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Amaç: Gebelik sırasında sigara ve alkol tüketimi doğum eylemi üzerinde istenmeyen etkilere neden olmaktadır. Altta yatan mekanizmalar hala tam olarak anlaşılmamış olmakla birlikte, bozulmuş miyometriyum fonksiyonel yanıtları bu komplikasyonların nedenlerinden biri olabilir. Bu çalışmada, kronik sigara ve alkol tüketiminin izole term-gebe sıçan miyometriyum şeritlerinin fonksiyonel yanıtlarına etkisini araştırdık. Yöntem: 21 Wistar albino sıçanı üç gruba ayrıldı: Kontrol; Sigara grubu, sıçanlar 12 hafta boyunca sigara dumanına maruz kaldı; Alkol grubu, sıçanlara 12 hafta boyunca etanol uygulandı (n = 7, her bir grupta). Doğum dönemlerinde bulunan sıçanlardan izole edilen miyometriyal düz kas şeritleri, izometrik kayıt almak üzere organ banyosuna yerleştirildi. Karbakol (10-8-10-4 M), oksitosin (10-9-10-3 M) ve diltiazem (10-8-10-4 M) kümülatif konsantrasyonlarının miyometriyal spontan kasılmalar üzerindeki etkileri ölçüldü. Bulgular: Karbakol kasılma yanıtlarının amplitüd ve frekansları sigara grubunda anlamlı olarak artarken, alkol grubunda azaldı. Oksitosin ile indüklenen miyometriyal kasılmaların frekansı sigara maruziyetiyle artarken, kasılmaların amplitüdü değişmedi. Amplitüd ve frekans olarak oksitosin kasılmaları alkol grubunda azaldı. Her iki grupta da diltiazem gevşeme yanıtları arasında kontrollerine göre anlamlı olarak fark yoktu. Sonuç: Bu bulgular miyometriyal düz kasının kasılma ve gevşeme yanıtlarını değiştirmek yoluyla, sigara maruziyetinin erken doğuma neden olabileceğini ve alkol maruziyetinin gebelik süresini uzatabileceğini göstermektedir. Diltiazem gebelikte her iki durumda da tokoliz için yararlı bir etkiye sahip olabilir.

We investigated the effect of resveratrol on endothelial and neuronal nitric oxide synthase (eNOS and nNOS) expression in the corpus cavernosum from chronic unpredictable mild stress (CUMS)-exposed rats in order to examine possible role of proinflammatory cytokines, which might play a role on erectile dysfunction (ED). Rats were randomly and equally divided into four groups such as control, control+resveratrol, CUMS and CUMS + resveratrol (20 mg/kg/day, i.p/8 weeks). Sucrose intake and forced swimming tests were used to evaluate depressive-like behaviors. nNOS, eNOS expressions, inflammatory markers, corticosterone and testosterone levels were analyzed either in blood samples and/or penile tissues. CUMS-exposed rats displayed depressive-like behaviors, reduced penile nNOS and eNOS expressions, and serum testosterone levels and enhanced serum and penile tissue levels of proinflammatory markers compared to controls. Resveratrol reversed depressive-like behaviors and suppressed serum and penile levels of proinflammatory markers, increased nNOS and eNOS expressions and testosterone levels in CUMS-exposed rats. Resveratrol exerted antidepressant-like effects and protected the development of CUMS-induced impairment of cavernosal eNOS and nNOS expressions associated with ED, which might be related to its anti-inflammatory action.

Erectile dysfunction (ED) has been reported to be associated with inflammation. This study investigated the effects of tumor necrosis factor alpha (TNF-α) inhibitor etanercept on penile neuronal nitric oxide synthase (nNOS) and endothelial nitric oxide synthase (eNOS) expressions, testosterone concentrations, neurogenic and endothelium-dependent relaxations of corpus cavernosum (CC), and circulating and cavernosal levels of inflammatory markers in aged rats. Animals were separated into control, aged, and etanercept-treated aged groups. Aged rats displayed significantly increased serum and cavernosal TNF-α, C-reactive protein (CRP), monocyte chemoattractant protein-1 (MCP-1) and intercellular adhesion molecule (ICAM–1) levels, and decreased penile nNOS and eNOS expressions and serum testosterone levels compared with controls. In etanercept-treated aged group, NOS expressions were similar to that of the control group. The circulating and cavernosal concentrations of TNF-α, CRP, MCP-1, ICAM-1, and testosterone were also normalized by etanercept. Neurogenic and endothelium-dependent relaxant responses significantly decreased in aged rats and etanercept treatment markedly improved these relaxation responses. Our findings indicate that aging decreases penile NOS expression, neurogenic and endothelium-dependent relaxations of CC, and also suppresses serum testosterone levels by inducing inflammatory response that may contribute to the development of ED. TNF-α antagonism may be a novel strategy to treat aging-associated ED.

Normal aging may lead to cognitive deficits, which is associated with endothelial dysfunction and neuroinflammation. Dysregulation of TNFα expression contributes to vascular aging and dementia. In this study, we investigated the effects of etanercept, which is a TNFα inhibitor, on cognitive and endothelial function in aged rats. Male Wistar albino rats were divided into 3 groups: Young (4 month), aged (24 month) aged+ETA (24 month+etanercept). Etanercept (0.8 mg/kg/weekly) was given to the aged+ETA group subcutaneously for 8 weeks. Then passive avoidance test (PAT) and the Morris water maze test (MWMT) were used to evaluate cognitive functions of rats. After the behavioral tests, the rats were subjected to systolic blood pressure (SBP) measurement, and then endothelial function of thoracic aorta was evaluated by isolated organ bath system. Thoracic eNOS expression, hippocampal BDNF expression and serum and hippocampal TNF levels were also measured. In aged rats, it was shown that cognitive performances in MWMT and PAT were abolished whereas SBP unchanged. Furthermore, aging resulted in endothelial dysfunction, decreased expressions of thoracic eNOS and hippocampal BDNF, and increased level of TNF in serum and hippocampus. In contrast, ETA improved age-related cognitive deficits and endothelial dysfunction. In addition, ETA reversed changes in protein expression in aged rats. The results of this study indicate that ETA prevents cognitive deficits, endothelial dysfunction, peripheral and neuro-inflammation and decreament of neurotrophin expression in aged rats. These findings suggest that ETA may be beneficial with neuroprotective and vasculoprotective effects in elderly patients.

Amac: Bu calismada, genetik absans epilepsili WAG/Rij sicanlarda kronik etosuksimid (ETS) tedavisinin absans nobetler ve gozlenebilecek olasi kardiyovaskuler degisiklikler uzerindeki etkilerinin arastirilmasi amaclanmistir. Gerec ve Yontem: Iki aylik erkek Wistar ve WAG/Rij sicanlar; Wistar kontrol, Wistar ETS, WAG/Rij kontrol ve WAG/Rij ETS gruplarina ayrilmistir (n=20). ETS gruplari 3 ay boyunca kronik ETS tedavisi (oral, 300 mg/kg/gun) almislardir. Uc aylik tedavi periyodunun sonunda EEG kayitlari kullanilarak diken dalga desarjlarinin (DDD) toplam sure, ortalama sure ve sayisi degerlendirilmistir. Ortalama arteriyel kan basinci (OAB) ve kalp hizi (KH) olcumleri gerceklestirilmistir. Bulgular: ETS tedavisi WAG/Rij sicanlarda DDD’leri toplam sure, ortalama sure ve sayi acisindan anlamli olarak azaltmistir. OAB, WAG/Rij kontrol grubunda Wistar kontrol grubuna gore anlamli olarak artmistir. KH, Wistar ETS grubunda Wistar kontrol grubuna gore anlamli olarak azalmistir. KCl aracili kasilma yanitlarinda Wistar kontrol grubuna gore Wistar ETS grubunda anlamli artma, WAG/Rij kontrol grubunda anlamli azalma saptanmistir. Sonuc: Sonuclarimiz OAB ve vaskuler reaktivitenin WAG/Rij sicanlarda arttigini gostermistir. ETS tedavisi, WAG/Rij sicanlarda kardiyovaskuler parametreleri degistirmezken Wistar sicanlarda KH ve vaskuler reaktiviteyi azaltmis OAB’yi etkilememistir. Bu degisikliklerde T-tipi Ca++ kanallarinin rol oynayabilecegi dusunulmektedir.

