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 rescues cognitive deficits, depression-like symptoms, and spike-wave discharge incidence in WAG/Rij rat model of absence epilepsy.

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.

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.

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.

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.

Resveratrol improves vascular endothelial dysfunction in the unpredictable chronic mild stress model of depression in rats by reducing inflammation.

Chronic psychological stress may cause depression and it is a risk factor for vascular endothelial dysfunction. Inflammation may contribute to endothelial dysfunction. Resveratrol, which has antiinflammatory and vasculoprotective properties, has been reported its beneficial effects on endothelial dysfunction induced by hypertension, diabetes and, aging. The effects of resveratrol on stress-induced endothelial dysfunction is not investigated yet. This study aimed to investigate the efficacy of resveratrol on vascular function in the unpredictable chronic moderate stress (UCMS) model of rats and to examine the possible mechanisms of resveratrol by assessment of proinflammatory markers. Male rats were assigned to 4 groups (n = 8 for each group): Control, Control+Resveratrol, UCMS, UCMS+Resveratrol. UCMS and UCMS+Resveratrol groups were exposed to the UCMS procedure for 12 weeks. Resveratrol (20 mg/kg/day, i.p., during 12 weeks) was given to the Control+Resveratrol and UCMS+Resveratrol groups.Then depressive-like behaviors were evaluated by forced swimming test. After behavioral tests, systolic blood pressure was recorded. Endothelial function of the thoracic aorta was evaluated by isolated organ bath system. Vascular eNOS expression and inflammatory markers such as TNF-α, IL-1ß, IL-6, CRP, ICAM1, MCP in serum and vascular tissue were analyzed to explore the mechanisms of resveratrol. UCMS resulted in depressive-like behavior, endothelial dysfunction and increased inflammatory cytokines in both serum and tissue samples. Resveratrol treatment improved depressive-like behavior, ameliorated vascular dysfunction, and reversed stress-induced inflammation. Our findings suggest that resveratrol exerted antidepressant-like effect and prevented vascular endothelial dysfunction by reducing systemic and peripheral inflammation in UCMS-induced depression in rats. Therefore, resveratrol may be a therapeutic option with a vasculoprotective effect in depression.

Age-dependent decline in learning and memory performances of WAG/Rij rat model of absence epilepsy.

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.

Effects of resveratrol on ileal smooth muscle reactivity in polymicrobial sepsis model.

OBJECTIVE: To determine the effects of resveratrol on the ileal smooth muscle reactivity in polymicrobial sepsis. MATERIAL AND METHODS: Polimicrobial sepsis was induced by the cecal ligation and perforation (CLP) procedure. Sprague Dawley rats were divided into three groups. Rats in resveratrol group received resveratrol after CLP (100 mg/kg, i.p.). Rats received saline immediately after CLP in the sepsis group. Control group rats underwent sham operation. The rats were sacrificed and the ileum was excised 24 h after the operation. Contractile and relaxant responses in isolated smooth muscle strips (SMS) were determined using an in vitro muscle technique. TNFα and IL-6 levels were measured in blood samples. RESULTS: Contractile responses to carbachol and KCl and relaxant responses to transmural electrical field stimulation (EFS) were significantly decreased in the sepsis group compared with control and resveratrol groups. No significant changes were observed for smooth muscle reactivity in the resveratrol and control groups. Sodium nitroprusside (SNP) or papaverine-induced relaxations were similar in the all groups. Resveratrol treatment supressed increased TNFα and IL-6 levels in blood seen in sepsis group. CONCLUSION: Ileal smooth muscle reactivity was improved after resveratrol treatment in rats with sepsis. The results of the present study indicate that the beneficial effects of resveratrol might be, at least in part, attributed to its effects on non-adrenergic non-cholinergic pathway and/or anti-inflammatory and antioxidant activity.

Etanercept Prevents Endothelial Dysfunction in Cafeteria Diet-Fed Rats.

Obesity is associated with endothelial dysfunction and this relationship is probably mediated in part by inflammation. Objective: The current study evaluated the effects of etanercept, a tumor necrosis factor-alpha (TNF-α) inhibitor, on endothelial and vascular reactivity, endothelial nitric oxide synthase (eNOS) immunoreactivity, and serum and aortic concentrations of TNF-α in a diet-induced rat model. Design and results: Male weanling Wistar rats were exposed to a standard diet and cafeteria diet (CD) for 12 weeks and etanercept was administered during CD treatment. Isolated aortas of the rats were used for isometric tension recording. Carbachol-induced relaxant responses were impaired in CD-fed rats, while etanercept treatment improved these endothelium-dependent relaxations. No significant change was observed in papaverine- and sodium nitroprusside (SNP)-induced relaxant responses. eNOS expression decreased in CD-fed rats, but no change was observed between etanercept-treated CD-fed rats and control rats. CD significantly increased both the serum and the aortic levels of TNF-α, while etanercept treatment suppressed these elevated levels. CD resulted in a significant increase in the body weight of the rats. Etanercept-treated (ETA) CD-fed rats gained less weight than both CD-fed and control rats.

