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Purpose: Thrombotic stroke is a type of ischemic stroke characterized by motor dysfunction and memory impairments. In the present study, the effect of treadmill exercise on motor function and short-term memory was evaluated in relation with synaptic plasticity in the mice with photothrombotic stroke.Methods: Photothrombotic stroke was induced by cortical photothrombotic vascular occlusion. The mice in the treadmill exercise groups performed running on a motorized treadmill for 28 days. Motor function was determined using rota-rod test and foot fault test. Step-through avoidance task was conducted to evaluate short-term memory. Immunohistochemistry for 5-bromo-2′-deoxyuridine and doublecortin was conducted to detect new cell generation. Postsynaptic density protein 95, synaptophysin, brain-derived neurotrophic factor (BDNF), and tyrosine kinase B receptor (TrkB) were determined using western blot. The number of dendritic spines was determined using Golgi stain.Results: Treadmill exercise improved motor function and short-term memory in mice with the photothrombotic stroke. The infarct size was reduced and the number of dendritic spines and expression of postsynaptic density protein 95 and synaptophysin in the peri-infarct cortex and hippocampus were increased by treadmill exercise in photothrombotic stroke mice. Treadmill exercise enhanced neurogenesis through increasing the expression of the hippocampal BDNF and TrkB in photothrombotic stroke mice.Conclusions: Treadmill exercise improved motor function and short-term memory through increasing synaptic plasticity and neurogenesis in photothrombotic stroke mice. Treadmill exercise can be used as an effective treatment strategy to improve brain function related to stroke.

Neuronal cell death in the hippocampus by cerebral ischemia causes disability of memory function. Cerebral ischemia also alters the expressions of brain-derived neurotrophic factor (BDNF), cyclic adenosine monophosphate-responsive element binding protein (CREB), extracellular signal-regulated protein kinase (ERK), and phosphatidylinositol 3-kinase/protein kinase B (Akt). In the present study, we investigated the effect of treadmill exercise on cerebral ischemia in relation with ERK-Akt-CREB-BDNF signaling pathway in the hippocampus using gerbils. Induction of cerebral ischemia deteriorated short-term memory with suppression of phosphorylation of ERK-Akt-CREB-BDNF pathway in the hippocampus of gerbils. Enhancement of apoptosis in the hippocampus was accompanied in the ischemia gerbils. Treadmill exercise improved short-term memory through enhancing phosphorylation of ERK-Akt-CREB-BDNF pathway with suppressing apoptosis in the hip-pocampus of the ischemia gerbils. The present results suggest that improvement of memory function after cerebral ischemia by treadmill exercise may be involved in the ERK-Akt-CREB-BDNF signaling pathway, resulting in inhibition of apoptosis in the hippocampus.

Purpose: Poloxamer-407 (P-407) is used to induce hyperlipidemia. Exercise is effective in improving arteriosclerosis and cognitive impairment. In this research, the effect of treadmill running on short-term memory in the P-407-treated hyperlipidemia rats was studied focusing on neuroinflammation.Methods: Rats were classified in normal group, normal and treadmill exercise group, P-407-treated group, and P-407-treated and treadmill exercise group. Hyperlipidemia rats were made by single intraperitoneal injection with P-407 (500 mg/kg). Treadmill exercise was conducted for 30 minutes once a day, 5 days per week during 28 days. Step-down avoidance task was done to measure short-term memory. Glial fibrillary acidic protein and ionized calcium binding adaptor molecule 1 were assessed by immunohistochemistry. Expression of adhesion molecules and proinflammatory cytokines was determined by western blot analysis.Results: Treadmill exercise alleviated lipid profiles in the P-407-induced hyperlipidemia rats. Treadmill exercise improved short-term memory, inhibited reactive astrogliosis and microglia activation, and suppressed expression of adhesion molecules and proinflammatory cytokines in the hyperlipidemic rats.Conclusions: Treadmill exercise exerts alleviating effect on memory deficits by inhibiting hippocampal neuroinflammation in the hyperlipidemia. The current results suggest that treadmill running serves as the treatment strategy for the cognitive dysfunction caused by hyperlipidemia.

Sildenafil citrate is a potent and selective inhibitor of phosphodiesterase type-5 used to treat erectile dysfunction. We investigated the effects of sildenafil citrate treatment on peripheral fatigue and exercise performance after exhaustive swimming exercise in rats. The rats in the sildenafil citrate-treated groups received sildenafil citrate orally once a day for 14 consecutive days at respective dosage. On the 14 days after starting experiment, each animal was submitted to swimming test with intensity equivalent to overload. The exhaustion was defined as a state in which coordinated movements did not return to the water surface for breathing within 10 sec. Western blot for monocarboxylate transporter (MCT)1, MCT4, and neuronal nitric oxide synthase (nNOS) were performed. Exhaustive swimming exercise decreased time of exhaustion and increased lactate concentration, however, sildenafil citrate enhanced time of exhaustion and decreased lactate concentration. Exhaustive swimming exercise increased MCT1 and MCT4 expressions in the gastrocnemius muscles and sildenafil citrate further enhanced MCT1 and MCT4 expressions in the exhaustive swimming exercise rats. Exhaustive swimming exercise decreased nNOS expression in the gastrocnemius muscles and sildenafil citrate enhanced nNOS expression in the exhaustive swimming exercise rats. The most potent effect appeared in the 20-mg/kg sildenafil citrate. Sildenafil citrate might be proposed as a potential ergogenic aid through antiperipheral fatigue.

Purpose Goserelin is a drug used for chemical castration. In a rat model, we investigated whether surgical and chemical castration affected memory ability through the protein kinase A (PKA)/cyclic adenosine monophosphate response elementbinding protein (CREB)/brain-derived neurotrophic factor (BDNF) and c-Raf/mitogen-activated protein kinases-extracellular signal-regulated kinases (MEK)/extracellular signal-regulated kinases (ERK) pathways in the hippocampus. Methods Orchiectomy was performed for surgical castration and goserelin acetate was subcutaneously transplanted into the anterior abdominal wall for chemical castration. Immunohistochemistry was done to quantify neurogenesis. To assess the involvement of the PKA/CREB/BDNF and c-Raf/MEK/ERK pathways in the memory process, western blots were used. Results The orchiectomy group and the goserelin group showed less neurogenesis and impaired short-term and spatial memory. Phosphorylation of PKA/CREB/BDNF and phosphorylation of c-Raf/MEK/ERK decreased in the orchiectomy and goserelin groups. Conclusion Short-term memory and spatial memory were affected by surgical and chemical castration via the PKA/CREB/BDNF and c-Raf/MEK/ERK signaling pathways.