Chronic stress is associated with male sexual problems including ejaculatory dysfunctions. The aim of this study was to determine whether resveratrol (RS) or quercetin (QE) has protective effects on vas deferens (VD) contractility in the unpredictable chronic mild stress (UCMS) rat model of depression. Animals were separated into six groups: control, control + RS and control + QE, stress, stress + RS, and stress + QE. Stress groups were subjected to UCMS procedure for 5 weeks. Animals in treatment groups were injected intraperitoneally with RS (20 mg/kg) or QE (30 mg/kg) for 5 weeks during UCMS period. UCMS caused depressive-like behaviors and enhanced systemic levels of corticosterone. The nerve-evoked contractile responses of VD significantly impaired and, noradrenaline- and ATP-induced contractile responses of VD significantly increased in stressed rats. UCMS exposure also markedly enhanced oxidative stress and inflammation in VD tissues. Treatment with RS or QE significantly ameliorated all the aforementioned parameters. The current study demonstrated that RS or QE protected against chronic stress-induced VD dysfunction by their antioxidant and anti-inflammatory effects on VD, suggesting that oxidative stress and inflammation may be synergistic parts in the development of VD dysfunction associated with chronic stress-induced depression.

Pro-inflammatory cytokines have been shown to be associated with the development of seizures in the WAG/Rij rat model of absence epilepsy. Importantly, WAG/Rij rats also exhibit cognitive deficits and depression-like behaviors. It is possible that pro-inflammatory cytokines mediate these comorbid conditions of absence epilepsy given their well-established effects on cognition and affective responses. The current study investigated the potential therapeutic effect of etanercept (tumor necrosis factor inhibitor) on cognitive impairment, depression-like behavior, and spike-wave discharges (SWDs) typically observed in the WAG/Rij rats. Eight-month-old male WAG/Rij rats and Wistar controls were tested in Morris water maze (MWM), passive avoidance (PA), forced swimming, sucrose preference, and locomotor activity tests, and electroencephalogram (EEG) recordings were taken from a separate group of WAG/Rij rats after 8 weeks of etanercept or vehicle treatment. Consistent with earlier work, WAG/Rij rats exhibited cognitive deficits and depression-like behavior. From these, the cognitive deficits and despair-like behavior were rescued by etanercept administration, which also reduced the frequency of SWDs without affecting their duration. Our results support the hypothesis that pro-inflammatory cytokines mediate the absence seizures and comorbid symptoms of absence epilepsy.

Purpose To determine whether resveratrol improves the adverse effects age on vascular function in mesenteric arteries (MAs), and diminishes the hyperactivity in adrenal gland with age. Methods Male F344 x Brown Norway rats were assigned to 6-month control (YC), 6-month resveratrol (YR), 24-month control (OC) and 24-month resveratrol (OR). Resveratrol (15 mg/kg) was provided to resveratrol groups in drinking water for 14 days. Results Concentration response curves to phenylephrine (PE, 10(-9)-10(-5)M), acetylcholine (Ach, 10(-9)-10(-5)M) and resveratrol (10(-8)-10(-4)M) were evaluated in pressurized isolated MAs. The Ach concentration-response curve was right shifted with maximal response diminished in OC compared with YC rats. These effects were reversed by resveratrol treatment. The resveratrol-mediated relaxant responses were unchanged with age or resveratrol suggesting an endothelium-independent mechanism. Resveratrol tended to increase endothelial nitric oxide synthase; caused no effect on copper-zinc superoxide dismutase; and normalized the age-related elevatation in DβH and NPY levels in adrenal medulla, two indicators of sympathetic activity. Conclusion These data indicate that resveratrol reverses age-related dysfunction in endothelium-dependent vasodilation in MAs and partially reverses hyperactivity of adrenomedullary function with age. This treatment may have a therapeuticpotential in the treatment of cardiovascular diseases or hypertension in the elderly.

OBJECTIVES: The impairment of cognitive functions in diabetes mellitus (DM) is well known. Nitric oxide (NO)-guanyly cyclase (GC)-cyclic guanosine monophosphate (cGMP) pathway is an important role in cognitive functions, and, consequently, phosphodiesterase-5 (PDE-5) inhibitors as well as NO-GC activators are of considerable interest in the treatment of cognitive deficits. Therefore, we aimed to investigate the effects of YC-1 (3-5-hydroxymethyl-2-furyl)-1-benzyl-indazole), an NO-GC activator, and zaprinast, a PDE-5 inhibitor, on cognitive dysfunction in streptozotocin (STZ)-induced diabetic rats. METHODS: Male Wistar rats were divided into five groups (nine rats in each): Control, Vehicle (DMSO), Diabetic (50 mg/kg/i.p. streptozotocin), Diabetic-YC-1 (1 mg/kg/day/i.p., for 4 weeks), and Diabetic-Zaprinast (10 mg/kg/day/i.p., for 4 weeks) group. The Morris water maze, passive avoidance, locomotor activity, and foot shock sensitivity tests were applied to assess the effect of YC-1 and zaprinast on learning and memory. To explore the mechanisms of YC-1 and zaprinast on learning and memory performance, protein expressions of brain-derived neurotrophic factor (BDNF) in hippocampus were examined immunohistochemically. RESULTS: Thirty days after the induction of DM, rats exhibited severe learning and memory dysfunctions associated with decreased BDNF expression. Both chronic YC-1 and zaprinast treatment improved cognitive performance and hippocampal BDNF expression in diabetic rats. In the locomotor activity and foot shock sensitivity test, no significant differences were observed between the groups. Furthermore, hyperglycaemia did not affect cognition enhancement effects of YC-1 or zaprinast in diabetic rats. CONCLUSIONS: Our findings highlight the beneficial effects of nitric oxide-guanylyl cyclase activators and PDE-5 inhibitors to improve cognitive function in diabetes.

31st Congress of the European-College-of-Neuropsychopharmacology (ECNP) -- OCT 06-09, 2018 -- Barcelona, SPAIN WOS:000458400500354 Background: Diabetes mellitus (DM) is associated with modest impairments in cognition. Common molecular pathways to cellular and metabolic dysfunction have been implicated in both DM and cognitive dysfunctions. It has been shown in rodent models that cognitive impairment might be an adverse effect of diabetes. These models are being increasingly used to study pathogenesis and to develop new treatments [1,2]. Agmatine is an endogenous guanidoamine produced from L-arginine in many organs, including brain. Studies suggest that agmatine could be regarded as a neurotransmitter and shown to facilitate memory and learning in rats, in scopolamine-induced amnesia, streptozotocin (STZ)-induced Alzheimer model and chronic stress-induced depression [3]. Hence, the present study was conducted to examine the effect of agmatine as a possible antidiabetic agent in STZ-induced diabetes mellitus (DM) model in rats by evaluating cognitive functions, molecular mechanisms of neuroinflammation and neuroplasticity besides histological changes due to astrosit/microglial activation. European Coll Neuropsychopharmacol

