Eun-Sang Ji

Treadmill exercise and methylphenidate ameliorate symptoms of attention deficit/hyperactivity disorder through enhancing dopamine synthesis and brain-derived neurotrophic factor expression in spontaneous hypertensive rats.

Attention deficit/hyperactivity disorder (ADHD) is a developmental disorder of cognition. Behavioral symptoms of ADHD are inattention, hyperactivity, and impulsivity. We investigated the effects of treadmill exercise and methylphenidate (MPH) on activity and spatial learning memory in relation to dopamine synthesis and brain-derived neurotrophic factor (BDNF) expression using spontaneously hypertensive adult male rats. The rats in the MPH-treated group received 1mg/kg MPH orally once a day for 28days. The rats in the treadmill exercise group were made to run on a treadmill for 30min once a day, five times a week, for 28days. Activity was determined by an open-field test and spatial learning memory was evaluated by an 8-arm maze test. Immunohistochemistry and Western blotting were conducted to examine the levels of tyrosine hydroxylase (TH), the rate-limiting enzyme in the synthesis of dopamine, and BDNF. The rats in the ADHD group showed hyperactivity and spatial learning memory deficit. Reduction of TH in the striatum and substantia nigra and BDNF in the hippocampus was observed of the rats in the ADHD group. Treadmill exercise and MPH alleviated the ADHD-induced hyperactivity and spatial learning memory impairment. Expressions of TH and BDNF in the ADHD rats were also increased by both treadmill exercise and MPH. These findings provide a possibility that exercise may be used as an effective therapeutic intervention for ADHD patients as MPH treatment.

Treadmill exercise improves behavioral outcomes and spatial learning memory through up-regulation of reelin signaling pathway in autistic rats

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.

Treadmill exercise ameliorates symptoms of attention deficit/hyperactivity disorder through reducing Purkinje cell loss and astrocytic reaction in spontaneous hypertensive rats

Attention deficit/hyperactivity disorder (ADHD) is a neurobehavioral disorder of cognition. We investigated the effects of treadmill exercise on Purkinje cell and astrocytic reaction in the cerebellum of the ADHD rat. Adult male spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKYR) weighing 210± 10 g were used. The animals were randomly divided into four groups (n= 15): control group, ADHD group, ADHD and methylphenidate (MPH)-treated group, ADHD and treadmill exercise group. The rats in the MPH-treated group as a positive control received 1 mg/kg MPH orally once a day for 28 consecutive days. The rats in the treadmill exercise group were made to run on a treadmill for 30 min once a day for 28 days. Motor coordination and balance were determined by vertical pole test. Immunohistochemistry for the expression of calbindinD-28 and glial fibrillary acidic protein (GFAP) in the cerebellar vermis and Western blot for GFAP, Bax, and Bcl-2 were conducted. In the present results, ADHD significantly decreased balance and the number of calbindin-positive cells, while GFAP expression and Bax/Bcl-2 ratio in the cerebellum were significantly increased in the ADHD group compared to the control group (P< 0.05, respectively). In contrast, treadmill exercise and MPH alleviated the ADHD-induced the decrease of balance and the number of calbindine-positive cells, and the increase of GFAP expression and Bax/Bcl-2 ratio in the cerebellum (P< 0.05, respectively). Therefore, the present results suggested that treadmill exercise might exert ameliorating effect on ADHD through reduction of Purkinje cell loss and astrocytic reaction in the cerebellum.

Alcohol exposure induces depression-like behavior by decreasing hippocampal neuronal proliferation through inhibition of the BDNF-ERK pathway in gerbils

Abstract Depression is one of the most prevalent diseases of alcohol abuse. Brain-derived neurotrophic factor (BDNF) plays a critical role in cell survival in the hippocampus. Phosphorylation of extracellular signal-regulated kinase 1/2 (p-ERK1/2) is induced by BDNF, and it regulates cell proliferation and differentiation in the brain. We investigated the effects of alcohol intake on depression-like behavior, cell proliferation, expressions of BDNF and its downstream molecules in the hippocampus using Mongolian gerbils. The gerbils were divided into four groups: control group, 0.5 g/kg alcohol-treated group, 1 g/kg alcohol-treated group, 2 g/kg alcohol-treated group. Each dose of alcohol was orally administered for 3 weeks. The present results demonstrated that alcohol intake induced depression-like behavior. Both 5-hydroxytryptamine synthesis and its synthesizing enzyme tryptophan hydroxylase expression in the dorsal raphe and cell proliferation in the hippocampal dentate gyrus were decreased by alcohol intake. Alcohol intake suppressed BDNF expression, and resulted in the decrease of its downstream molecules, pERK1/2 and Bcl-2, in the hippocampus. We showed that alcohol intake may lead to a depressed-like state with reduced hippocampal cell proliferation through inhibition of the BDNF-ERK signaling pathway.