Natural products such as Raphanus sativus Linn would be the potential candidate to benefit to atherosclerosis without side effects. Thus, this study aimed to investigate anti-atherosclerotic effect of radish extracts and to determine their mechanism. For that purpose, ApoE-/- mice were fed with a high-cholesterol diet for 12 weeks and treated with radish extracts. Then, histological observation, plasma lipid profile, mRNA expression, and urine metabolomics were performed. As a result, the formation of aortic plaque was attenuated by atorvastatin, white radish extract, and purple radish extract. Treatment of white radish extract provided the most beneficial effects on reducing triglycerides (9.236 mM), while treatment of purple radish extract significantly reduced low-density lipoprotein-cholesterol (202.5 mg/dL). In detail, purple radish extract improved the level of total cholesterol (219.3 mg/dL) and high-density lipoprotein-cholesterol (64.3 mg/dL) and thereby significantly lowered atherogenic index (3.47) and cardiac risk factor (4.47). Both radish extracts significantly reduced expression of inflammatory cytokines including TNF-α, IL-1β, and IL-6 as well as urinary arachidonate. In addition, radish extracts regulated NO synthesis by increasing urinary arginine and balancing iNOS and eNOS expressions. High expression of VCAM-1 and ICAM-1 were lowered by radish extracts. In conclusion, we demonstrated the anti-atherosclerotic effect of white and purple radish extracts comparable to atorvastatin and further revealed their mechanisms in which include regulation of mRNA expression of inflammatory mediators and endothelial factors along with regulation of urinary arachidonate and arginine. These findings may provide a potential clinical implication in not only prevention but also treatment of atherosclerosis.

Purpose Rotenone is the most widely used neurotoxin for the making Parkinson disease (PD) animal model. The neurodegenerative disorder PD shows symptoms, such as slowness of movements, tremor at resting, rigidity, disturbance of gait, and instability of posture. We investigated whether treadmill running improves motor ability using rotenone-caused PD rats. The effect of treadmill running on PD was also assessed in relation with apoptosis of cerebellar Purkinje cells. Methods Treadmill running was applied to the rats in the exercise groups for 30 minutes once a day for 4 weeks, starting 4 weeks after birth. We used rota-rod test for the determination of motor coordination and balance. In this experiment, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining, immunohistochemistry for calbindin, glial fibrillary acidic protein (GFAP), Iba-1, and western blot analysis for Bax and Bcl-2 were performed. Results Treadmill running enhanced motor balance and coordination by preventing the loss of Purkinje cells in the cerebellar vermis. Treadmill running suppressed PD-induced expression of GFAP-positive reactive astrocytes and Iba-1-positive microglia, showing that treadmill running suppressed reactive astrogliosis and microglia activation. Treadmill running suppressed TUNEL-positive cell number and Bax expression and enhanced Bcl-2 expression, demonstrating that treadmill running inhibited the progress of apoptosis in the cerebellum of rotenone-induced PD rats. Conclusion Treadmill running improved motor ability of the rotenone-induced PD rats by inhibiting apoptosis in the cerebellum. Apoptosis suppressing effect of treadmill running on rotenone-induced PD was achieved via suppression of reactive astrocyte and inhibition of microglial activation.

Peripheral nerve injuries are commonly encountered clinical problem and often result in chronic pain and severe functional deficit. Diosgenin is a plant steroidal saponin and has anti-inflammatory and anticancer effects. In the present study, we investigated the effect of diosgenin on functional recovery following sciatic crushed nerve injury in rats. Walking track analysis for the functional recovery which can be quantified with the sciatic function index (SFI) was conducted. Immunohistochemistry for c-Fos in the ventrolateral periaqueductal gray (vlPAG) and paraventricular nucleus (PVN) and western blot for brain-derived neurotrophic factor (BDNF), tyrosine kinase B (TrkB), cyclooxygenase-2 (COX-2), and inducible nitric oxide synthesis (iNOS) in the sciatic nerve were performed. The right sciatic nerve was crushed for 30 sec using a surgical clip. The animals in the diosgenin-treated groups received orally once a day at the respective doses for 7 consecutive days, starting one day after surgery. Sciatic crushed nerve injury showed characteristic gait changes showing decrease of SFI value. Diosgenin treatment increased the SFI value and suppressed nerve injury-induced c-Fos expression in the vlPAG and PVN. Diosgenin treatment inhibited nerve injury-induced increase of BDNF, TrkB, COX-2, and iNOS expressions. It is possible that diosgenin can be used as the new therapeutic agent for pain control and functional recovery following peripheral nerve injury.

Diabetes mellitus is associated with the impairment of sexual function including desire and orgasmic dysfunction. Sexual dysfunction in the diabetes mellitus is due to a selective defect of the nitric oxide synthase (NOS) within paraventricular nucleus (PVN). c-Fos is an immediate ear-ly gene and c-Fos expression represents neuronal activity in response to various stimuli. In the present study, we investigated the effects of treadmill exercise on sexual behaviors and the expressions of NOS and c-Fos in the PVN were evaluated using streptozotocin (STZ)-induced diabetic rats. Diabetes mellitus was induced by intraperitoneal injection of STZ. The rats in the treadmill exercise groups were made to run on a treadmill for 30 min once a day during 4 weeks. Male sexual behaviors were evaluated by recording the number of mounting, intromission, and ejaculation frequency. The present results revealed that treadmill exer-cise ameliorated sexual dysfunction in the STZ-induced diabetic rats. Treadmill exercise restored the contents of NOS and c-Fos in the PVN. The improving effect of treadmill exercise on sexual function can be considered as the neuronal activating effect of exercise through in-creasing expressions of NO and c-Fos.