Diabetes is one of the risk factors for the development of vascular dementia (VD), leading to endothelial dysfunction and cognitive impairment. Resveratrol has been shown to have antioxidant, antiinflammatory, and neuroprotective effects. The previous studies have also reported that resveratrol improves cognitive and vascular endothelial functions in several pathological conditions. In the present study we aimed to evaluate the effect of resveratrol on cognitive and vascular endothelial function and to explore the mechanisms of its effects in the streptozotocin-induced diabetic rat model of VD. Male Wistar rats were divided into 3 groups (n = 10 in each group): Control, diabetes (DM), DM + resveratrol (DM + RSV) groups. Rats from the DM + RSV group received resveratrol (20 mg/kg/day, ip) for 4 weeks after induction of diabetes and then cognitive functions of the rats were tested by the Morris water maze and a passive avoidance tests. After behavioral tests, endothelial function of thoracic aorta (the endothelium-dependent and -independent vasorelaxant responses) was investigated. To explore the mechanisms of resveratrol, endothelial eNOS, aortic superoxide dismutase (SOD), NADPH oxidase, heme oxygenase-1 (HO-1) levels, TNF-α and IL-1β expressions; serum SOD and NADPH oxidase levels and, hippocampal BDNF, TNF-α and IL-1β expressions were measured. It was shown that DM resulted in severe learning and memory deficits associated with endothelial dysfunction, increased expression of TNF-α and IL-1β, increased oxidative stress levels and decreased expression of eNOS and BDNF. In contrast, resveratrol treatment improved the cognitive decline. It was also found that chronic treatment with resveratrol ameliorated the impaired vascular reactivity. Reveratrol significantly reversed diabetes-induced changes of protein expression. Our data suggest that resveratrol prevents memory deficits, endothelial dysfunction, increased oxidative stress, inflammation and impairment of neurotrophin expression in a VD rat model. Thus, the vasculoprotective and neuroprotective effects of resveratrol may be beneficial in DM patients.

Psychological stress may lead to erectile dysfunction (ED), and inflammation has been evaluated as a major contributing factor. The goal of this study was to investigate the effects of etanercept (ETN), an anti-tumor necrosis factor α (TNF-α) protein, on cavernosal function in the unpredictable chronic mild stress (UCMS) rat model of depression. Animals were divided into 4 groups: animals not exposed to UCMS, animals not exposed to UCMS and treated with ETN, animals exposed to UCMS, and animals treated with ETN while exposed to UCMS. UCMS significantly impaired the neurogenic and endothelium-dependent relaxation responses; reduced cavernosal endothelial nitric oxide (NO) synthase (eNOS) and neuronal NO synthase (nNOS) expressions; decreased testosterone levels; enhanced systemic levels of corticosterone, TNF-α, interleukin 1β (IL-1β), interleukin 6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), and intercellular adhesion molecule 1 (ICAM-1); and also increased cavernosal levels of TNF-α, IL-1β, and IL-6 in rats. ETN administration restored NO-mediated neurogenic and endothelium-dependent relaxation responses of the corpus cavernosum, increased cavernosal eNOS and nNOS expressions, enhanced testosterone levels, and decreased corticosterone levels in UCMS-exposed rats. Also, systemic inflammatory markers and cavernosal proinflammatory cytokine levels were reduced by ETN. Our results demonstrate the role of TNF-α-mediated inflammation in the development of depression and ED in rats exposed to chronic stress.

Objective: Purinergic 2X7 receptor (P2X7R) activation is known to be involved in pathogenesis of depression. Our aims were to investigate P2X7R-activated inflammasome pathways in parallel with induction of depression and to test the antidepressant-like effects of the selective P2X7R antagonist Brilliant Blue G (BBG) in a rat model of chronic unpredictable mild stress (CUMS). Methods: Male Wistar albino rats were divided into control, CUMS, CUMS+BBG25 (25 mg/kg/day) and CUMS+BBG50 (50 mg/kg/day) groups (n=10 for each group). Various stressors were applied to rats for 6 weeks to establish the CUMS model and daily BBG treatment was started at the end of 3rd week. Sucrose preference test and forced swim test (FST) were performed to assess antidepressant-like effects. Brain samples were obtained for real-time polymerase chain reaction and immunohistochemistry analysis. Results: In FST, duration of immobility was reduced in the CUMS+BBG50 group. Also, BBG treatment significantly enhanced sucrose preference. While NLRP3 gene expression levels were unchanged in rats exposed to the CUMS protocol, expression levels of other inflammasome pathway factors NLRP1, caspase-1, ASC, NF-kappa B, IL-1 beta, IL-6 and P2X7R were increased. BBG treatment reduced expression levels of these factors. Likewise, Iba-1 and GFAP immunoreactivities were enhanced by the CUMS protocol and this action was reversed by BBG treatment. Conclusion: Chronic administration of BBG in CUMS model results in antidepressant-like activity in a dose dependent manner. Molecular and histological results show that these effects might be at least partially related to the suppression of inflammasome-related neuroinflammatory responses and suggest involvement of NLRP1 in depression.

Introduction Diabetes is associated with anxiety and depression. Resveratrol, one of the most potent natural polyphenols with antioxidant properties, has been demonstrated to have benefits against diabetes. In the current study, we investigated the effects of resveratrol on depression and anxiety-like behaviors in diabetic rats. Methods Adult male Wistar albino rats were assigned for control and diabetic groups, and these groups were divided into four subgroups as follows: Saline-treated, DMSO-treated, resveratrol-treated and imipramine-treated animals (n=10). Diabetes was induced by a single intraperitoneal injection of streptozotocin (STZ) (50 mg/kg), and 2 days after the STZ injection the rats having hyperglycemia (>300 mg/dl) were assigned to be diabetic. Rats in treatment groups were injected intraperitoneally with resveratrol (20 mg/kg) and imipramine (10 mg/kg) for 4 weeks. After 4-week-treatment period, tail suspension test (TST), forced swimming test (FST), elevated plus maze test (EPM) and locomotor activity test were performed. Blood samples were collected to estimate serum superoxide dismutase (SOD) and NADPH oxidase (Nox) levels. Results Diabetic rats displayed depressive-like behaviors in the FST and TST, and anxiety-like behaviors in the EPM. Resveratrol and imipramine decreased anxiety-like and depressive-like behaviors without affecting locomotor activity in diabetic rats. A significant reduction in SOD levels and a marked increase in Nox levels were observed in diabetic rats. Resveratrol treatment normalized these levels, while imipramine did not affect neither SOD nor Nox levels. Conclusion This study indicates that chronic resveratrol treatment may able to treat comorbid anxiety-and depressive-like behaviors in diabetes through inhibition of oxidative stress.

Background The aim of this study was to investigate the effects of a potent nitric oxide-guanylate cyclase activator, 3-(5′-hydroxymethyl-2′-furyl)-1-benzylindazole (YC-1), on learning and memory functions in aged rats. Material/Methods Rats were divided into 2 groups as 4-month-old and 24-month-old rats. Rats received YC-1 (1 mg/kg/day) for 2 weeks long-term. Morris water maze (MWM) and passive avoidance (PA) tests were used to determine learning and memory functions. Results In the MWM test, there is a significant increase in the acquisition latency (1–4 days) of 24-month-old rats. There is a significant reduction in the “time spent in the escape platform’s quadrant” in 24-month-old rats compared to 4-month-old rats in the probe trial of the MWM test. YC-1 treatment reversed the reduction of the “time spent in the escape platform’s quadrant” of 24-month-old rats. In the PA test, there was no significant difference in the 1st-day latency of rats in all groups. On the 2nd day, retention latency significantly decreased in the 24-month-old rats compared to 4-month-olds. YC-1 reversed the diminished retention latency in 24-month-old rats. YC-1 treatment and aging did not affect results of the locomotor activity test or the foot-shock sensitivity test, suggesting our results were not due to a change in motor activity or disability of the animals. Conclusions Our findings suggest that activation of the NO-sGC-cGMP pathway plays an important role in spatial and emotional learning and memory functions in aged rats.

