Therapeutic Effects of AF219 on Interstitial Cystitis/Bladder Pain Syndrome Induced by Cyclophosphamide or Water Avoidance Stress in Rats.

INTRODUCTION AND HYPOTHESIS: To evaluate the effect of AF219, a P2X3 receptor antagonist, in animal models of interstitial cystitis/bladder pain syndrome (IC/BPS) induced by cyclophosphamide (CYP) or water avoidance stress (WAS). METHODS: Thirty-two adult female Wistar albino rats were used in each IC/BPS model. Assessment of nociception and anxiety and severity of inflammation in the bladder were assessed by behavioral experiments and histopathological examinations respectively. The contraction responses of the bladder were evaluated in vitro and protein levels of P2X3, P2X7, Trk-A, TRPV1, and TRPA1 were analyzed by Western blot. RESULTS: The IC/BPS groups had shorter response times to noxious stimuli, exhibited more anxiety-like behavior, had higher inflammation-based histological scores, and showed greater increased contraction responses to carbachol, adenosine triphosphate, and electrical field stimulation in in vitro bladder strips than controls for both models (p < 0.05). The improvements in behavioral and bladder contraction responses and inflammation scores in the IC/BPS + AF219 groups were similar to control findings (p > 0.05). Exposure to WAS or CYP increased P2X3 expression in the bladder compared with the controls (p < 0.05). Apart from TRPA1, the levels of P2X7, Trk-A, and TRPV1 were also higher in the IC/BPS groups than in the controls (p < 0.05). No significant differences were observed between IC/BPS + AF219 and controls regarding P2X3, P2X7, Trk-A, and TRPV1 in the WAS model (p > 0.05). Moreover, P2X3 and P2X7 levels were significantly lower in IC/BPS + AF219 than in the AF219-untreated WAS model (p < 0.05). CONCLUSIONS: These findings suggest that P2X3 receptors play a significant role in bladder functional responses, nociception, and also the pathogenesis of IC/BPS. AF219 may be a promising therapeutic strategy for IC/BPS. Comparing AF219 with current IC/BPS treatment agents in future studies may yield valuable insights into its efficacy.

Etanercept Ameliorates Vascular, Endocrine, and Ovarian Changes in a Rat Model of DHEA-Induced Polycystic Ovary Syndrome.

Polycystic ovary syndrome (PCOS) is a metabolic and endocrine disorder affecting women of reproductive age. This study examined the efficacy of etanercept (ETA), an anti-TNF-α drug, in alleviating endocrine, metabolic, and vascular dysfunction in a rat model of PCOS. Prepubertal female Wistar rats were divided into three groups: control, PCOS, and PCOS+ETA. The PCOS groups received dehydroepiandrosterone (DHEA) treatment, whereas the PCOS+ETA group received both DHEA and ETA. After 35 days, various biomarkers were evaluated, including systemic blood pressure, endothelial function, and eNOS and TNF-α expression levels in the thoracic aorta and ovaries. The PCOS group exhibited ovarian morphological changes, increased body weight, and hormonal imbalances, whereas the PCOS+ETA group showed restored levels of these parameters. Systemic blood pressure, urinary albumin levels, and protein excretion did not differ significantly differ among the groups. Endothelium-dependent relaxation, eNOS expression, TNF-α expression in the thoracic aorta, and TNF-α expression in the ovaries were restored to normal levels in the PCOS+ETA group. Furthermore, ovarian morphology was improved in the PCOS+ETA group. In conclusion, etanercept treatment shows promise in mitigating hormonal disturbances and vascular dysfunction in patients with PCOS, suggesting potential therapeutic advantages.

Propolis prevents vascular endothelial dysfunction by attenuating inflammation and oxidative damage in the chronic unpredictable stress model of depression in rats.

OBJECTIVES: Chronic stress may lead to depression and vascular endothelial dysfunction. We aimed to evaluate the effects of propolis on vascular functions and the possible mechanisms of its vascular effects in the rat model of chronic unpredictable mild stress (CUMS)-induced depression. METHODS: Male Wistar rats were divided into control, stress (exposure to CUMS), control+propolis and stress+propolis groups (n = 8/each group). CUMS model was induced by exposing rats to various mild stressors daily for 5 weeks. The extract of propolis (100 mg/kg/day) was administered orally to propolis-treated groups for 5 weeks. The depression-like behaviours were assessed with the forced swimming test (FST). Chronic stress resulted in increased immobility response in FST and elevated serum corticosterone levels. Thoracic endothelial functions and expressions of endothelial nitric oxide synthase (eNOS), tumor necrosis factor-alpha (TNFα), interleukin-1beta (IL-1ß), Heme oxygenase-1 (HO-1) and superoxide dismutase (SOD) level were assessed. KEY FINDINGS: Compared to control group, stress group exhibited a significant decrease in endothelium-dependent relaxations, and eNOS, SOD and HO-1 expressions, whereas a significant increase in the thoracic expressions of TNFα and IL-1ß. Propolis ameliorated depression-like behaviours, vascular endothelial dysfunctions and alterations of protein expressions. CONCLUSION: Propolis exerted antidepressant-like and vasculoprotective effects in CUMS-induced depression in rats. Chronic propolis treatment may have a protective effect on CUMS-induced vascular endothelial dysfunction by its anti-inflammatory and antioxidant effects.