Purpose Hyperlipidemia, which promotes the development of atherosclerosis, ischemic stroke, and other forms of brain injury, can be induced by poloxamer-407. Berberine is a primary pharmacological active component of Coptidis Rhizoma that has a number of therapeutic activities. This study investigated the effects of berberine on poloxamer-407-induced brain inflammation by evaluating its effects on short-term memory, cell proliferation, inflammation, and apoptosis in the hippocampus. Methods To induce hyperlipidemia in a rat model, 500 mg/kg of poloxamer-407 was injected intraperitoneally. Berberine was orally administered to the rats in the berberine-treated groups once a day for 4 weeks. The step-down task avoidance task was performed to measure short-term memory. An analysis of serum lipids, immunohistochemistry for 5-bromo-2'-deoxyuridine, glial fibrillary acidic protein (GFAP), and ionized calcium-binding adapter molecule 1 (Iba1) in the dentate gyrus, and western blot analysis for Bax, Bcl-2, and cytochrome c in the hippocampus were performed. Results In hyperlipidemic rats, berberine reduced the levels of triglycerides, total cholesterol, and low-density lipoprotein cholesterol and increased the level of high-density lipoprotein cholesterol in hyperlipidemic rats. Berberine also increased cell proliferation and short-term memory, as well as decreasing the expression of GFAP, Iba1, Bax, and cytochrome c and increasing Bcl-2 expression. Conclusion Berberine treatment improved short-term memory in hyperlipidemia by increasing neuronal proliferation and inhibiting neuronal apoptosis. Berberine treatment also improved lipid metabolism.

Obesity, caused by a high-fat diet (HFD), leads to insulin resistance, which is a precursor of diabetes and a risk factor for impaired cognitive function, dementia, and brain diseases, such as Alzheimer&rsquo, s disease. Physical exercise has positive effects on obesity and brain functions. We investigated whether the decline in cognitive function caused by a HFD could be improved through exercise by examining insulin signaling pathways and neuroplasticity in the hippocampus. Four-week-old C57BL/6 male mice were fed a HFD or a regular diet for 20 weeks, followed by 12 weeks of treadmill exercise. To ascertain the effects of treadmill exercise on impaired cognitive function caused by obesity, the present study implemented behavioral testing (Morris water maze, step-down). Moreover, insulin-signaling and neuroplasticity were measured in the hippocampus and dentate gyrus. Our results demonstrated that HFD-fed obesity-induced insulin resistance was improved by exercise. In addition, the HFD group showed a decrease in insulin signaling and neuroplasticity in the hippocampus and the dentate gyrus and increased cognitive function impairment, which were reversed by physical exercise. Overall, our findings indicate that physical exercise may act as a non-pharmacologic method that protects against cognitive dysfunction caused by obesity by improving hippocampal insulin signaling and neuroplasticity.

PURPOSE Rocuronium bromide is a nondepolarizing neuromuscular blocking drug and has been used as an adjunct for relaxation or paralysis of the skeletal muscles, facilitation of endotracheal intubation, and improving surgical conditions during general anesthesia. However, intravenous injection of rocuronium bromide induces injection pain or withdrawal movement. The exact mechanism of rocuronium bromide-induced injection pain or withdrawal movement is not yet understood. We investigated whether rocuronium bromide treatment is involved in the induction of inflammation and pain in vascular endothelial cells. METHODS For this study, calf pulmonary artery endothelial (CPAE) cells were used, and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, Western blot, nitric oxide detection, and prostaglandin E2 immunoassay were conducted. RESULTS Rocuronium bromide treatment inhibited endothelial nitric oxide synthase and suppressed nitric oxide production in CPAE cells. Rocuronium bromide activated cyclooxygenase-2, inducible nitric oxide synthase and increased prostaglandin E2 synthesis in CPAE cells. CONCLUSIONS Rocuronium bromide induced inflammation and pain in CPAE cells. Suppressing nitric oxide production and enhancing prostaglandin E2 synthesis might be associated with rocuronium bromide-induced injection pain or withdrawal movement.

Diabetic retinopathy is a severe microvascular complication amongst patients with diabetes, and is the primary cause of visual loss through neovascularization. Betaine is one of the components of Fructus Lycii. In the present study, the effects of betaine on the expression levels of vascular endothelial growth factor (VEGF) and hypoxia-inducible factor (HIF)-1α in association with the Akt pathway were investigated in the retinas of streptozotocin (STZ)-induced diabetic rats using western blot and immunohistochemical analyses. The results of the present study revealed that the expression levels of VEGF, HIF-1α, and Akt were increased in the retinas of the STZ-induced diabetic rats. Betaine treatment attenuated this increase in VEGF and HIF-1α expression via suppression of diabetes-induced Akt activation in the retinas of the diabetic rats. The results suggested that betaine may potentially be used to delay the onset of complications associated with diabetic retinopathy via inhibition of retinal neovascularization in patients with diabetes.

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.

Caffeine may promote incontinence through its diuretic effect, particularly in individuals with underlying detrusor overactivity, in addition to increasing muscle contraction of the bladder smooth muscle. Caffeine may also affect bladder function via central micturition centers, including the medial preoptic area, ventrolateral periaqueductal gray, and pontine micturition center. However, the biochemical mechanisms of caffeine in central micturition centers affecting bladder function remain unclear. In the present study, the effects of caffeine on the central micturition reflex were investigated by measuring the degree of neuronal activation, and by quantifying nerve growth factor (NGF) expression in rats. Following caffeine administration for 14 days, a urodynamic study was performed to assess the changes to bladder function. Subsequently, immunohistochemical staining to identify the expression of c‑Fos and NGF in the central micturition areas was performed. Ingestion of caffeine increased bladder smooth muscle contraction pressure and time as determined by cystometry. Expression levels of c‑Fos and NGF in all central micturition areas were significantly increased following the administration of caffeine. The effects on contraction pressure and time were the most potent and expression levels of c‑Fos and NGF were greatest at the lowest dose of caffeine. These results suggest that caffeine facilitates bladder instability through enhancing neuronal activation in the central micturition areas.

Purpose 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. Methods 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. Results 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. Conclusions 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.