Sexual dysfunction is a common and underestimated effect of antidepressants. However, the mechanism by which these drugs cause erectile dysfunction is unclear. We investigated the reactivity of the corpus cavernosum of rabbits that were treated with either chronic imipramine, which is a tricyclic agent; agomelatine, which is a melatonergic agonist and serotonin 5HT(2c) antagonist; or moclobemide, which is a reversible inhibitor of monoamine-oxidase A. Twenty rabbits were randomly divided into four groups: the control group (n=5), the imipramine-treated group (n=5), which received i.p. injections of 10 mg/kg/day of imipramine, the moclobemide-treated group (n=5), which received i.p. injections of 20 mg/kg/day of moclobemide, and the agomelatine-treated group (n=5), which was orally administered 10 mg/kg/day of agomelatine. The reactivities of corpus cavernosum tissue obtained from the antidepressant-treated and the control groups were studied in organ chambers after the animals were subjected to 21 days of drug administration. The acetylcholine-induced endothelium-dependent and the electrical field stimulation (EFS)-induced neurogenic relaxation of the corpus cavernosum of the imipramine-treated group was significantly decreased compared with the control group. However, neither the acetylcholine- nor EFS-induced relaxation was changed in the moclobemide- or agomelatine-treated groups. There were no change in the relaxant response to the nitric oxide (NO) donor sodium nitroprusside and contractile response to KCl between the groups. This study suggests that chronic imipramine treatment but not agomelatine and moclobemide treatments causes significant functional changes in the penile erectile tissue of rabbits and that these changes may contribute to the development of impotence.

ObjectivePurinergic 2X7 receptor (P2X7R) activation has recently been considered to be involved in depression at least partially by triggering microglial activation. The aim of the present study was to examine whether the chronic administration of brilliant blue G (BBG), a highly selective P2X7R antagonist, has antidepressant-like effects and microglial (Iba-1) immunoreactivity in chronic unpredictable mild stress (CUMS) model in rats.MethodsMale Wistar Albino rats (290–360 g) were divided into groups such as control (saline), CUMS, CUMS + Imipramine (20 mg/kg; i.p.), CUMS + BBG25 (25 mg/kg; i.p.), CUMS + BBG50 (50 mg/kg; i.p.) groups (n = 10–12 in each). In CUMS model, various stressors were applied for 40 days. On day 20, the treatment of BBG was started for 20 days. At the end, sucrose preference and forced swimming tests were performed. Then brains were removed with paraformaldehyde perfusion for Iba-1 immunohistochemical analysis in hippocampus. One-way analysis of variance and Tukey's test were used for statistical analysis.ResultsThe time of immobility in forced swim test was significantly reduced while sucrose preference was increased in Imipramine and CUMS + BBG50 groups compared to control and CUMS groups, respectively. In immunohistochemical experiments, Iba-1 was overexpressed in CUMS group and BBG significantly reduced the overexpression of Iba-1.ConclusionOur results suggest that chronic administration of BBG has an antidepressant-like activity supporting the notion of P2X7 receptors involvement in depression by modulating microglial activation.This research was supported by grant from Marmara University, Scientific Research Projects – SAG-C-YLP-110915-0416 and SAG-E-120613-0233.Disclosure of interestThe authors have not supplied their declaration of competing interest.

Antidepressant therapy is considered as one of the factors leading to male infertility. In this study, the effects of long-term treatment with fluoxetine or venlafaxine were investigated on electrical field stimulation (EFS, 1-64 Hz), noradrenaline (10(-8) to 10(-4) M), serotonin (10(-8) to 10(-4) M), adenosine 5'-triphosphate [ATP (10(-8) to 10(-4) M)] and 80 mM KCl-induced contractile responses in the epididymal and prostatic portions of rat isolated vas deferens strips. Serotonin-induced contractile responses were significantly increased in the epididymal portion of the vas deferens obtained from the fluoxetine-treatment group, whereas in the prostatic portion there was no change. However, venlafaxine treatment had no effect on serotonin responses in the either portion of the vas deferens. Both fluoxetine and venlafaxine treatment significantly inhibited ATP-evoked contractions of the prostatic and epididymal portions of the rat vas deferens, but had no effect on EFS, noradrenaline- and KCl-evoked contractions of the vas deferentia in both portions. In conclusion, these results suggest that chronic treatment with fluoxetine and venlafaxine affects vas deferens motility. Purinoceptors may, at least in part, responsible for the impaired motility in chronic treatment of venlafaxine and fluoxetine.

Nitrergic relaxations of the isolated duodenum, induced by streptozotocin, were investigated in the experimental 8-week diabetes rat model. The effects of elevated glucose were also examined in the incubated duodenal muscles (in Krebs-Henseleit solution containing 44 mM glucose for 6 h) taken from nondiabetic rats. The relaxations induced by electrical field stimulation (EFS) and nicotine were significantly reduced in diabetic rats compared with control rats. Incubating of duodenal tissues in medium containing elevated glucose revealed significantly impaired relaxations to EFS and nicotine compared to responses obtained after normal glucose incubation. However, the relaxant responses to sodium nitroprusside and papaverine were similar in all groups. Incubating in hyperosmolar solutions containing sucrose, the relaxant responses were not affected. In conclusion, impairment of NO-mediated relaxations in diabetes may be related to hyperglycemia. The alterations caused by elevated glucose are not due to a hyperosmotic effect because the same concentration of sucrose had no effect on the relaxations.

Objectives It is now well established that hydrocephalus is associated with impaired bladder function. The aim of this study was to determine the effects of hydrocephalus on bladder smooth muscle (BSM) reactivity in the rat model. Materials and Methods Hydrocephalus was induced in 7-day-old rats by injection of kaolin into the cisterna magna (AH group). Control group rats underwent a sham operation. After 10 days, rats were decapitated. Each bladder was excised and BSM strips placed in an organ bath where contractile and relaxant responses were studied. Results Contractile response of BSM to KCl decreased in the AH group. Increased response to muscarinic agonist carbachol was observed in the AH group. The relaxant response to adrenergic agonist isoprenaline was significantly decreased in the AH group, whereas non–receptor-dependent agonist papaverine was unchanged in 2 groups. Conclusion Bladder smooth muscle reactivity is affected by the formation of hydrocephalus essentially by both receptor-dependent and non–receptor-dependent mechanisms. This pathway may be a novel target for the pharmacologic treatment of bladder dysfunction secondary to hydrocephalus.

The role of nitric oxide (NO) on cognitive performance in a modified elevated plus-maze (mEPM) and passive-avoidance (PA) task was investigated by using the NO synthase (NOS) inhibitor 7-nitroindazole (7-NI) and an NO precursor l -arginine. The interaction between the activation of N -methyl- d -aspartate (NMDA) receptors and NO synthesis on memory retention was also studied. 7-NI, l -arginine or MK-801, a non-competitive NMDA receptor antagonist were injected intraperitoneally (i.p) to male Wistar rats 30 min before the first training session of the PA test or 30 min before on the first day testing (acquisition session) of mEPM task. Transfer latency, the time rat took to move from the open arm to the enclosed arm, was used as an index of learning and memory in a mEPM test. The retention session was performed 24 h after the acquisition one. In the PA task, the retention test was carried out 24 h after training and reduction of retention latency was used to evaluate the acquisition of learning and memory. Blood glucose level and locomotor activity of the rats was also evaluated. 7-NI (10, 20, 25, 50 mg/kg) and MK-801 (0.15 mg/kg) significantly prolonged the transfer latency on retention session in a mEPM test and shortened step-through latency in PA test. 7-NI-induced impairment in memory and learning was partly reversed by l -arginine (200 mg/kg), a competitive substrate for NOS. However subeffective doses of 7-NI (5 mg/kg) and MK-801 (0.075 mg/kg) given in combination significantly impaired plus-maze and PA performances in rats. Thus NMDA receptor mediated NO pathways may be implicated in the PA and mEPM behaviours in rats. Since 7-NI does not affect blood pressure and did not alter blood glucose level and locomotor activity in conscious rats, 7-NI-induced impairment of memory is not due to either hypertension, changes in blood glucose level or effects on locomotor activity.