Treadmill exercise ameliorates motor disturbance through inhibition of apoptosis in the cerebellum of valproic acid-induced autistic rat pups

Autism is a neurological disorder that occurs during childhood and is characterized by impairments in social interaction and communication, as well as restricted and repetitive behaviors. Abnormalities of the cerebellum in autism include Purkinje cell loss and motor disturbance. In the present study, we evaluated the effect of treadmill exercise on motor coordination and balance in correlation with reelin expression and the rate of apoptosis in the cerebellum of autistic rat pups. For the induction of the autism-like animal models, 400 mg/kg valproic acid was subcutaneously injected into rat pups on postnatal day 14. Rat pups in the exercise groups were forced to run on a treadmill for 30 min, once a day, five times a week for 4 weeks, starting on postnatal day 28. Motor coordination and balance, as measured using the rotarod test and vertical pole test, were affected by the induction of autism. By contrast, treadmill exercise ameliorated motor dysfunction in the autistic rat pups. The expression levels of reelin, GAD67 and cyclin D1 in the cerebellum of the autistic rat pups were decreased, while the expression levels of these molecules were increased in autistic rat pups who engaged in treadmill exercise. In the cerebellum of the autistic rat pups, Bcl-2 expression was decreased and Bax expression was increased. By contrast, treadmill exercise enhanced Bcl-2 expression and suppressed Bax expression. The therapeutic effect of treadmill exercise on motor deficits may be due to the reelin-mediated anti-apoptotic effect on cerebellar Purkinje neurons.

Treadmill exercise improves spatial learning ability by enhancing brain-derived neurotrophic factor expression in the attention-deficit/hyperactivity disorder rats

Attention-deficit/hyperactivity disorder (ADHD) patients show learning difficulty and impulsiveness. Exercise is known to improve learning ability and memory function. In the present study, we investigated the duration-dependence of the effect of treadmill exercise on spatial learning ability in relation with brain-derived neurotrophic factor (BDNF) expression in ADHD rats. For this study, radial 8-arm maze test and western blot for BDNF and tyrosine kinase B (TrkB) were performed. Spontaneous hypertensive rats were used as the ADHD rats and Wistar-Kyoto rats were used as 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 a day for 28 consecutive days. ADHD rats displayed impairment of spatial learning ability, in contrast treadmill exercise ameliorated impairment of spatial learning ability. Treadmill exercise for 30 min per day showed most potent ameliorating effect on impairment of spatial learning ability. BDNF and TrkB expressions in the hippocampus were decreased in the ADHD rats, in contrast treadmill exercise enhanced BDNF and TrkB expressions. Treadmill exercise for 30 min and for 60 min per day showed enhancing effects on BDNF and TrkB expressions. Treadmill exercise alleviated deficits in the spatial learning ability through enhancing BDNF and TrkB expressions in the ADHD rats. Treadmill exercise for 30 min per day can be considered as the most effective therapeutic modality for the ADHD symptoms.

Treadmill exercise inhibits apoptotic neuronal cell death with suppressed vascular endothelial growth factor expression in the retinas of the diabetic rats

Diabetic retinopathy is one of the most important microvascular complications in diabetes, and it is the major cause of visual loss. Physical exercise is known to ameliorate the symptoms of metabolic syndromes such as diabetic mellitus. In the present study, we investigated the effects of treadmill exercise on vascular endothelial growth factor (VEGF) expression and apoptotic cell death in the retinas of streptozotocin (STZ)-induced diabetic rats. The male Sprague-Dawley rats were randomly divided into three groups (n = 10 in each group): control group, STZ-induce diabetes group, STZ-induced diabetes and treadmill exercise group. To induce diabetes in the experimental animals, a single intraperitioneal injection of STZ (50 mg/kg) was given to each animal. The rats in the exercise group were forced to run on a motorized treadmill for 30 min once a day during 1 week starting 6 weeks after STZ injection. In the present results, VEGF expression in the retinas was increased by induction of diabetes. The numbers of caspase-3-positive and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL)-positive cells in the retinas were also enhanced by induction of diabetes. Treadmill exercise significantly decreased VEGF expression and suppressed the number of TUNEL-positive and caspase-3-positive cells in the retinas of diabetic rats. In the present study, we have shown that treadmill exercise might alleviate the progression of diabetic retinopathy through suppressing VEGF expression and apoptotic cell death in the retinas of the diabetic rats.