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the selective loss of nigral dopaminergic neurons and a reduction in striatal dopaminergic fibers, which result in tremors, rigidity, bradykinesia and gait disturbance. In addition to motor dysfunction, dementia is a widely recognized symptom of patients with PD. Berberine, an isoquinoline alkaloid isolated from Berberis vulgaris L., is known to exert anxiolytic, analgesic, anti-inflammatory, antipsychotic, antidepressant and anti-amnesic effects. In the present study, we investigated the effects of berberine on short-term memory in relation to dopamine depletion and hippocampal neurogenesis using a mouse model of PD, induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/probenecid (MPTP/P) treatment. Mice in the berberine-treated groups were orally administered berberine once a day for a total of 5 weeks. Our results revealed that the injection of MPTP/P induced dopaminergic neuronal death in the substantia nigra and fiber loss in the striatum. This resulted in impaired motor balance and coordination, as assessed by the beam walking test. We further demonstrated that MPTP/P-induced apoptosis in the hippocampus deteriorated short-term memory, as shown by the step-down avoidance task. By contrast, neurogenesis in the hippocampal dentate gyrus, which is a compensatory adaptive response to excessive apoptosis, was increased upon PD induction. However, treatment with berberine enhanced motor balance and coordination by preventing dopaminergic neuronal damage. Treatment with berberine also improved short-term memory by inhibiting apoptosis in the hippocampus. Berberine demonstrated maximal potency at 50 mg/kg. Based on these data, treatment with berberine may serve as a potential therapeutic strategy for the alleviation of memory impairment and motor dysfunction in patients with PD.

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.

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.

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.

Ulinastatin is an intrinsic serine-protease urinary trypsin inhibitor that can be extracted and purified from human urine. Urinary trypsin inhibitors are widely used to treat patients with acute inflammatory disorders, such as shock and pancreatitis. However, although the anti-inflammatory activities of urinary trypsin inhibitors have been investigated, the mechanisms underlying their actions are not yet fully understood. In the present study, we evaluated the effect of ulinastatin on lipopolysaccharide (LPS)-induced inflammation in relation with nuclear factor-κB (NF-κB) activation using BV2 mouse microglial cells. To accomplish this, we performed a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, reverse transcription-polymerase chain reaction (RT-PCR), western blot analysis, electrophoretic mobility gel shift assay (EMSA), prostaglandin E(2) (PGE(2)) immunoassay and nitric oxide (NO) detection. The results demonstrated that ulinastatin suppressed PGE2 synthesis and NO production by inhibiting the LPS-induced mRNA and protein expression of cyclooxygenase-2 (COX-2) and inducible NO synthase (iNOS) in BV2 mouse microglial cells. Ulinastatin suppressed the activation of NF-κB in the nucleus. These findings demonstrate that ulinastatin exerts analgesic and anti-inflammatory effects that possibly occur via the suppression of COX-2 and iNOS expression through the downregulation of NF-κB activity.

This study was conducted to determine the effects of Phellinus linteus (PL) on serotonin synthesis in the brain and on the expression of monocarboxylate transporters (MCTs) in muscles during exhaustive exercise in rats. In this study, 60 male Sprague-Dawley rats were divided into the following 6 groups: control; exercise; exercise and 50 mg/kg of PL treatment; exercise and 100 of mg/kg PL treatment; exercise and 200 mg/kg of PL treatment; and exercise and 100 mg/kg of caffeine treatment. Treatment with 200 mg/kg of PL led to a significant increase in the time to exhaustion in response to running on a treadmill and a significant decrease in 5-hydroxytryptamine synthesis and tryptophan hydroxylase expression in the dorsal raphe of rats. MCT1 and MCT4 expression of the gastrocnemius muscles was also increased in response to treatment with 200 mg/kg of PL. The results of the present study demonstrated that the administration of PL increased endurance exercise performance through inhibition of serotonin production in the brain and increased the expression of MCT1 and MCT4 in muscles. These results suggest that PL exerts an ergogenic effect.

Purpose 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. Methods 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. Results 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. Conclusions 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.

Stress urinary incontinence (SUI) is a common condition that primarily affects women. Here, we investigate the effects of human adipose-derived stem cells (ADSCs) in a rodent model of SUI. Female Sprague-Dawley rats at 7 weeks of age were randomly divided into three groups (n=8 per group): sham-operation, SUI-induction by transabdominal urethrolysis, and SUI-induction followed by transplantation of human ADSCs into the urethra. The abdominal leak point pressure at 8 weeks after the operation was markedly decreased by transabdominal urethrolysis, confirming successful induction of SUI. Interestingly, transplantation of human ADSCs into the urethra significantly blunted the decrease of abdominal leak point pressure in SUI-induced rats. Accordingly, we observed expression of α-smooth muscle actin in a significant proportion of transplanted ADSCs, indicating differentiation of ADSCs into smooth muscle cells in the urethra. Moreover, the SUI-induced elevations of c-Fos immunoreactivities in the pontin...

SUMMARY Clematis chinensis is the root of Clematis chinensis OSBECK and is classified in Ranunculaceae.Clematis chinensis is a traditional medicinal herb possesses analgesic, diuretic, anti-tumorigenic,and anti-inflammatory effects. In this study, the effect of aqueous extract of Clematis chinensisagainst lipopolysaccharide-induced inflammation was investigated in mouse BV2 microglialcells. The aqueous extract of Clematis chinensis at the respective concentration was treated onehour before the lipopolysaccharide treatment in mouse BV2 microglial cells. From the presentresults, pre-treatment with the aqueous extract of Clematis chinensis suppressed prostaglandin E 2 synthesis and nitric oxide production by inhibiting on the lipopolysaccharide-stimulatedcyclooxygenase-2 and inducible nitric oxide synthase expressions in mouse BV2 microglial cells.The present study suggests that Clematis chinensis may offer a valuable mean of therapy for braininflammatory diseases. Key words: Clematis chinensis; Lipopolysaccharide; Cyclooxygenase-2; Inducible nitric oxidesynthase; Prostaglandin E

SUMMARY Lycii fructus is the fruit of Lycium chinense Miller and is part of the Solanaceae family. Lycii fructusproduces various effects such as hypotensive, hypoglycemic, anti-pyretic, and anti-stress activities. Lyciifructus is known to contain betaine, carotene, nicotinic acid, zeaxanthin, and cerebroside. In thepresent study, the effects of Lycii fructus aqueous extract on lipopolysaccharide (LPS)-inducedinflammation in murine raw 264.7 macrophage cells were investigated. In this study we utilizedthe 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, reverse transcription-polymerase chain reaction (RT-PCR), Western blotting, and nitric oxide (NO) detection. Lycii fructusaqueous extract suppressed NO production by inhibiting the LPS-induced expressions ofinducible nitric oxide synthase (iNOS) and tumor necrosis factor-alpha (TNF- α) mRNA and iNOSprotein in murine raw 264.7 macrophage cells. Also, Lycii fructus aqueous extract suppressed theactivation of nuclear factor-kappa B (NF-κB) in the nucleus. These results demonstrated that Lyciifructus aqueous extract causes an anti-inflammatory effect that was likely produced by thesuppression of iNOS expression through the down-regulation of NF-eB binding activity.Key words: Lycii fructus; Lipopolysaccharide; Inducible nitric oxide synthase; Nitric oxide;Nuclear factor-kappa B