Aim Esophagitis is associated with an impaired esophageal peristalsis. A few studies have been aimed at understanding the pathophysiology of abnormal peristaltic activity. The mechanism of impaired esophageal smooth muscle reactivity in the chronic gastroesophageal reflux (GER) model is investigated in vitro for the first time. Materials and Methods The chronic GER rat model was created by partial gastric outlet obstruction. The histopathological findings related to esophagitis were evaluated. Smooth muscle strips of the tunica muscularis mucosa of esophagus were studied in standard organ chambers. Carbachol- and KCl-induced contractile responses and serotonin- and papaverine- induced relaxant responses in both reflux and sham-operated control groups were determined. Results Histopathologically, chronic reflux esophagitis was observed in all specimens of the reflux group. Contractile (carbachol- and KCl-induced) smooth muscle responses were significantly decreased in the reflux group. When compared to control group, relaxant response of smooth muscle to serotonin was also significantly decreased in the reflux group. However, there was no difference in papaverine-induced relaxant responses between 2 groups. Conclusions Our study describes the effects of chronic GER on rat esophageal smooth muscle contractility in vitro. We found that both receptor- (carbachol, serotonin) and nonreceptor-mediated (KCl) esophageal smooth muscle reactivity were impaired in chronic reflux esophagitis. These changes may correspond to the functional motor abnormalities of the esophagus seen in patients with chronic reflux esophagitis.

Purpose: An association between chronic renal failure (CRF) and gastroesophageal reflux (GER) is well known. The aim of this study was to pharmacologically characterize and investigate the possible contribution of smooth muscle reactivity pathways involving GER on the CRF rat model. Material and Methods: Chronic renal failure was created in Sprague-Dawley rats by 5 of 6 nephrectomy. The rats were divided into 2 groups: the CRF-induced group (CRF group) and the sham-operated group (control group). Esophageal smooth muscle strips were studied in vitro for their contractile (KCl, carbachol) and relaxant (isoproterenole, serotonin, and papaverine) response to receptor activation in the organ chambers set up. Subsequently, the in vitro lower esophageal sphincter (LES) smooth muscle study was generated by KCl, carbachol, isoproterenole, nicotine, sodium nitroprusside (SNP), and papaverine. Results: Compared with controls, esophageal strips taken from CRF-induced rats associated with decreased smooth muscle responses to carbachol, serotonin, and increased response to KCl. Isoproterenole- and papaverine-induced relaxant responses were not affected. Contractility of the isolated LES strips were significantly increased to KCl and carbachol in the CRF group compared with the control group. Similar relaxant responses were obtained in LES strips stimulated by isoproterenole, SNP, and papaverine in the CRF and control group. Nicotine-induced relaxant responses were decreased in the CRF group compared with the control group. Conclusions: Our study revealed alterations of receptor-dependent esophageal and LES smooth muscle reactivity in the CRF-induced rats. Impaired foregut smooth muscle reactivity may contribute to the development of GER-related functional abnormalities in patients with CRF.

Previous findings have shown that patients with depression express higher levels of proinflammatory cytokines such as TNF-α and IL-6. We have recently found that Infliximab (a TNF-α inhibitor) decreased anhedonia and despair-like behavior in the rat unpredictable chronic mild stress (UCMS) model of depression suggesting that inflammation might play an important role in depression. An increasing number of studies suggest that inflammation is also associated with cognitive impairments. The current study aimed to investigate the effect of UCMS on the cognitive performance of rats and their hippocampal BDNF levels and the effect of chronic Infliximab (5mg/kg/weekly, i.p.) treatment on these measures. Rats were subjected to different types of stressors daily for a period of 56 days to induce depression-like state. The UCMS resulted in impairments in spatial and emotional memory acquisition and retention with no effect on the level of locomotor activity. These behavioral effects of UCMS were accompanied by reduction in the level of BDNF in the CA1 and CA3 regions of the hippocampus. Chronic Infliximab treatment prevented the UCMS-induced cognitive impairments as well as the reduction in the levels of hippocampal brain-derived neurotrophic factor (BDNF). These results suggest that Infliximab improves the spatial and emotional memory impairments induced by chronic stress in rats likely through its effects on hippocampal function by modulating inflammation.

Resveratrol, a polyphenol phytoalexine, has been shown to play a neuroprotective role in the neurodegenerative process in Alzheimer's disease (AD) and improve memory function in dementia. However, the in vivo effect of resveratrol in normal aging models of learning and memory has not yet been evaluated. Therefore, the present neurobehavioral study was undertaken to evaluate the effect of resveratrol on cognitive impairment induced by aging in passive avoidance and Morris water maze (MWM) tests. Male Wistar albino rats were divided into four groups: young control (4month), young resveratrol (4month+RESV), old control (24month) and old resveratrol (24month+RESV). Resveratrol (50mg/kg/day) was given to the 4month+RESV and 24month+RESV groups orally for 12weeks. There was no significant difference between the groups for the first day of latency, while in aged rats, the second day of latency was significantly shortened compared to the young group in the passive avoidance test (p

An association between hydrocephalus and gastroesophageal motor abnormalities that cause gastroesophageal reflux (GER) is well known. Our aim was to investigate hydrocephalus-induced alterations in esophageal and gastric smooth muscle reactivity and their modulation by pharmacological interventions in the rat model.Hydrocephalus was induced in infantile rats by injection of kaolin into the cisterna magna. Hydrocephalic and sham-operated rats were exsanguinated 2 weeks after surgery. Esophageal and gastric fundus smooth muscle strips were studied in vitro for their contractile and relaxant response to receptor activation in the organ chambers set up. Additionally, esophageal and gastric tissue specimens were examined histologically for GER-induced changes.No histological evidence of esophageal and gastric changes reflecting GER was observed in the specimens of the control and hydrocephalus-induced rats. Maximum contractile responses of esophageal and gastric fundus smooth muscle to KCl and muscarinic receptor agonist carbachol were increased in the hydrocephalic groups compared with the control groups. These changes were statistically significant. Relaxant responses to beta adrenoceptor agonist isoprenaline were similar in the esophageal muscle strips of both hydrocephalic groups and the control groups. However, isoprenaline-induced relaxant responses of the gastric fundus muscle strips in the hydrocephalus-induced groups were significantly decreased as compared with the control groups. The relaxant responses to papaverine in the esophageal and gastric fundus smooth muscle strips were similar in the two groups.Our study revealed alterations of receptor-dependent and receptor-independent foregut smooth muscle reactivity in the hydrocephalus-induced rat pups. Therefore, we suggest that impaired smooth muscle reactivity at least in part may contribute to abnormalities of foregut motor function seen in patients with hydrocephalus.

