Vardenafil Enhances Oxytocin Expression in the Paraventricular Nucleus without Sexual Stimulation

PurposeOxytocin 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.MethodsMale 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.ResultsOxytocin 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.ConclusionsIn 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

Treadmill Exercise Improves Motor Function by Suppressing Purkinje Cell Loss in Parkinson Disease Rats

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. Conclusions 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

Vardenafil Increases Cell Proliferation in the Dentate Gyrus through Enhancement of Serotonin Expression in the Rat Dorsal Raphe

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

Search for heavy resonances decaying to two Higgs bosons in final states containing four b quarks

A search is presented for narrow heavy resonances X decaying into pairs of Higgs bosons (H) in proton-proton collisions collected by the CMS experiment at the LHC at root s = 8 TeV. The data correspond to an integrated luminosity of 19.7 fb(-1). The search considers HH resonances with masses between 1 and 3 TeV, having final states of two b quark pairs. Each Higgs boson is produced with large momentum, and the hadronization products of the pair of b quarks can usually be reconstructed as single large jets. The background from multijet and t (t) over bar events is significantly reduced by applying requirements related to the flavor of the jet, its mass, and its substructure. The signal would be identified as a peak on top of the dijet invariant mass spectrum of the remaining background events. No evidence is observed for such a signal. Upper limits obtained at 95 confidence level for the product of the production cross section and branching fraction sigma(gg -> X) B(X -> HH -> b (b) over barb (b) over bar) range from 10 to 1.5 fb for the mass of X from 1.15 to 2.0 TeV, significantly extending previous searches. For a warped extra dimension theory with amass scale Lambda(R) = 1 TeV, the data exclude radion scalar masses between 1.15 and 1.55 TeV

Measurement of the top quark mass using charged particles in pp collisions at root s=8 TeV

Peer reviewe

Effects of endurance exercise on expressions of glial fibrillary acidic protein and myelin basic protein in developing rats with maternal infection-induced cerebral palsy