Aging leads to functional changes in the hippocampus, and consequently induces cognitive deficits, such as failure of memory. Neurogenesis in the hippocampal dentate gyrus continues throughout life, but steadily declines from early adulthood. Apoptosis occurs under various pathologic and physiologic conditions, and excessive apoptotic cell death can cause a number of functional disorders in humans. Apoptosis in the hippocampus also disturbs cognitive functions. In this study, we examined the effect of treadmill exercise on memory in relation to neurogensis and apoptosis in the hippocampal dentate gyrus of old-aged rats. The present results showed that loss of memory by aging was associated with a decrease in neurogenesis and an increase in apoptosis in the hippocampal dentate gyrus. Treadmill exercise improved short-term and spatial memories by enhancing neurogenesis and suppressing apoptosis in the hippocampal dentate gyrus of old-aged rats. In the present study, we showed that treadmill exercise is a very useful strategy for preventing failure of memory in the elderly.

Objectives: Angelicae Tenuissimae Radix has traditionally been used for treating headache, flu-like symptoms, limb-ache and disability, and even for treating toothache. We investigated the anti-inflammatory and analgesic effect of Angelicae Tenuissimae Radix on lipopolysaccharide-induced inflammation. Methods: For this study, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, reverse transcription-polymerase chain reaction, prostaglandin E2 immunoassay and nitric oxide detection in mouse BV2 microglial cells were performed. Results: Angelicae Tenuissimae Radix suppressed prostaglandin E2 synthesis and nitric oxide production by inhibiting the lipopolysaccharide-induced expressions of cyclooxygenase-2 and inducible nitric oxide synthase messenger RNA in mouse BV2 microglial cells. Discussion: The present study indicates that Angelicae Tenuissimae Radix can be applied as a valuable treatment for brain inflammation and headache.

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.

Stress urinary incontinence leads to the involuntary loss of urine during abdominal strain caused by sneezing, laughing, and coughing. Acupuncture has been widely used for the treatment and prevention of a variety of diseases in traditional medicine. Acupuncture has also been used to relieve the symptoms of functional disorders of the lower urinary tract. In the present study, we investigated the effect of acupuncture at the Sanyinjiao (SP6) acupoint on stress urinary incontinence in rats. The present results showed that abdominal leak point pressure was decreased in rats with stress urinary incontinence, while acupuncture at the SP6 acupoint significantly enhanced the abdominal leak point pressure. The expression of c-Fos in the pontine micturition center (PMC), ventrolateral periaqueductal gray (vlPAG), and medial preoptic nucleus (MPA) regions was increased by the induction of stress urinary incontinence, and acupuncture at the SP6 acupoint significantly decreased c-Fos expression in these areas. In the present study, we showed that acupuncture has therapeutic effect on the symptoms of stress urinary incontinence, and this effect of acupuncture is associated with modulation of c-Fos expression in the brain.

SUMMARY Angelica dahurica (Umbelliferae) grows in China, Japan, Russia, and Korea. The root of Angelicadahurica has been used as a traditional folk medicine to treat headache and toothache. In thisstudy, the effects of the aqueous extract of Angelica dahurica on acetic acid-induced abdominalpain, carrageenan-induced edema, and thermal hyperalgesia were investigated using mice andrats. The present results showed that the aqueous extract of Angelica dahurica inhibited acetic acid-induced abdominal pain in mice and reduced carrageen-induced edema in rats. The presentstudy showed that the aqueous extract of Angelica dahurica possesses anti-inflammatory andanalgesic effects.Key words: Angelica dahurica; Analgesic and anti-inflammatory effect; Edema; Thermal pain INTRODUCTION The aromatic medicinal plant Angelica dahurica(Umbelliferae) is a perennial herb growing to 2.5 mwith large three-branched leaves and umbelsbearing many white flower heads. It grows wildin thickets in China, Japan, Russia, and Korea.The roots of this species have been used astraditional folk medicine to treat headache,toothache, aching eyes, abdominal pain, hysteria,bleeding, menstrual disorder, and neuralgia.Several coumarins that are constituents of Angelicadahurica have been extensively studied for theirchemical structures (Saiki et al., 1971; Wang et al.,2001), and pharmacological effects (Kimura et al.,1982; Kim et al., 1992; Kwon et al., 1997).Pain is the most common symptom encounteredin clinical practice. It is believed that currentanalgesic drugs such as opiates and non-steroidalanti-inflammatory drugs (NSAID) are not alwaysuseful in many painful conditions, because oftheir side effects and potency. As a result, thesearch for other alternatives seems necessary andbeneficial. The writhing test is a well-known animalmodel of inflammatory and visceral pain. It isuseful in animal model studying anti-nociceptiveeffects. Carrageenan-induced local inflammationis a commonly used method to evaluate the

Peripheral nerve injuries are a commonly encountered clinical problem and often result in a chronic pain and severe functional deficits. c-Fos expression is sometimes used as a marker of increased neuronal activity. We have developed herbal bath “HAC” for pain control using the following herbs: Harpagophytum procumbens, Atractylodes japonica, and Corydalis tuber. In the present study, we investigated the effects of herbal bath “HAC” on the recovery rate of the locomotor function and the expression of c-Fos in the ventrolateral periaqueductal gray (vlPAG) region of brain following sciatic crushed nerve injury in rats. Walking track analysis for the evaluation of functional recovery and immunohistochemistry for the c-Fos expression were used for this study. In the present results, characteristic gait change with dropping of the sciatic function index (SFI) was observed and c-Fos expression in the vlPAG was suppressed following sciatic crushed nerve injury in rats. Immersion into herbal bath “HAC” enhanced SFI value and restored c-Fos expression in the vlPAG to the control value. These results suggest that herbal bath “HAC” might activate neurons in the vlPAG, and it facilitates functional recovery from peripheral nerve injury. Here we showed that herbal bath “HAC” could be used as a new therapeutic intervention for pain control and functional recovery from peripheral nerve injury.