Treadmill exercise improves short-term memory by enhancing hippocampal cell proliferation in quinolinic acid-induced Huntington’s disease rats

Huntington’s disease (HD) is an inherited genetic disorder, characterized by cognitive dysfunction and abnormal body movements called chorea. Quinolinic acid (QA) is an endogenous metabolite of tryptophan in the kynurenine pathway. QA-induced alterations are similar to the symptoms of HD patients. Physical exercise has beneficial effects on the brain functions. Exercise increases production of neurotrophic factors in the brain and improves learning ability and memory function. In the present study, we investigated the effects of treadmill exercise short-term memory on QA-induced HD rats in relation with cell proliferation. For the induction of Huntington’s animal model, 2 μL of 100 nmol QA was intrastriatal injected into the rats. The rats in the treadmill exercise groups were forced to run on a treadmill for 30 min once a day, five times a week for 2 weeks. Step-down avoidance test was conducted for the determination of short-term memory. Cell proliferation in the hippocampal dentate gyrus was determined by 5-bromo-2′-deoxyuridine (BrdU) and doublecortin (DCX) immunohistochemistry. Western blot for brain-derived neurotrophic factor (BDNF) and tyrosine kinase B (TrkB) were performed. In the present results, treadmill exercise alleviated QA-induced short-term memory impairment in HD rats. Treadmill exercise increased cell proliferation in the hippocampal dentate gyrus through enhancing BDNF expression in the HD rats. These results revealed that treadmill exercise is effective for the symptom improvement in the HD patients.

Swimming exercise alleviates the symptoms of attention-deficit hyperactivity disorder in spontaneous hypertensive rats

Attention-deficit hyperactivity disorder (ADHD) is a neurobehavioral disorder characterized by inattention, hyperactivity and impulsivity. In the present study, we investigated the effects of swimming exercise on the symptoms of ADHD in correlation with the expression levels of dopamine and the dopamine D2 receptor. Adult male spontaneous hypertensive rats (SHRs) were used as animal models of ADHD and Wistar-Kyoto rats were used as controls. The activity, impulsivity and levels of non-aggressive and aggressive behaviors in rats were measured. The short-term memory in the animal models of ADHD was assessed using an open-field test. The social interaction test, elevated plus maze test and step-through avoidance test were additionally performed. The expression levels of tyrosine hydroxylase (TH), which catalyzes the rate‑limiting step of dopamine synthesis, and the dopamine D2 receptor in the prefrontal cortex, substantia nigra and striatum were evaluated. The expression levels of TH and the dopamine D2 receptor were detected using immunohistochemistry and western blotting, respectively. In ADHD rats, the activity, impulsivity and levels of non-aggressive and aggressive behaviors were higher than that in control rats. By contrast, short-term memory in ADHD rats deteriorated. Swimming exercise suppressed hyperactivity, impulsivity and non-aggressive and aggressive behaviors, and alleviated the short-term memory impairment observed in ADHD rats. The expression levels of TH and the dopamine D2 receptor were decreased and increased in ADHD rats, respectively, when compared with control rats. Swimming exercise enhanced the expression of TH and suppressed the expression of the dopamine D2 receptor in ADHD rats. In the present study, swimming exercise improved the symptoms of ADHD by upregulating the expression of dopamine and downregulating the expression of the dopamine D2 receptor.

Treadmill exercise ameliorates intracerebral hemorrhage-induced depression in rats

Intracerebral hemorrhage (ICH) is a severe type of stroke causing neurological dysfunction with high mortality rate. Depression is one of the most common complications of ICH. In the present study, the effects of treadmill exercise on ICH-induced depressive symptoms in relation with apoptosis were investigated using rats. ICH rat model was induced by injection of collagenase into the hippocampus using stereotaxic instrument. Open field test for activity and forced swimming test for depressive symptoms were conducted. Apoptosis in the hippocampus was detected using terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assay, immunohistochemistry for caspase-3, and western blot for Bcl-2 and Bax. Western blot analysis for 5-hydroxy-tryptamine (5-HT, serotonin) and tryptophan hydroxylase (TPH) in the dorsal raphe was also conducted for biomarkers of depression. In the present results, immobility time was increased and climbing time was decreased by induction of ICH and treadmill exercise inhibited immobility time and increased climbing time in ICH rats. DNA fragmentation and caspase-3 expression in the hippocampal dentate gyrus were enhanced by induction of ICH and treadmill exercise suppressed ICH-induced DNA fragmentation and caspase-3 expression. Bax expression in the hippocampus was increased by induction of ICH and treadmill exercise inhibited Bax expression in the ICH rats. Expressions of 5-HT and TPH in the dorsal raphe were decreased by induction of ICH and treadmill exercise increased expressions of 5-HT and TPH in the ICH rats. In the present study, treadmill exercise ameliorated depressive symptoms through inhibiting apoptosis.