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. INTRODUCTION Approximately 10% of newborns are born prematurely, and se vere disturbances in mental development and perinatal brain inju ries have been observed in premature infants Maternal LPS administration increases the number of GFAPpos itive astrocytes, decreases MBP expressions and alters microglia immunoreactivity in the brain of offspring It is well known that exercise induces several physiological and biochemical changes in the brain In the present study, we investigated whether treadmill walk ing would have a protective effect on astrogliosis and hypomyelin ation in rats with PVL. The animal model of PVL was induced by maternal intracervical injection of LPS. In the present study, im munohistochemistry was performed for the detection of GFAP in the striatum and MBP in the corpus callosum. MATERIALS AND METHODS Animals and treatments This study was performed in accordance with the guidelines of the National Institutes of Health (NIH) and the Korean Academy of Medical Sciences. Female SpragueDawley rats (180±10 g, 8 weeks old, n=20) were allowed to mate with male rats for a peri od of 24 h. The female rats were then individually housed in plas tic home cages under controlled temperature (20±2˚C) and a light -dark cycle consisting of 12 h of light and 12 h of darkness (lights on from 07:00 to 19:00 h). Food and water were made available ad libitum. The pregnant rats were divided into two groups: the sham group and the LPStreated group (n=4 in each group). On the 9th, 13th, and 17th day of pregnancy, the pregnant rats in the LPStreated group received intracervical injections of 1.0 mg/kg LPS (from Escherichia coli, serotype 055:B5, Sigma Chemical Co., St. Louis, MO, USA) suspended in pyrogenfree saline (PFS), and the preg nant rats in the sham group were treated with PFS. After birth, the neonatal rats were divided into three groups: the sham group, the LPStreated group, and the LPStreated and exercise group (n=4 in each group). Exercise protocol Eight weeks after birth, the rats in the exercise group were forced to walk on a motorized treadmill for 30 min three times a week for 4 weeks. The exercise load consisted of walking at the speed of 8 meters/min at an inclination of 0˚. Tissue preparation The animals were sacrificed immediately after the completion of the last exercise. The rats were weighed and given an overdose of Zoletil 50 ® (10 mg/kg i.p.; Vibac Laboratories, Carros, France). After a complete lack of response was observed, the rats were tran scardially perfused with 50 mM phosphatebuffered saline (PBS) and subsequently fixed with freshly prepared 100 mM phosphate buffer (PB, pH 7.4) containing 4% paraformaldehyde. The brains were removed and fixed in the same fixative overnight and then transferred to a 30% sucrose solution for cryoprotection. Serial cor onal sections of 40μm thickness were obtained using a freezing microtome (Leica, Nussloch, Germany). GFAP and MBP immunohistochemistry An average of six sections within the striatum spanning from Bregma 1.20 mm to 0.96 mm and six sections within the corpus callosum spanning from Bregma 0.84 mm to 0.60 mm were ob tained from each brain. Tissue sections were incubated overnight with rabbit antiGFAP antibody or antiMBP antibody (Santa Cruz Biotechnology, Santa Cruz, CA, USA) at a dilution of 1:500. The sections were then incubated with antirabbit secondary antibody (1:200, Vector Laboratories, Burlingame, CA, USA). The sections were subsequently incubated with avidin biotinperoxi dase complex (1:100, Vector Laboratories) for 1 h at room tem perature. Immunoreactivity was visualized by incubating the sec tions in a solution containing 0.02% 3, 3´diaminobenzidine tet rahydrochloride (DAB) and 0.03% H2O2 in 50 mM TrisHCl (pH 7.6) for approximately 5 min. The sections were then washed three times with PBS and mounted onto gelatincoated slides. The slides were airdried overnight at room temperature, and covers lips were mounted using Permount ® (Fisher Scientific, New Jer sey, NJ, USA). Data analysis The intensities of GFAP and MBP staining were quantitatively assessed using a microdensitometrical method based on optical density (the mean gray scale) with the use of an image analyzer (Multiscan, Fullerton, CA, USA). Before starting the image anal ysis, the light source was adjusted to the brightness that generated the best possible contrast between immunopositive and immu nonegative cells. Statistically significant differences were determined by oneway analysis of variance (ANOVA) followed by Duncan's Post-hoc analy sis. The results were expressed as the mean±standard error of the mean (SEM). Differences were considered significant at P<0.05. RESULTS Effects of treadmill walking exercise on body weight in rats with maternal endotoxin-induced PVL Eight weeks after birth, the mean body weight of the rats was 297±3.85 g in the sham group, 246±24.33 g in the LPStreated group, and 299±2.00 g in the LPStreated and exercise group. After 4 weeks of exercise, the mean body weight of the rats was 394±4.60 g in the sham group, 347±7.54 g in the LPStreated group, 342±7.50 g in the LPStreated and exercise group. There was no significant difference in body weight between the groups. Effect of treadmill walking exercise on GFAP expression in the striatum of rats with maternal endotoxin-induced PVL Photomicrographs of GFAP expression in the striatum are pre sented in Effect of treadmill walking exercise on MBP expression in the corpus callosum of rats with maternal endotoxininduced PVL Photomicrographs of MBP expression in the corpus callosum are presented in DISCUSSION Maternal infection as well as increased levels of proinflamma tory cytokines in amniotic fluid and fetal blood is associated with preterm birth and neonatal neurological disorders In the present results, intracervical injection of LPS into the ma ternal rats induced astrogliosis in the striatum of rats that was re presented by enhanced expression of GFAP in the striatum. Many studies have shown that PVL is closely associated with the increased number of GFAPpositive astrocytes in the white matter lesion of infant brains In the present results, intracervical injection of LPS into the ma ternal rats induced hypomyelination in the corpus callosum of rats, that was represented by suppressed expression of MBP in the cor pus callosum. MBP is the most abundant protein in the myelin sheath. One possible reason for the reduced MBP staining is a re duction MBP production by the oligodendrocyte or a reduction in the number of oligodendrocytes after maternal LPS treatment. Re duced myelination and oligodendrocytes are concomitantly ob served in the infant brains with PVL In the present results, we investigated the effects of treadmill walking exercise on astrogliosis and hypomyelination in rats with PVL. Treadmill walking exercise suppressed LPSinduced astro gliosis in the striatum and alleviated LPSinduced hypomyelin ation in the corpus callosum of the rats with PVL. The present study revealed that treadmill walking exercise is effective for the http://www.e-jer.org 13 http://dx.doi.org/10.12965/jer.140084 Kim K, et al. • Effects of Endurance Exercise on GFAP and MBP Expressions suppressing astrogliosis and hypomyelination associated with PVL. In the present study, we showed that treadmill walking exercise may be effective therapeutic strategy for alleviating the detrimen tal effects of CP

Exercise Alleviates Cognitive Functions by Enhancing Hippocampal Insulin Signaling and Neuroplasticity in High-Fat Diet-Induced Obesity

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’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