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.
Amnesia; Exercise test; Short-term memory; Acetylcholinesterase
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.
Alzheimer’s disease; Treadmill exercise; Short-term memory; Neurogenesis; Apical dendritic length
Periventricular leukomalacia (PVL) is a common white matter lesion affecting the neonatal brain. PVL is closely associated with cerebral palsy (CP) and characterized by increase in the number of astrocytes, which can be detected by positivity for glial fibrillary acidic protein (GFAP). Change in myelin basic protein (MBP) is an early sign of white matter abnormality. Maternal or placental infection can damage the neonatal brain. In the present study, we investigated the effects of treadmill walking exercise on GFAP and MBP expressions in rats with maternal lipopolysaccharide (LPS)-induced PVL. Immunohistochemistry was performed for the detection of GFAP and MBP. The present results showed that intracervical maternal LPS injection during pregnancy increased GFAP expression in the striatum and decreased MBP expression in the corpus callosum of rats. The results also showed that treadmill walking exercise suppressed GFAP expression and enhanced MBP expression in the brains of rats with maternal LPS-induced PVL. The present study revealed that treadmill walking exercise is effective for the suppressing astrogliosis and hypomyelination associated with PVL. Here in this study, we showed that treadmill walking exercise may be effective therapeutic strategy for alleviating the detrimental effects of CP.
Periventricular leukomalacia; Cerebral palsy; Glial fibrillary acidic protein; Myelin basic protein; Treadmill walking exercise
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.
Prenatal noise stress; Postnatal treadmill exercise; Spatial learning ability; Neurogenrsis
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.
Treadmill exercise; Exercise duration; Cell proliferation; Glucocorticoid receptor; 5-hydroxytryptamine; Tryptophan hyroxylase
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.
Overactive bladder syndrome; Tamsulosin; Sildenafil; Neuronal activity; Afferent pathways of micturition
Substantia nigra and striatum are vulnerable to hypoxic ischemia brain injury. Physical exercise promotes cell survival and functional recovery after brain injury. However, the effects of treadmill exercise on nigro-striatal dopaminergic neuronal loss induced by hypoxic ischemia brain injury in neonatal stage are largely unknown. We determined the effects of treadmill exercise on survival of dopamine neurons in the substantia nigra and dopaminergic fibers in the striatum after hypoxic ischemia brain injury. On postnatal 7 day, left common carotid artery of the neonatal rats ligated for two hours and the neonatal rats were exposed to hypoxia conditions for one hour. The rat pups in the exercise groups were forced to run on a motorized treadmill for 30 min once a day for 12 weeks, starting 22 days after induction of hypoxic ischemia brain injury. Spatial learning ability in rat pups was determined by Morris water maze test after last treadmill exercise. The viability of dopamine neurons in the substantia nigra and dopamine fibers in the striatum were analyzed using immunohistochemistry. In this study, hypoxic ischemia injury caused loss of dopamine neurons in the substantia nigra and dopaminergic fibers in the striatum. Induction of hypoxic ischemia deteriorated spatial learning ability. Treadmill exercise ameliorated nigro-striatal dopaminergic neuronal loss, resulting in the improvement of spatial learning ability. The present study suggests the possibility that treadmill exercise in early adolescent period may provide a useful strategy for the recovery after neonatal hypoxic ischemia brain injury.
Hypoxic ischemia; Substantia nigra; Striatum; Dopamine; Treadmill exercise
Prenatal environmental conditions affect the development of the fetus. In the present study, we investigated the effects of exposure to music and noise during pregnancy on neurogenesis and thickness in the motor and somatosensory cortex of rat pups.
The pregnant rats in the music-applied group were exposed to 65 dB of comfortable music for 1 hour, once per day, from the 15th day of pregnancy until delivery. The pregnant rats in the noise-applied group were exposed to 95 dB of sound from a supersonic sound machine for 1 hour, once per day, from the 15th day of pregnancy until delivery. After birth, the offspring were left undisturbed together with their mother. The rat pups were sacrificed at 21 days after birth.
Exposure to music during pregnancy increased neurogenesis in the motor and somatosensory cortex of rat pups. In contrast, rat pups exposed to noise during pregnancy showed decreased neurogenesis and thickness in the motor and somatosensory cortex.