Infliximab prevents dysfunction of the vas deferens by suppressing inflammation and oxidative stress in rats with chronic stress.

AIMS: Chronic stress leads to the development of male sexual problems such as ejaculatory dysfunctions. The rhythmic contractions of vas deferens (VD) play an important role on the ejaculatory process. In the current study, we investigated whether infliximab (IFX) treatment has any beneficial effects on possible alterations in contractility of VD obtained from rats exposed to unpredictable chronic mild stress (UCMS). MATERIALS AND METHODS: The rats were randomly divided into four groups: control, control+IFX, UCMS and UCMS+IFX. IFX (5 mg/kg/week, i.p.) was administrated for 5 weeks during UCMS period. Depressive like-behaviors were evaluated using locomotor activity, forced swimming and sucrose consumption and preference tests. The blood was collected for serum biochemical determinations. VD tissues were harvested for functional studies and, measurements of oxidative stress, inflammatory and apoptotic biomarkers. KEY FINDINGS: We observed increased serum concentration of corticosterone and depressive-like behaviors in rats exposed to UCMS. In VD tissues of UCMS-exposed rats, noradrenaline- and adenosine triphosphate (ATP)-induced contractile responses significantly enhanced and electrical field stimulation (EFS)-induced contractile responses markedly decreased. UCMS exposure induced inflammation, oxidative stress and apoptosis in VD. However, IFX treatment significantly improved all the aforementioned parameters. SIGNIFICANCE: The results of the present study revealed that chronic stress-induced depression caused VD dysfunction by promoting inflammation and oxidative stress in VD. IFX protected against VD dysfunction through its anti-inflammatory and antioxidant effects.

Anxiolytic-Like and Antidepressant-Like Effects of Resveratrol in Streptozotocin-Induced Diabetic Rats.

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.

Depression induced by chronic stress leads to penile cavernosal dysfunction: protective effect of anti-TNF-α treatment.

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 1ß (IL-1ß), 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-1ß, 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.

Improvement of penile neurogenic and endothelial relaxant responses by chronic administration of resveratrol in rabbits exposed to unpredictable chronic mild stress.

Chronic stress is an important public health problem known as a risk factor for depression, cognitive deficits, and also erectile dysfunction (ED). Resveratrol, a plant polyphenol, was reported to activate constitutive endothelial nitric oxide synthase (eNOS). Although resveratrol has been proven to exert beneficial effects on the unpredictable chronic mild stress (UCMS)-induced decline in cognitive functions, its potential protecting effect on the penile tissue subjected to UCMS was in fact not investigated. Therefore, restorative effects of resveratrol on neurogenic and endothelium-dependent relaxations were evaluated in the corpus cavernosum of rabbits exposed to UCMS. Eighteen male New Zealand white rabbits were assigned into three groups (n = 6 in each group): controls; UCMS; and UCMS rabbits treated with resveratrol (20 mg/kg/day, i.p.) for 12-week period of stress induction. UCMS was induced by a couple of defined adverse conditions applied in a shuffled order for 12 weeks. Neurogenic and endothelium-dependent relaxations of corpus cavernosum were assessed by using organ bath studies. Both the electrical field stimulation (EFS)-induced neurogenic and carbachol-induced endothelium-dependent relaxant responses significantly decreased in physiological stress and resveratrol treatment exhibited a marked improvement in these relaxation responses in vitro. Our results indicated that chronic psychological stress could lead to ED by reducing neurogenic and endothelium-dependent relaxations and resveratrol prevents impairment of the functional responses, suggesting a potential new treatment approach for treatment of ED during psychological stress.

TNF-α antagonism with etanercept enhances penile NOS expression, cavernosal reactivity, and testosterone levels in aged rats.

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.

Protective effects of resveratrol on aging-induced cognitive impairment in rats.

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<0.05). Additionally, in the MWM test, the results showed a decrease in the time spent in the escape platform's quadrant in the probe test in aged rats (p<0.05). The administration of resveratrol at 50mg/kg/day increased the retention scores in the passive avoidance test and the time spent in the escape platform's quadrant in the MWM task (p<0.05). Furthermore resveratrol attenuated the protein levels of TNFα and IL1ß in the 24-month group. These findings indicate that aging impairs emotional and spatial learning-memory and resveratrol reverses the effect of age-related learning and memory impairment. The results of this study suggest that resveratrol is effective in preventing cognitive deficit in aged rats by inhibiting the production of inflammatory cytokines.

Anti-inflammatory and ultrastructural effects of Turkish propolis in a rat model of endotoxin-induced uveitis.