Purpose: The aim of the study was to investigate the gastric smooth muscle reactivity in the Adriamycin-induced esophageal atresia (EA) rat model. Methods: The fetuses were divided into 3 groups. The control group was exposed to saline. The second group was comprised of fetuses that were exposed to Adriamycin but did not have EA (Adriamycin-no-EA group). The third group was comprised of fetuses that were exposed to Adriamycin and had EA (Adriamycin-EA group). Gastric fundus strips were studied in vitro for their contractile response to receptor activation in the 3 groups. Results: Contractile responses of gastric smooth muscle to carbachol and KCl were increased in the Adriamycin-EA group compared with the Adriamycin-no-EA group. Also serotonin-induced contractile response in the Adriamycin-EA group decreased compared with the Adriamycin-no-EA group. Relaxation of gastric smooth muscle strips to isoproterenol was comparably unaffected in the Adriamycin-EA and Adriamycin-no-EA groups. Likewise, no change in the response to agonist studies was observed between the control and Adriamycin-no-EA groups. The relaxant response to papaverine was not different in the 3 groups. Conclusions: This study found changes of receptor-dependent and receptor-independent contraction of the gastric fundus smooth muscle in the fetuses with EA. Therefore, impaired contractile responses may be, at least in part, a contributing factor in the abnormal gastric motility seen in EA.

Purpose. We investigated late effects of caustic lye injury on esophageal smooth muscle reactivity in the rat model. Materials and methods. Male Sprague–Dawley rats were divided into two groups. Through a median laparatomy incision, abdominal esophageal segment was isolated. Orogastric and gastric (via gastrotomy) catheters were placed and tied over the isolated esophageal segment. Saline (0.9%) or 50% sodium hydroxide (1 ml) solution were instilled via orogastric catheter to the isolated segment in the control and caustic esophagus (CE group) groups, respectively. Then, the esophagus was rinsed with 0.9% saline via gastric catheter. The esophagus was removed and studied in organ chambers 28 days after the operation. Results. Carbachol- and KCl-induced contractile responses of esophageal smooth muscle were significantly reduced in the CE group with decreased Emax value compared with the control group. Relaxant responses to serotonin were significantly reduced in the CE group with decreased Emax value compared with the control group. No significant differences were found in Emax and pD2 values for papaverine acting on esophageal strips from the two groups. Conclusion. The results provide evidence that, a surgically created caustic injury causes impaired smooth muscle reactivity that may contribute to esophageal

Muscular contraction of the gallbladder is the primary determinant of bile delivery into duedonum. Gallbladder filling and emptying are influenced by both inhibitory and excitatory stimuli, and NO plays a key role in normal relaxation. In this study, to determine whether nicotine acts on the gallbladder muscle, the mechanism of its effect on strips of guinea pig gallbladder was studied in vitro.Guinea pig gallbladder muscle strips were mounted in organ bath with modified Krebs-Henseleit solution and aerated with Carbogen. Tension was measured with isometric force transducers, and muscle relaxation was expressed as percent decrease of precontraction induced by carbachol.Nicotine produced concentration dependent relaxation when preparations were precontracted by carbachol (10(-6) M). Nicotine-induced relaxation was 51.6 +/- 3.2% of phenylephrine contraction and was not affected by guanethidine (10(-5) M), propranolol (10(-6) M), hexamethonium (10(-4) M), indomethacin (10(-5) M), N(w)-nitro L-arginine methyl ester (L-NAME) (3 x 10(-5) M), methylene blue (10(-5) M), glibenclamide (10(-5) M), clotrimazole (10(-6) M), tetraethylammonium (3 x 10(-4) M), or 4-aminopyridine (10(-3) M). Nicotine did not exhibit a calcium antagonizing effect.From these results, we concluded that nicotine-induced relaxation of the guinea pig gallbladder is not mediated by the release of noradrenaline, nitric oxide (NO), prostaglandins, or a related substance, or by the activation of potassium channels, or by the stimulation of nicotinic cholinoceptors. Further work is needed to determine the cellular mechanism(s) of action by which nicotine acts on gallbladder smooth muscle.

Diabetes mellitus (DM) is related to an increase in the incidence of vascular dementia. Inflammation is an important cause of endothelial dysfunction and cognitive deficits. The anti -tumor necrosis factor (TNF)-α fusion protein etanercept has been reported to exhibit memory-enhancing effects and endothelial protection. We tested the effect of etanercept on the cognitive endpoints and compared it with the cognitive dysfunction in streptozotocin (STZ )- induced DM rats by using the Morris water maze test (MWMT) and passive avoidance test (PAT). Systolic blood pressure (SBP), thoracic endothelial function, endothelial nitric oxide synthase (eNOS) expression, and hippocampal brain-derived neurotrophic factor (BDNF) expression were assessed. Thirty days after the induction of DM, rats exhibited severe learning and memory deficits associated with endothelial dysfunction and decreased expression of eNOS and BDNF. Chronic treatment with etanercept (0.8 mg/kg, s.c., every week for 30 days) improved cognitive performance, endothelial function, and expression of eNOS and BDNF in DM rats. Furthermore, the memory-improving effects of etanercept were independent of hyperglycemia. These data suggest that etanercept treatment prevents changes in endothelial function, eNOS expression, and hippocampal expression of BDNF and, consequently, vascular dementia in DM rats.

Inflammation has been suggested to be associated with stress-induced depression and cardiovascular dysfunction. Tumor necrosis factor alpha (TNF-α) is a major cytokine in the activation of neuroendocrine, immune, and behavioral responses. In this study, we investigated the effects of infliximab (a TNF-α inhibitor) on endothelium-dependent vascular reactivity, systemic blood pressure, and endothelial nitric oxide synthase (eNOS) immunoreactivity in the unpredictable chronic mild stress (UCMS) model of depression in rats. There was no significant change between all groups in the systemic blood pressure. In UCMS, endothelium-dependent relaxation of the smooth muscle in response to carbachol was significantly decreased with 50 % maximal response (E max) and pD2 values compared with the controls. Infliximab was able to reverse this UCMS effect. Relaxation in response to the nitric oxide (NO) donor sodium nitroprusside and papaverine and KCl-induced contractile responses was similar between groups. In UCMS, decreased expression of eNOS was detected. Moreover, there was no significant change in UCMS + infliximab group with respect to control rats. Our results suggest that tumor necrosis factor-alpha (TNF-α) could be a major mediator of vascular dysfunction associated with UCMS, leading to decreased expression of eNOS.

Objective To investigate the effects of chronic ethanol consumption on the reactivity of detrusor smooth muscle. Materials and methods Eight male rats received ethanol (7.2% v/v) in a modified liquid diet for 4 weeks. Two control groups were assessed; eight rats in one group were fed sucrose and received a liquid diet, and 12 rats in the second group received standard rat chow and water for 4 weeks. The reactivity of detrusor smooth muscle strips from ethanol-fed animals and control animals was evaluated in organ chambers. Results The relaxation response elicited by isoprenaline or adenosine was unaffected in the both control groups while it was significantly inhibited, with decreased maximum responses and pD2 values, in the ethanol-fed group. Contractile responses of detrusor smooth muscle to carbachol or 80 mmol/L KCl and relaxant responses to papaverine were similar in the control groups and the ethanol-fed group. There was no change in agonist potency among the groups. Conclusion Chronic ethanol consumption impairs β-adrenoceptor- and purinoceptor-mediated relaxation but not cholinoceptor-mediated contraction of the rat detrusor smooth muscle. Thus, it appears that different regulatory mechanisms are involved in ethanol-induced alterations in β-adrenergic, purinergic and muscarinic receptors in detrusor strip.

WOS: 000167513000008, PubMed ID: 11313837, An experimental study was done to examine a potential role of phosphodiesterase (PDE) inhibitors in the treatment of diabetic erectile dysfunction, Relaxant effect of specific PDE inhibitors were measured in strips of corpus cavernosum smooth muscle taken from control and diabetic groups. Diabetes mellitus was induced in New Zealand white rabbits using alloxan, Penises excised from diabetic rabbits 8 weeks after the induction of diabetes mellitus, In the organ bath strips from control and diabetic rabbit corpus cavernosum were precontracted and increasing doses of several PDE inhibitors were added. In the precontracted rabbit cavernous tissue, sulmazole and zaprinast specific PDE V inhibitors were equally potent and efficacious in vitro but amrinone, a specific PDE III inhibitor, exhibits low relaxant effects. All PDE inhibitors tested showed a similar relaxation effect on corpus cavernosum smooth muscle from control and 8-week diabetic rabbits, The present study provides the possibility of using selective PDE III and V inhibitors in the treatment of diabetic impotence.

