesis in amyloid beta-induced Alzheimer disease rats 
Alzheimer’s disease is one of the most devastating neurodegenerative disorders, and this disease is characterized by severe memory impairment and decline of cognition. Hippocampal neurons are vulnerable to injury induced by Alzheimer’s disease. Physical exercise is known to promote cell survival and functional recovery after brain injuries. In the present study, we investigated the effects of treadmill exercise on short-term memory in relation with neurogenesis in the rats with amyloid β25–35 (Aβ25–35)-induced Alzheimer’s disease. The rat model of Alzheimer’s disease was induced by the intracerebroventricular (ICV) injection of Aβ25–35, using a stereotaxic instrument. The rats in the exercise group were forced to run on a treadmill for 30 min once daily for 4 consecutive weeks, starting 2 days after Aβ25–35 injection. Presently, short-term memory was deteriorated and apical dendritic length in the hippocampus was shortened in the hippocampus by Aβ25–35 injection. In contrast, treadmill exercise alleviated memory impairment and increased apical dendritic length in the Aβ25–35-injected rats. Neurogenesis and brain-derived neurotorphic factor (BDNF) and tyrosine kinase B (trkB) in the hippocampal dentate gyrus were decreased by Aβ25–35 injection. Treadmill exercise increased neurogenesis and expressions of BDNF and trkB expressions. The present study shows that treadmill exercise may provide therapeutic value for the alleviating symptoms of Alzheimer’s disease.
PMCID: PMC3952831  PMID: 24678498
Alzheimer’s disease; Treadmill exercise; Short-term memory; Neurogenesis; Apical dendritic length
25.  An animal study to compare the degree of the suppressive effects on the afferent pathways of micturition between tamsulosin and sildenafil 
Tamsulosin, an α1-adrenoceptor antagonist, and sildenafil, a phosphodiesterase (PDE) inhibitor, are reported to improve lower urinary tract symptoms including overactive bladder (OAB). This study is aimed at investing the effects of tamsulosin and sildenafil and comparing the degree of the suppressive effects on the afferent pathways of micturition between them using an animal model of OAB, the spontaneously hypertensive rat (SHR).
The cystometric parameters, the basal pressure and duration of bladder contraction, were significantly increased in the SHR group as compared with the Wistar-Kyoto (WKY) group. The intercontraction interval also significantly decreased in the SHR group. In the SHR-Tam 0.01 mg/kg group and the SHR-Sil 1 mg/kg group, however, the basal pressure and duration were significantly reduced and the intercontraction interval was significantly prolonged. Moreover, the degree of the expression of c-Fos and NGF was significantly higher in the SHR group as compared with the WKY group. But it was significantly reduced in the SHR-Tam 0.01 mg/kg group and the SHR-Sil 1 mg/kg group. Furthermore, tamsulosin had a higher degree of effect as compared with sildenafil.
In conclusion, α1-adrenergic receptor antagonists and PDE-5 inhibitors may have an effect in improving the voiding functions through an inhibition of the neuronal activity in the afferent pathways of micturition.
PMCID: PMC3871018  PMID: 24160992
Overactive bladder syndrome; Tamsulosin; Sildenafil; Neuronal activity; Afferent pathways of micturition

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