INTRODUCTION: Experimental animal models of acute uveitis, an inflammatory eye disease, can be established via endotoxin-induced inflammation. Propolis, a natural substance collected by honeybees from buds and tree exudates, has antioxidant, antibacterial, antiviral, and anti-inflammatory effects. We investigated the effects of propolis, obtained from the Sakarya province of Turkey, on endotoxin-induced uveitis using immunohistochemical, ultrastructural, and biochemical approaches. MATERIAL AND METHODS: Male Wistar albino rats (n = 6/group) received intraperitoneal (ip) lipopolysaccharide (LPS) endotoxin (150 µg/kg) followed by aqueous extract of propolis (50 mg/kg ip) or vehicle; two additional groups received either saline (control) or propolis only. After 24 h, aqueous humor (AH) was collected from both eyes of each animal for analysis of tumor necrosis factor-α (TNF-α) and hypoxia-inducible factor-1α (HIF-1α). Right eyeballs were paraffin-embedded for immunohistochemical staining of nuclear factor κB (NF-κB)/p65 and left eyeballs were araldite-embedded for ultrastructural analysis. RESULTS: Treatment of LPS-induced uveitis with propolis significantly reduced ciliary body NF-κB/p65 immunoreactivity and AH levels of HIF-1α and TNF-α. Ultrastructural analysis showed fewer vacuoles and reduced mitochondrial degeneration in the retinal pigment epithelium, as compared to the uveitis group. The intercellular spaces of the inner nuclear layer and outer limiting membrane were comparable with those of the control group; no polymorphonuclear cells or stasis was observed in intravascular or extravascular spaces. CONCLUSIONS: This is the first report demonstrating an anti-inflammatory effect of Turkish propolis in a rat model of LPS-induced acute uveitis, suggesting a therapeutic potential of propolis for the treatment of inflammatory ophthalmic diseases.

Vasodilation Responses to Non-Selective α-Adrenergic Blockage of Coronary Bypass Grafts in Diabetic and Non-Diabetic Patients: In Vitro Study.

BACKGROUND: Adrenergic tonus is increased in atherosclerotic coronary arteries. In this study, we aimed to demonstrate in vitro effects of phentolamine, a reversible nonselective alpha (α) adrenergic blocker, on coronary artery bypass grafts (CABG) and compare its effects in diabetic and nondiabetic patients. METHODS: A total number of 30 patients (15 diabetic and 15 nondiabetic) who were assigned to elective CABG surgery were enrolled into the study. For both groups of patients, 16 internal mammarian artery (IMA) samples, 16 saphenous vein (SV) samples and 16 radial artery (RA) samples were collected and studied in the tissue bath system. The vasodilatation responses to increasing doses of phentolamine were recorded. RESULTS: When grafts were compared in terms of amount of vasodilatation to phentolamine, IMA had the most prominent vasodilatation followed by RA and SV respectively. Although the vasodilatation responses in nondiabetic patients were numerically higher than diabetic patients, there was no statistically difference between the groups. CONCLUSION: Phentolamine, a nonselective α adrenergic blocker, is proven to have equal vasodilatory effects in diabetic and nondiabetic CABG grafts and can safely be used both intravenously and topically in the perioperative period.

The effect of N-methyl-D-aspartate receptor antagonist (memantine) on esophageal and gastric smooth muscle: functional investigation in a rat hydrocephalus model.

OBJECT: The purpose of this study was to investigate the effect of N-methyl-d-aspartate (NMDA) receptor antagonist on esophageal and gastric smooth muscle reactivity in a rat hydrocephalus model. MATERIAL AND METHODS: Hydrocephalus was induced in rats by injection of kaolin into the cisterna magna. Two weeks after the procedure, memantine (20 mg/kg per day, 2 weeks) was given to rats with hydrocephalus in the memantine group (MG). The rest of the rats with hydrocephalus received serum physiologic (hydrocephalus group, HG). The control group (nonhydrocephalic rats, CG) was sham operated. The fourth group consisted of nonhydrocephalic rats with treated memantine (memantine control group, MC). Contractile (KCl, carbachol) and relaxant (isoprenaline, papaverine) esophageal and gastric smooth muscle reactivity were determined by in vitro muscle technique. RESULTS: No significant difference was found in the KCl (nonreceptor-mediated)-induced esophageal smooth muscle reactivity among the groups. Carbachol (receptor-mediated)-induced smooth muscle reactivity significantly decreased in HG compared to other groups. The isoprenaline (receptor-mediated)-induced smooth muscle reactivity significantly decreased in HG compared to other groups. No significant difference was found in smooth muscle reactivity to papaverine (nonreceptor-mediated) among the groups. Gastric smooth muscle reactivity to KCl significantly increased in HG compared to other groups. Also, KCl-induced smooth muscle reactivity significantly increased in MG compared to CG and MC. Carbachol-induced smooth muscle reactivity significantly decreased in HG compared to MG, CG, and MC. No significant difference was observed in isoprenaline- and papaverine-induced smooth muscle reactivity among the groups. CONCLUSION: Our findings suggest that memantine may influence esophageal and gastric smooth muscle reactivity in hydrocephalus.