An animal model was developed to elucidate the effect of chronic obstruction of the internal pudendal artery on the responsiveness of the corpus cavernosum. In male albino rabbits, the internal pudendal artery was chronically ligated unilaterally with a silk tie and the occlusion was maintained for 1 month. The control group was sham-operated. The reactivity of corpus cavernosum tissue from the ligated animals and the control animals was studied in organ chambers. Unilateral chronic ligation of the internal pudendal artery caused an impaired contractile response to α-adrenoceptor stimulation with decreased Em and pD2 values and an impaired relaxant response to electrical field stimulation but resulted in a marked increase in the endothelium-dependent relaxant response to carbachol with an increased pD2 value. However chronic obstruction of the pudendal artery had no effect on adenosine-, papaverine- and sodium nitroprusside-induced relaxant responses, and there was no change in agonist potency. These data indicate that altered penile hemodynamics have an effect on the reactivity of the corpus cavernosum and may contribute to the etiology of impotence.

Succinic acid monomethyl ester (SAM) was recently proposed as an insulinotropic tool in non-insulin-dependent diabetes mellitus. The present study was designed to define whether SAM has the vascular effect in thoracic aorta of streptozotocin (STZ)-diabetic rats. (1) Body weights of diabetic rats were significantly increased after SAM treatment (P0.05). (2) Ten-day SAM treatment did not significantly affect blood glucose levels in SAM-treated control and SAM-treated STZ-diabetic rats. (3) Maximum tension responses to noradrenaline and KCl (80 mmol l-1) were not significantly different among all the experimental groups. (4) pD2 (-log EC50) values for noradrenaline of untreated diabetic rats were significantly less than those of controls, SAM-treated control and SAM-treated diabetic rats (P0.01, P0.001 and P0.05, respectively). SAM treatment normalized the decreased sensitivity of noradrenaline response in diabetic rats. (5) Fast, slow and total components of responses to noradrenaline (10(-5) mol l-1 approximately equal to EC90) were not significantly different among all the experimental groups. (6) There were no significant differences between aorta precontracted with noradrenaline from controls and STZ-diabetic (untreated and SAM-treated) rats in pD2 values and the potency of maximum relaxation to acetylcholine or in pD2 values to sodium nitroprusside. In conclusion, 10-day SAM treatment increases the sensitivity of diabetic-aortic rings to noradrenaline compared to untreated diabetic control rats.

WOS: 000072668400005, PubMed ID: 9566022, It is known that diabetes mellitus alters the vascular responsiveness to several vasoconstrictors and vasodilators. Endothelium-derived nitric oxide is a potent endogenous nitrovasodilator, and endothelin-1 (ET-1) is a potent endothelium-derived vasoconstrictor substance. They play a major role in the modulation of vascular tone. Selective impairment of endothelium-dependent relaxation and impaired vasoconstriction in response to ET-1 could result in vascular disorders. The purpose of our study was to determine whether vascular responses to ET-1 and endothelium-dependent relaxing substances are impaired in rats with streptozotocin-induced diabetes of 2 weeks duration. Endothelium-dependent relaxations produced by carbachol and ATP in aortic rings precontracted with phenylephrine were significantly attenuated in rings from diabetic rats, but the endothelium-independent relaxations produced by sodium nitroprusside and adenosine in diabetic preparations were not changed when compared to the corresponding controls. The ET-1-induced contractions were significantly attenuated with no change in agonist potency (pD(2) value) in aortae with and without endothelium obtained from diabetic rats when compared to those from controls. Mechanical removal of the endothelium did not significantly change ET-1 responses of aortae from either diabetic or control rats compared with responses of aortae with intact endothelium. These results suggest that, in this diabetic model, the contractile responsiveness of thoracic aortic muscles and the endothelial functions are significantly altered during 2 weeks of diabetes.

Growing evidence indicates that there is a correlation between depression and inflammation. Administration of anti-tumor necrosis factor (TNF) agents for treatment of chronic inflammatory diseases, such as psoriasis, was associated with decreased depressive symptoms and increased quality of life in some clinical studies. The aim of the present study was to investigate the effects of chronic etanercept, a TNF-α inhibitor, on anxiety- and depression-like neurobehaviors in rats. Male rats were treated for 8 weeks with either saline or etanercept (0.8 mg/kg/week, subcutaneously). The anxiety levels of rats were evaluated using the elevated plus maze, a classical rodent model of anxiety and depression was measured using the force swimming test, a behavioral despair task. The anxiety-like neurobehaviors of the animals were found significantly decreased after the etanercept treatment. Etanercept significantly decreased immobility time in rat model of despair test, seemed to have an antidepressive effect in rats. Compared to saline treatment, long-term etanercept treatment had no effect on the total number and pattern of locomotor activities. Findings of the study supported the hypothesis that TNF-α has a role in the modulation of emotional processes and its inhibition may represent a novel strategy for the treatment of affective disorders.

WOS: A1996UE76500005, PubMed ID: 8724877, Obstructive jaundice is associated with a predisposition to systemic hypotension and acute renal failure. Altered vascular reactivity may contribute to the development of hypotension. In this experimental study on dogs, alterations in vascular contractile responses to noradrenaline, serotonin and KCI were investigated. Contractile responses to noradrenaline, serotonin,,, KCI and relaxation responses to papaverin and acetylcholine were provoked in isolated femoral arteries of both control dogs and animals with obstructive jaundice. In this situation concentration-response curves of noradrenaline and serotonin were blunted when compared with controls. This blunting disappeared when endothelium was removed. In rings precontracted with phenylephrine, EDRF relaxation responses to acetylcholine were increased significantly as compared to controls; at lower concentrations maximal relaxation response occured. Contractile responses to KCI and relaxation responses to papaverin did not differ between the groups, endothelium present or removed. These results indicate that obstructive jaundice induces a decrease in vascular contractile responses and an increased EDRF relaxation response. We suggest that an excess in the amount of released EDRF may be one of the causes inducing systemic hypotension in obstructive jaundice.

Stress has been recognized as a risk factor for cardiovascular disease and depression, but the correlation is not well understood. However, inflammation is known to have a crucial role in both cardiovascular disease and depression. Tumor necrosis factor alpha (TNF-α) is a major cytokine for the activation of neuroendocrine, immune and behavioral responses. Therefore, we aimed to explore the effects of etanercept, an anti-TNF-α fusion protein, on endothelium-dependent vascular reactivity, blood pressure and endothelial nitric oxide synthase (eNOS) immunoreactivity in a model of unpredictable chronic mild stress (UCMS). Male rats were exposed to UCMS for 8 weeks, and etanercept (0.8 mg/kg, weekly) was administered during UCMS induction. The systolic blood pressure was recorded by the tail cuff method, and the relaxant responses of the aorta induced by carbachol, sodium nitroprusside (SNP) and papaverine were evaluated in an isolated organ bath system. UCMS rats exhibited an impaired carbachol-induced relaxant response compared to control rats, but there were no significant differences in the SNP- and papaverine-induced relaxant responses between the control and stressed rats. Etanercept treatment improved the carbachol-induced endothelium dependent relaxations observed in rats that experienced UCMS. No significant change in the systemic blood pressure was observed, but decreased expression of eNOS was detected in the UCMS group. Moreover, there were no significant changes in the etanercept treatment group compared to the control rats. Our results suggest that TNF-α could be a mediator of vascular dysfunction associated with UCMS, which leads to decreased expression of eNOS.