Our study suggests that music and noise during the developmental period are important factors influencing brain development and urogenital disorders.
Music; Noise; Neurogenesis; Motor cortex; Somatosensory cortex
Stress has a deteriorating effect on hippocampal function. It also contributes to symptom exacerbation in many disease states, including overactive bladder and interstitial cystitis/bladder pain syndrome. We investigated the effects of various types of stresses (restraint, noise, and cold) on short-term memory and apoptosis in relation with corticotropin-releasing factor (CRF) expression.
Rats in the restraint stress group were restrained in a transparent Plexiglas cylinder for 60 minutes twice daily. Rats in the noise stress group were exposed to the 120 dB supersonic machine sound for 60 minutes twice daily. Rats in the cold stress group were placed in a cold chamber at 4℃ for 60 minutes twice daily. Each stress was applied for 10 days. A step-down avoidance test for short-term memory, immunohistochemistry for caspase-3 expression, and western blot analysis for Bax and Bcl-2 expressions were conducted.
Latency time was decreased and CRF expression in the hippocampal dentate gyrus and hypothalamic paraventricular nucleus were increased in all of the stress groups. The number of caspase-3-positive cells in the hippocampal dentate gyrus was increased and the expressions of Bax and Bcl2 in the hippocampus were decreased in all of the stress groups.
All of the stress groups experienced short-term memory impairment induced by apoptosis in the hippocampus. The present results suggest the possibility that these stresses affecting the impairment of short-term memory may also induce functional lower urinary tract disorders.
Restrain stress; Noise stress; Cold stress; Short-term memory; Apoptosis
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.
Parkinson’s rats; 6-Hydroxydopamine; Treadmill exercise; Cell proliferation; Apoptosis
Autism is a complex neurodevelopmental disability with impairments of social interaction and communication, and repetitive behavior. Reelin is an extracellular glycoprotein that is essential for neuronal migration and brain development. Neuroprotective effects of exercise on various brain insults are well documented, however, the effects of exercise on autism in relation with reelin expression are not clarified. In the present study, we investigated the effects of treadmill exercise on the functional recovery and on the expressions of reelin and its downstream molecules, phosphatidylinositol-3-kinase (PI3K), phosphorylated Akt (p-Akt), phosphorylated extracellular signal-regulated protein kinase 1 and 2 (p-ERK1/2), using autistic rats. For the induction of autism-like animal model, 400 mg/kg valproic acid was subcutaneously injected into the rats on the postnatal day 14. The rat in the treadmill exercise groups were forced to run on a treadmill for 30 min once a day, five times a week for 4 weeks, starting postnatal day 28. To investigate autism-like behaviors and memory deficit, open field, social interaction, and radial 8-arm maze were performed. Immunohistochemistry and western blotting were conducted. In the present results, treadmill exercise alleviated aggressive tendency and improved correct decision in the spatial learning memory in the autistic rats. Treadmill exercise increased neurogenesis and the expressions of reelin and its down-stream molecules, PI3K, p-Akt, and p-ERK1/2, in the hippocampus of the autistic rats. The present study showed that treadmill exercise ameliorated aggressive behavior and improved spatial learning memory through activation of reeling signaling pathway in the valproic acid-induced autistic rats.
Autism; Valproic acid; Treadmill exercise; Reelin; Hippocampus; Neurogenesis
The overactive bladder (OAB) syndrome is characterized by urgency usually with frequency and nocturia. Tamsulosin, α1-adrenergic receptor antagonist, is widely used to reduce symptoms of urinary obstruction and prostatic hyperplasia. Tamsulosin can across the blood-brain barrier. We investigated the effects of tamsulosin on the symptoms of OAB in relation to neuronal activity using rats.