SUMMARY Bupleuri radix (Umbelliferae), the dried root of Bupleurum Chinense DC, has been clinically used tomitigate pain sensation. The descending pain control system consists of three major components,and modulation of pain in the periaqueductal gray is the most extensively studied descendingpain control system. However, the relation of Bupleuri radix on the descending pain controlsystem has not been clarified. In the present study, modulation of the aqueous extract of Bupleuriradix on glycine-induced ion current in the acutely dissociated periaqueductal gray neurons wasinvestigated by using nystatin-perforated patch-clamp technique under voltage-clamp condition.In the present results, the glycine-induced ion current was significantly suppressed by 0.1 mg/mlBupleuri radix, while treatment with 10 -5 M naltrexone, opioid receptor antagonist, alleviatedBupleuri radix-induced inhibition on glycine-induced ion current. The present study showed thatthe aqueous extract of Bupleuri radix may activate descending pain control system throughinhibition on glycine-induced ion current in the periaqueductal gray neurons and this effect ismediated by opioid receptors.Key words: Bupleuri radix; Glycine; Periaqueductal gray; Naltrexone; Patch Clamp

SUMMARY Paeonia radix is the root of Paeonia aliflora Pallas, which is a perennial plant classified in the familyPaeoniaceae. Paeonia radix possesses several pharmacological effects such as analgesic, anti-inflammatory and anti-allergic, anti-oxidative, and anti-coagulant activities. In this study, weinvestigated the effect of the aqueous extract of Paeonia radix on the lipopolysaccharide-inducedinflammation in mouse BV2 microglial cells. The aqueous extract of Paeonia radix at respectiveconcentration was treated one hour before lipopolysaccharide treatment. In the present results,the aqueous extract of Paeonia radix suppressed prostaglandin E 2 synthesis and nitric oxideproduction by inhibiting the lipopolysaccharide-stimulated mRNA expressions of cyclooxygenase-2 andinducible nitric oxide synthase in mouse BV2 microglial cells. These results demonstrate thatPaeonia radix exerts anti-inflammatory and analgesic effects probably by suppressing mRNAexpressions of cyclooxygenase-2 and inducible nitric oxide synthesis. The present studydemonstrates that Paeonia radix may offer a valuable mean of therapy for brain inflammatory diseases.Key words: Paeonia radix; Lipopolysaccharide; Cyclooxygenase-2; Prostaglandin E

Maternal alcohol-intoxication during pregnancy exerts detrimental effects on fetal development and is known to influence learning ability and memory capability by altering neuronal activity in the hippocampus. c-Fos expression represents neuronal activity and plays a crucial role in the brain development. Physical exercise is known to enhance neuronal plasticity and activity. In the present study, we investigated the influence of postnatal treadmill running on the c-Fos expression in the hippocampus of rat pups born from the alcohol-intoxicated mothers. The results obtained show that maternal alcohol-intoxication suppressed c-Fos expression in the hippocampus of rat pups and that postnatal treadmill exercise enhanced c-Fos expression in the hippocampus of these rat pups. The present study suggests that exercise should be considered as a therapeutic means of countering the effects of maternal alcohol-intoxication, and that it may provide a useful strategy for enhancing the neuronal activity of children born from the mothers who abuse alcohol during pregnancy.

Intracerebral hemorrhage is one of the most devastating types of stroke. Caspases are essential players in apoptotic cell death both as initiators and executioners. The v-Fos FBJ murine osteosarcoma viral oncogene homolog (Fos, c-Fos) is an immediate early gene, and Fos expression is sometimes used as a marker for stimuli-induced changes in the metabolic activity of neurons. The expressions of caspase3 and Fos are enhanced with neuroregeneration and with neuronal cell death, respectively. Cells proliferation the dentate gyrus of adult rodents is enhanced by certain pathologic events as seizures and ischemic insult, and such up-regulation of cell proliferation occurring during pathologic situations is thought to be a compensatory response to lesion-induced cell death in the brain. In the present study, we investigated the effects of acupuncture on the intrastriatal hemorrhage-induced caspase3 expression in the striatum and on the Fos expression and cell proliferation in the dentate gyrus of rats.For this study, immunohistochemistry for caspase3, Fos and 5-bromo-2'-deoxyuridine (BrdU) was performed.Caspase3 expression in the striatum was increased by intrastriatal hemorrhage. Fos expression and cell proliferation in the dentate gyrus of rats with intracerebral hemorrhage were also increased. Acupunctural treatment, especially at the ST36 acupoint, suppressed the intracerebral hemorrhage-induced caspase3 expression in the stratum, and it also inhibited expression of Fos and cell proliferation in the dentate gyrus.In the present study, we have shown that acupuncture treatment has a neuroprotective effect on intrastrstriatal hemorrhage-induced neuronal cell death, and this suggests that acupuncture can aid in the recovery of the central nervous system following stroke.

Nitric oxide (NO) is endogenously synthesized from l-arginine by the enzyme NO synthase (NOS). Three isoforms of NOS have been characterized: neuronal NOS (nNOS), endothelial NOS, and inducible NOS. Acting as a neuronal messenger in the brain, NO is crucial in learning and memory processes. Starvation is known to decrease learning ability and memory capability. In the present study, we examined the effect of treadmill exercise on the expression of NOS and nNOS in the hippocampus of food-deprived rats. Food deprivation suppressed the NOS and nNOS expression in the CA1 region, the CA2 and CA3 regions, and the dentate gyrus of the hippocampus. We have observed that treadmill running overcomes the food deprivation–induced suppression of the NOS and nNOS expression in the various hippocampal regions. The present results suggest that treadmill exercise may overcome the starvation-induced decrease of learning ability and memory function in the hippocampus.