Pro-inflammatory cytokines have been proposed to be associated with the pathogenesis of depression. Consistent with this notion, several clinical observations have suggested the antidepressant efficacy of TNF-α inhibitors in patients with chronic inflammatory diseases. In this study, we evaluated the antidepressant and anxiolytic effects of chronic TNF-α inhibitor (infliximab, 5 mg/kg, i.p., weekly) administration in the chronic mild stress (CMS) model of depression. Rats were divided into three groups: saline-control (no stress), saline-CMS, and infliximab-CMS. Rats in the latter two groups were exposed to CMS for 8 weeks. Saline (former two groups) or infliximab was injected weekly during this period. After CMS, total locomotor activity, anxiety-like behaviour and depression-like behaviours were evaluated using automated locomotor activity cage, elevated plus maze (EPM), and sucrose preference (SPT) and forced swimming (FS) tests, respectively. As expected, the saline-CMS group exhibited higher depression-like behaviours in FS and SPT tests compared with the saline-control group. There were no differences between these two groups in terms of the anxiety-like behaviour or total locomotor activity. Infliximab reduced the depression-like behaviour of CMS rats compared with saline-CMS group, and anxiety-like behaviour of CMS rats compared with saline-CMS and saline-control groups. Our findings suggest that chronic and systemic TNF-α inhibition reduced depression and anxiety-like behaviour in the CMS model of depression in rats.

Epidemiological evidence showed that chronic ethanol consumption is a major risk factor in the development of impotence. The present study investigated the effects of carbachol-, electrical field stimulation (EFS)-, sodium nitroprusside (SNP)- and papaverine-induced relaxant responses in the isolated corpus cavernosum tissues from rabbits submitted to an 12-week course of chronic low (5% v/v) or high ethanol intake (30% v/v). Increased carbachol- and EFS-induced relaxant responses but not SNP and papaverine, were observed in low ethanol-fed rabbits compared with controls. However, impaired carbachol- and EFS-induced relaxant responses were observed in high ethanol-fed rabbits compared with control rabbits. There were no significant differences in SNP- and papaverine-induced relaxant responses between control and high ethanol-fed rabbits. In addition, decreased neuronal nitric oxide synthase (nNOS) and endothelial NOS (eNOS) immunoreactivity in penile tissue were found in high ethanol-fed rabbits, but increased the immunoreactivity in low ethanol-fed group, compared with control group. These results suggest that alterations in nitric oxide (NO) production within the cavernous tissue in the high ethanol-fed rabbits are, at least in part, responsible for the erectile dysfunction. Kocaeli University Research FundKocaeli University [200319] This study was supported by a grant from Kocaeli University Research Fund (Project number: 200319). Research Foundation had no further role in the study design, in the collection, analysis and interpretation of data, in the writing of the report and in the decision to submit the paper for publication.

Depression is the most common psychiatric disorder. It is well established that endogenous nitric oxide (NO) contributes to chronic unpredictable mild stress (CUMS)-induced depression. The aim of this study was to investigate brain-derived neurotropic factor (BDNF) expression in CUMS-induced depression-like behaviour in rats. Rats were exposed to CUMS for 5 weeks. A specific and selective nNOS inhibitor, 3-bromo-7-nitroindazole (3-Br-7-NI; 20 mg/kg/day, i.p.), and a specific soluble guanylate cyclase (sGC) inhibitor, 1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one (ODQ; 10 mg/kg/day, i.p.), were administered during CUMS. The forced swimming test (FST) was used to assess despair and sucrose consumption, and sucrose preference test was used to assess anhedonia that are the main symptoms of the depression. We show that both 3-Br-7-NI and ODQ administration during CUMS suppressed CUMS-induced, depression-like behavioural changes, including reduced sucrose preference, body-weight and locomotor activity as well as increased immobility time in the FST. CUMS also significantly decreased BDNF protein levels in the CA1 and CA3 regions of the hippocampus, which was reversed by 3-Br-7-NI and ODQ administration. Our findings suggest a novel role for nNOS and sGC-cGMP in the development of the CUMS model of depression.

Recent clinical studies revealed emotional and cognitive impairments associated with absence epilepsy. Preclinical research with genetic models of absence epilepsy however have primarily focused on dysfunctional emotional processes and paid relatively less attention to cognitive impairment. In order to bridge this gap, we investigated age-dependent changes in learning and memory performance, anxiety-like behavior, and locomotor activity of WAG/Rij rats (a valid model of generalized absence epilepsy) using passive avoidance, Morris water maze, elevated plus maze, and locomotor activity cage. We tested 5 month-old and 13 month-old WAG/Rij rats and compared their performance to age-matched Wistar rats. Results revealed a decline in emotional and spatial memory of WAG/Rij rats compared to age-matched Wistar rats only at 13 months of age. Importantly, there were no significant differences between WAG/Rij and Wistar rats in terms of anxiety-like behavior and locomotor activity at either age. Results pointed at age-dependent learning and memory deficits in the WAG/Rij rat model of absence epilepsy., NA

Antidepressants, including selective serotonin reuptake inhibitors (SSRIs), cause erectile dysfunction: however, the mechanism by which they cause erectile function is unclear. We investigated the reactivity of the corpus cavernosum after chronic fluoxetine treatment in rabbits. Twelve rabbits were randomly divided into two groups: control (n = 6) or 20 mg/kg/day of fluoxetine delivered i.p. (n = 6). The reactivity of the corpus cavernosum tissue from the fluoxetine-treated and control groups was studied in organ chambers after 21 days of fluoxetine injection. In the fluoxetine-treated group, endothelium-dependent relaxation of the corpus cavernosum in response to acetylcholine was significantly decreased compared to the control group. However, the sensitivity (i.e., pD(2)) of the fluoxetine-treated cavernosal tissue strips to acetylcholine was not changed with respect to controls. Electrical field stimulation (EFS)-induced neurogenic relaxation was also significantly reduced in the fluoxetine-treated group. Relaxation in response to the nitric oxide (NO) donor sodium nitroprusside was similar between the cavernosal tissues from the two groups. There was also no change in agonist potency between the two groups. Additionally, chronic fluoxetine treatment had no effect on KCl-induced contractile responses. When tissue contraction was produced with phenylephrine to study relaxation in response to various stimuli, the tension induced was similar between the fluoxetine-treated and control groups. This study suggests that chronic fluoxetine treatment causes significant functional changes to the penile erectile tissue of rabbits, and these changes may contribute to the development of impotence. (C) 2011 Elsevier B.V. All rights reserved.

Aims The influence of 3-bromo-7-nitroindazole (3-Br 7-NI), a potent and selective neuronal nitric oxide synthase (nNOS) inhibitor, and [1H-[1,2,4]-oxadiazole[4,3a]-quinoxaline-1-one] (ODQ), a highly selective, irreversible inhibitor of soluble guanylate cyclase (sGC), on working and reference memory and emotional learning was investigated in rats. Main methods The effects were assessed in the three-panel runway and step-down passive avoidance task, respectively. Key findings 3-Br 7-NI (5, 10, and 20 mg/kg) and ODQ (5, 10, and 20 mg/kg) significantly increased the number of errors and latency of both working and reference memory performance of rats and impaired retention for the passive avoidance task. The effect of 3-Br 7-NI was reversed by l -arginine (250 mg/kg). Significance Findings of the study supported the hypothesis that nNOS inhibition disrupts reference and working memory processes in terms of an impairment in the strategies used for solving learning tasks, and, according to these results, nNOS-sGC may be required for emotional learning and both reference and working memory.