Adult female Sprague-Dawley rats, weighing 250±10 g (9 weeks old), were used in this study. The animals were divided into five groups (n=8 in each group): control group, OAB-induced group, OAB-induced and 0.01 mg/kg tamsulosin-treated group, OAB-induced and 0.1 mg/kg tamsulosin-treated group, and OAB-induced and 1 mg/kg tamsulosin-treated group. OAB was induced by intraperitoneal injection of cyclophosphamide (75 mg/kg) every third day for 10 days. The rats in the tamsulosin-treated groups orally received tamsulosin once a day for 14 consecutive days at the respective dose of the groups, starting 1 day after the induction of OAB. Cystometry for bladder pressure determination, immunohistochemistry for c-Fos, nicotinamide adenine dinucleotide phosphate-diaphorase histochemistry for nitric oxide synthase (NOS) in the neuronal voiding centers and western blot for inducible NOS in the bladder were conducted.
Cyclophosphamide injection enhanced contraction pressure and time, representing the induction of OAB. Contraction pressure and time were significantly suppressed by tamsulosin treatment. c-Fos and NOS expressions in the neuronal voiding centers were enhanced by induction of OAB. OAB-induced c-Fos and NOS expressions were suppressed by tamsulosin treatment.
Tamsulosin exerts inhibitory effect on neuronal activation in the neuronal voiding centers of OAB. The present results suggest the possibility that tamsulosin is effective therapeutic modality for ameliorating the symptoms of OAB.
Overactive bladder; Cyclophosphamide; Tamsulosin; Rats
During neurosurgical procedures, patients are often exposed to hypoxic and ischemic brain damage. Cerebral ischemia leads to neuronal cell death and eventually causes neurological impairments. Remifentanil is a new ultra-short acting phenylpiperidine opioid analgesic. In this study, we evaluated remifentanil to determine if it exerts an anti-apoptotic effect in the hippocampal dentate gyrus following transient global ischemia in gerbils.
Step-down avoidance task, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay, and immunohistochemical staining for caspase-3 were performed.
The numbers of TUNEL-positive cells and caspase-3-positive cells in the dentate gyrus were increased by ransient global ischemia. Latency in the step-down avoidance task was increased by transient global ischemia. Results revealed that apoptotic cell death in the dentate gyrus was increased significantly following transient global ischemia, resulting in memory impairment. However, treatment with remifentanil suppressed ischemia-induced apoptosis in the dentate gyrus, thereby alleviating the memory impairment that was induced by ischemic cerebral injury.
These results indicate that remifentanil may exert a neuroprotective effect on ischemic brain damage during surgery.
Apoptosis; Memory deficit; Remifenanil; Transient cerebral ischemia
Stress urinary incontinence (SUI) commonly occurs in women, and it has an enormous impact on quality of life. Surgery, drugs, and exercise have been recommended for the treatment of this disease. Among these, exercise is known to be effective for the relief of symptoms of SUI; however, the efficacy and underlying mechanisms of the effect of exercise on SUI are poorly understood. We investigated the effect of swimming the symptom of SUI in relation to the expression of nerve growth factor (NGF) in rats.
Transabdominal urethrolysis was used to induce SUI, in Sprague-Dawley rats. The experimental groups were divided into the following three groups: sham-operation group, transabdominal urethrolysis-induced group, and transabdominal urethrolysis-induced and swimming group. The rats in the swimming group were forced to swim for 30 minutes once daily starting 2 weeks after SUI induction and continuing for 4 weeks. For this study, determination of abdominal leak point pressure and immunohistochemistry for NGF in the urethra and in the neuronal voiding centers (medial preoptic nucleus [MPA], ventrolateral periaqueductal gray [vlPAG], pontine micturition center [PMC], and spinal cord [L4-L5]) were performed.
Transabdominal urethrolysis significantly reduced the abdominal leak point pressure, thereby contributing to the induction of SUI. Abdominal leak point pressure, however, was significantly improved by swimming. The expression of NGF in the urethra and in the neuronal voiding centers (MPA, vlPAG, PMC, and L4-L5) relating to micturition was enhanced by the induction of SUI. Swimming, however, significantly suppressed SUI-induced NGF expression.
Swimming alleviated symptoms of transabdominal urethrolysis-induced SUI, as assessed by an increase in abdominal leak point pressure. The underlying mechanisms of these effects of swimming might be ascribed to the inhibitory effect of swimming on NGF expression.