Armeniacae semen is the seed of Prunus armeniaca L. var. ansu MAXIM which is classified into Rosaceae. In traditional oriental medicine, Armeniacae semen has been used for the treatment of pain and inflammatory diseases. In this study, the effect of Armeniacae semen extract on lipopolysaccharide-induced inflammation was investigated using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, reverse transcription-polymerase chain reaction (RT-PCR), Western blot, prostaglandin E2 immunoassay, and nitric oxide detection on mouse BV2 microglial cells. In the present results, Armeniacae semen extract suppressed prostaglandin E2 synthesis and nitric oxide production by inhibiting the lipopolysaccharide-stimulated enhancement of cyclooxygenase-2 and inducible nitric oxide synthase mRNA expression in BV2 cells. These results show that Armeniacae semen exerts anti-inflammatory and analgesic effects probably by suppression of cyclooxygenase-2 and inducible nitric oxide synthase expressions.

Ma huang, the dried plant stem of Ephedra Intermedia Schrenk et C.A., contains an ephedrine-type alkaloid and has been used for weight loss. Neuropeptide Y (NPY), a 36-amino acid peptide, is concentrated in the hypothalamus and stimulates feeding desire. In this study, the effect of Ma huang on the expressions of NPY in the hypothalamus of rats was investigated using immunohistochemistry. Food-deprivation enhanced the NPY expression in the hypothalamus. Ma huang suppressed the food-deprivation-induced enhancement of NPY expression. Present results suggest that Ma huang curbs the food desire by suppressing the NPY expression under food-deprivation conditions.

c-Fos has been used as a neuronal activity marker. Here, we examined the influence of age on the treadmill running-induced c-Fos expression in rat hippocampus. Rats of exercise groups were forces to run on treadmill for 30 min. once a day for 5 consecutive days. Without exercise, c-Fos expression was highest in 8-week old rats. Treadmill exercise significantly enhanced the c-Fos expression in the hippocampus of rats in all ages. In the CA region, the increase of the c-Fos expression by treadmill exercise was highest in 4-week old rats. In the dentate gyrus, the increase of the c-Fos expression by treadmill exercise was highest in 62-week old rats. The data show that age is an important factor for the regulation of the c-Fos expression in the hippocampus and that the ability of the treadmill exercise enhancing the c-Fos expression is dependent on age status.

Nitric oxide (NO) is a free radical synthesized from L-arginine by nitric oxide synthase (NOS). NO is crucially involved in the regulation of food intake and it is also closely implicated in the abnormalities of food intake such as hyperphagia. In the present study, the effects of treadmill exercise on the expressions of NOS and neuronal nitric oxide synthase (nNOS) in the hypothalamus of streptozotocin-induced diabetic rats were investigated. Sprague-Dawley rats were divided into four groups; the control-rest group, the control-exercise group, the diabetes-rest group, and the diabetes-exercise group. Rats in the exercise groups were put on the treadmill to run for 30 minutes once a day for 6 consecutive days. The results of the present study is that treadmill exercise suppressed diabetes-induced increase of NOS and nNOS expressions in the hypothalamus. These results suggest the possibility that treadmill exercise may reduce the increased appetite induced by diabetes.

Nitric oxide is synthesized from L-arginine by nitric oxide synthase (NOS), and it is a free radical with signaling functions. Neuronal nitric oxide synthase (nNOS) is mainly expressed in the central nervous system, and it has been implicated in the pathogenesis of brain injury such as ischemia. In the present study, the effects of 7-nitroindazole, which specifically inhibits nNOS, on apoptosis and cell proliferation int he dentate gyrus after transient global ischemia in gerbils were investigated. Enhanced apoptotic neuronal cell death and cell proliferation were observed in the dentate gyrus of ischemic gerbils. However, 7-nitroindazole suppressed the ischemia-induced apoptosis and cell proliferation. These results suggest that 7-nitroindazole has an inhibitive effect on apoptosis and cell proliferation following transient global ischemia. The present study shows that nitric oxide, the synthesis of which is augmented by ischemia, plays an important role in the regulation of apoptosis and cell proliferation following ischemic injury.

Nitric oxide (NO) is synthesized from L-arginine by nitric oxide synthase (NOS). Alternation of NOS expression is implicated in the pathogenesis of numerous secondary complications of diabetes. Aqueous extract of Ginseng radix has traditionally been used for the various disorders including diabetes. In this study, the effect of Ginseng radix on the NOS expression in the hippocampus of streptozotocin (STZ)-induced diabetic rats was investigated via nicotinamide adenine dinucleotide phosphate-diaphorase (NADPH-d) histochemistry. Enhanced NOS expression was detected in the hippocampus of diabetic rats and administration of Ginseng radix suppressed NOS expression. Ginseng radix may aid the treatment of central nervous system complications in diabetes.

Cerebral ischemia resulting from transient or permanent occlusion of cerebral arteries leads to neuronal cell death and eventually causes neurological impairments. In the present study, the effects of treadmill exercise on apoptosis and cell proliferation in the hippocampal dentate gyrus following transient global ischemia in gerbils were investigated using terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay and immunohistochemistry for caspase-3 and 5-bromo-2'-deoxyuridine (BrdU). It was shown that apoptotic cell death and cell proliferation in the hippocampal dentate gyrus were significantly increased following transient global ischemia in gerbils and that treadmill exercise suppressed the ischemia-induced increase in apoptosis and cell proliferation in the dentate gyrus. The present results suggest that treadmill exercise may protect cells from apoptotic death and aid in recovery from the central nervous system sequelae following stroke.

In the present study, the effect of acupuncture at Zusanli acupoint on nitric oxide synthase (NOS) expression in the hippocampus of streptozotocin (STZ)-induced diabetic rats was investigated via nicotinamide adenine dinucleotide phosphate-diaphorase (NADPH-d) histochemistry. Animals were divided into four groups: the control group, the nondiabetic and acupunctured group, the STZ-induced diabetes group, and the STZ-induced diabetes and acupunctured group. From the results, NADPH-d-positive neurons in the hippocampus were decreased in STZ-induced diabetic rats, while acupuncture increased NOS expression significantly under diabetic conditions. In the present study, it can be suggested that acupuncture treatment may modulate NOS activity in the hippocampus under diabetic conditions.