Urinary incontinence; Swimming; Nerve growth factor; Rats
Oxytocin is associated with the ability to form normal social attachments. c-Fos is an immediate early gene whose expression is used as a marker for stimulus-induced changes in neurons. The effect of phosphodiesterase-5 (PDE-5) inhibitors on oxytocin activation in the brain without sexual stimuli has not yet been reported. In the present study, we investigated the effects of vardenafil on oxytocin and c-Fos expression in the paraventricular nucleus (PVN) of conscious rats.
Male Sprague-Dawley rats weighing 300±10 g were divided into 6 groups (n=5 in each group): the control group, the 1-day-0.5 mg/kg, the 1-day-1 mg/kg, the 1-day-2 mg/kg, the 3-day-1 mg/kg, and the 7-day-1 mg/kg vardenafil administration group. The experiment was conducted without sexual stimulation. Vardenafil was orally administered. The animals in the control group received an equivalent amount of distilled water orally. The expression of oxytocin and c-Fos in the PVN was detected by immunohistochemistry.
Oxytocin expression in the PVN was increased by 1 day administration of 2 mg/kg vardenafil, and this effect of vardenafil appeared in a duration-dependent manner. c-Fos in the oxytocin neurons of the PVN was increased by 1 day administration of 2 mg/kg vardenafil, and this effect of vardenafil also appeared in a duration-dependent manner. These results showed that vardenafil augments the expression of oxytocin with activation of oxytocin neurons in the PVN.
In this study, we showed that the PDE-5 inhibitor, vardenafil directly enhances oxytocin expression and also activates oxytocin neurons in the PVN, which indicates that vardenafil may exert positive effects on affiliation behavior and social interaction.
Vardenafil; Oxytocin; c-Fos; Paraventricular nucleus; Rats
This study was conducted to evaluate the effects of vardenafil (Levitra), a phosphodiesterase-5 (PDE-5) inhibitor, on cell proliferation in the hippocampal dentate gyrus and on 5-hyroxytryptamine (5-HT, serotonin) synthesis and tryptophan hydroxylase (TPH) expression in the rat dorsal raphe nucleus. Male Sprague-Dawley rats were divided into 6 groups (n=5 in each group): a control group, a 0.5 mg/kg-1 day vardenafil-treated group, a 1 mg/kg-1 day vardenafil-treated group, a 2 mg/kg-1 day vardenafil-treated group, a 1 mg/kg-3 day vardenafil-treated group, and a 1 mg/kg-7 day vardenafil-treated group. 5-bromo-2'-deoxyuridine (BrdU) immunohistochemistry was then performed to evaluate cell proliferation in the dentate gyrus. In addition, 5-HT and TPH immunohistochemistry was conducted to evaluate serotonin expression in the dorsal raphe. The results revealed that treatment with vardenafil increased cell proliferation in the dentate gyrus and enhanced 5-HT synthesis and TPH expression in the dorsal raphe in a dose- and duration-dependent manner. The findings demonstrate that the increasing effect of vardenafil on cell proliferation is closely associated with the enhancing effect of vardenafil on serotonin expression under normal conditions.
Vardenafil; Dentate Gyrus; Cell Proliferation; Serotonin; Tryptophan Hydroxylase
The purpose of this study is to investigate the mechanism of alternative responses to low dose irradiation for neuronal cell proliferation in the dentate gyrus of rats. To determine the effect of a single exposure to radiation, rats were irradiated with a single dose of 0.1, 1, 10 or 20 Gy. To determine the effect of the cumulative dose, the animals were irradiated daily with 0.01 Gy or 0.1 Gy from 1 to 4 days. The neuronal cell proliferation was evaluated using immunohistochemistry for 5-bromo-2'-deoxyuridine (BrdU), Ki-67 and terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) staining. Four consecutive daily irradiations with a 0.01 Gy/fraction increased the number of BrdU-positive and Ki-67-positive cells in a dose dependent manner, but this did not affect the number of TUNEL-positive cells. However, there was not a dose dependent relationship for the 0.1 Gy/fraction irradiation with the number of BrdU, Ki-67 and TUNEL positive cells. Our data support the explanation that the adaptive response, induced by low-dose radiation, in the hippocampus of rats is more likely a reflection of the perturbations of cell cycle progression.
Adaptive Response; Radiation Effects; Hippocampus Neurons