Ginseng radix, the root of Panax ginseng C. A. MEYER (Araliaceae), is one of the best-known Oriental medicinal herbs with numerous therapeutic applications. To investigate whether Ginseng radix possesses a protective effect against 1-methyl-4-phenylpyridine (MPP(+))-induced cytotoxicity in neuronal cells, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, flow cytometry, DNA fragmentation assay, reverse transcription-polymerase chain reaction (RT-PCR), Western blotting, and caspase-3 enzyme assay were performed on PC12 neuronal cells. Cells treated with MPP(+) exhibited various apoptotic features, while cell pretreated with Ginseng radix prior to MPP(+) exposure showed a decrease in the occurrence of apoptotic features. These results suggest that Ginseng radix may exert a protective effect against MPP(+)-induced apoptosis in PC12 cells.

In the present study, the effects of cold-water immersion on cell proliferation and nitric oxide synthase expression in the dentate gyrus of rats were investigated. Sprague-Dawley rats were divided into four groups: the control-rest group; the control-heat group; the cold-rest group; and the cold-heat group. Cold-water immersion for 5 min at 4 degrees C suppressed the numbers of 5-bromo-2'-deoxyuridine-positive and nicotinamide adenine dinucleotide phosphate-diaphorase-positive cells in the dentate gyrus, and these numbers were increased by warming for 30 min at 30 degrees C. In the present study, it was demonstrated that warming protects against cold stress-induced suppression of new cell formation, and results suggest that nitric oxide, the synthesis of which is affected adversely by cold-water immersion, may play an important role in the regulation of cell proliferation.

Intracerebral hemorrhage (ICH) is a severe type of stroke causing neurological dysfunction with a high mortality rate. Dexmedetomidine is an agonist for α2‑adrenoreceptors with sedative, anxiolytic, analgesic and anesthetic effects. In the present study, we investigated the effects of dexmedetomidine on short‑term and spatial learning memory, as well as its effects on apoptosis following the induction of ICH in rats. A rat model of IHC was created by an injection of collagenase into the hippocampus using a stereotaxic instrument. Dexmedetomidine was administered intraperitoneally daily for 14 consecutive days, commencing 1 day after the induction of ICH. The step‑down avoidance test for short‑term memory and the radial 8‑arm maze test for spatial learning memory were conducted. Terminal deoxynucleotidyl transferase‑mediated dUTP nick end-labeling (TUNEL) assay, immunohistochemistry for caspase‑3, and western blot analysis for Bcl‑2, Bax, Bid and caspase-3 expression were performed for the detection of apoptosis in the hippocampus. Western blot analysis for the brain‑derived neurotrophic factor (BDNF) and tyrosine kinase B (TrkB) was also performed for the detection of cell survival in the hippocampus. The induction of ICH deteriorated short‑term and spatial learning memory, increased apoptosis and suppressed BDNF and TrkB expression in the hippocampus. Treatment with dexmedetomidine ameliorated the ICH‑induced impairment of short‑term and spatial learning memory by suppressing apoptosis and enhancing BDNF and TrkB expression. In the normal rats, dexmedetomidine exerted no significant effects on memory function and apoptosis. The present results suggest the possibility that dexmedetomidine may be used as a therapeutic agent for the conservation of memory function in stroke patients.

Lipopolysaccharide (LPS) is an endotoxin derived from Gram‑negative bacteria, which induces brain inflammation. LPS‑induced brain inflammation deteriorates hippocampus‑dependent cognitive deficits. In the present study, we investigated the effects of forced treadmill exercise and voluntary wheel exercise on short‑term memory in relation to neuronal maturation in LPS‑induced brain inflammation of rats. Brain inflammation in rats was induced by an injection of LPS into the cerebral ventricle. Short‑term memory was evaluated using a step‑down avoidance task. Cell proliferation in the hippocampal dentate gyrus was determined by 5‑bromo‑2'‑deoxyuridine (BrdU), a marker of new cells, immunohistochemistry. Western blot analysis for the determination of doublecortin (DCX), a marker of immature neurons and neuronal nuclear antigen (NeuN), a marker of mature neurons, was performed. In the present study, LPS‑induced brain inflammation impaired short‑term memory by increasing DCX expression and suppressing NeuN expression. These results suggest that LPS‑induced brain inflammation disturbs neuronal maturation. The number of BrdU‑positive cells in the hippocampal dentate gyrus was increased by LPS injection. This increase in the number of BrdU‑positive cells can be ascribed to the increase in the number of of immature neurons following LPS injection. On the other hand, forced treadmill exercise and voluntary wheel exercise improved brain inflammation‑induced short‑term memory impairment by suppressing DCX expression and increasing NeuN expression, enhancing neuronal maturation. Forced treadmill exercise and voluntary wheel exercise showed similar efficacy. From these results, it can be inferred that forced treadmill exercise and voluntary wheel exercise may improve memory function deteriorated by brain inflammation.

Aims Parkinson's disease is a debilitating neurodegenerative disorder characterized by the gradual loss of dopaminergic neurons. We investigated the effects of treadmill exercise on dopaminergic neuronal loss and microglial activation using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/probenecid (MPTP/P)-induced Parkinson's disease mice. Main methods Parkinson's disease was induced in mice by injection of MPTP/P. The mice in the exercise groups were put on a treadmill to run for 30 min/day, five times per week for four weeks. Motor balance and coordination was measured using rota-rod test. Expressions of inducible nitric oxide synthase (iNOS) and phosphorylated extracellular signal-regulated kinase (p-ERK), phosphorylated NH 2 -terminal kinase (p-JNK), phosphorylated p-38 (p-p38), CD200, and CD200 receptor were determined by western blotting. Expressions of tyrosine hydroxylase (TH) and CD11b were evaluated by immunohistochemistry. Key findings Parkinson's disease mice displayed poor motor balance and coordination with loss of nigrostriatal dopaminergic neurons. iNOS expression was enhanced via up-regulation of phosphorylated mitogen-activated protein kinases (p-MAPKs) signaling, such as p-ERK, p-JNK, and p-p-38 in the Parkinson's disease mice. Microglial activation was also observed in the Parkinson's disease mice, showing increased CD11b expression with suppressed CD200 and CD200 receptor expressions. Treadmill exercise prevented the loss of nigrostriatal dopaminergic neurons, and ameliorated the motor balance and coordination dysfunction in the Parkinson's disease mice. Treadmill exercise suppressed iNOS expression via down-regulation of MAPKs and also inhibited microglial activation in the Parkinson's disease mice. Significance Treadmill exercise prevented dopaminergic neuronal loss by inhibiting brain inflammation through suppression of microglial activation in the Parkinson's disease mice.