Agmatine has beneficial effect on harmaline-induced essential tremor in rat.

Essential tremor (ET) is one of the most prevalent movement disorders and the most common cause of abnormal tremors. However, it cannot be treated efficiently with the currently available pharmacotherapy options. The pathophysiology of harmaline-induced tremor, most commonly used model of ET, involves various neurotransmitter systems including glutamate as well as ion channels. Agmatine, an endogenous neuromodulator, interacts with various glutamate receptor subtypes and ion channels, which have been associated with its' beneficial effects on several neurological disorders. The current study aims to assess the effect of agmatine on the harmaline model of ET. Two separate groups of male rats were injected either with saline or agmatine (40 mg/kg) 30 min prior to single intraperitoneal injection of harmaline (20 mg/kg). The percent duration, intensity and frequency of tremor and locomotor activity were evaluated by a custom-built tremor and locomotion analysis system. Pretreatment with agmatine reduced the percent tremor duration and intensity of tremor induced by harmaline, without affecting the tremor frequency. However, it did not affect the decreased spontaneous locomotor activity due to harmaline. This pattern of ameliorating effects of agmatine on harmaline-induced tremor provide the first evidence for being considered as a treatment option for ET.

N-Acetylcysteine improves disturbed ileal contractility following partial hepatectomy in rats.

BACKGROUND AND AIMS: It is well known that disturbed intestinal motility and bacterial overgrowth may occur following partial hepatectomy. These events have been followed by the translocation of enteric bacteria that play a major role in the development of infections. We designed the present study to evaluate the effect of N-acetylcysteine (NAC) on ileal muscle contractility as an indication of intestinal motility. METHODS: Sprague-Dawley rats were divided into four groups (n = 6): sham, sham plus preoperative intraperitoneal NAC injection, hepatectomy, and hepatectomy plus preoperative intraperitoneal NAC injection. Contractile and relaxant responses in isolated ileal smooth muscle strips were determined using an in vitro muscle technique. Statistical analyses were performed by Kruskal-Wallis and Mann-Whitney U-tests. RESULTS: Contractile responses to KCl and carbachol were significantly decreased in the ileal strips of the hepatectomy group when compared to the sham-operated control group. The impaired contraction of strips was markedly improved by preoperative NAC treatment. However, neither the electrical field stimulation nor the sodium nitroprusside-mediated relaxant responses changed in any of the groups. CONCLUSIONS: Our data indicated that disturbed ileal contractility after partial hepatectomy was remedied by preoperative NAC treatment, which in turn might cause attenuation of bacterial translocation.

Resveratrol and quercetin attenuate depressive-like behavior and restore impaired contractility of vas deferens in chronic stress-exposed rats: involvement of oxidative stress and inflammation.

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.

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.

NLRP1-Mediated Antidepressant Effect of Ketamine in Chronic Unpredictable Mild Stress Model in Rats.

OBJECTIVE: NOD-like receptor protein 1 (NLRP1) inflammasome complex has been recently associated with chronic unpredictable mild stress (CUMS) model of depression. Our aim was to investigate whether ketamine-induced antidepressant effect is associated with suppression of NLRP1. METHODS: Wistar albino rats were divided into control, CUMS, CUMS+acute ketamine (a single 10 mg/kg dose) and CUMS+chronic ketamine (daily 10 mg/kg injections for 3 weeks) groups (n=10 for each group). Sucrose preference test and forced swimming test were performed to assess anhedonia and immobility time respectively for the severety of depression symptoms. Brain tissues were dissected and prefrontal cortex and hippocampus regions were used for real-time polymerase chain reaction (PCR) and immunohistochemical analysis. RESULTS: CUMS procedure significantly induced depressive-like symptoms whereas both acute and chronic ketamine treatment ameliorated them. mRNA expression levels of NLRP1, caspase 1, apoptosis-associated speck-like protein containing a CARD (ASC), NF-κB, endothelial nitric oxide synthase, IL-1ß, IL-6, toll-like receptor 4 (TLR-4) and purinergic 2×7 receptor (P2X7R) and numbers of Iba- 1+and GFAP+glial cells were reduced by acute and/or chronic ketamine treatment. CONCLUSION: In the present study for the first time upstream and downstream elements of the NLRP1 inflammasome complex are shown to be suppressed by ketamine thus reinforcing the involvement of NLRP1 in the physiopathology of depression.

Etanercept improves aging-induced cognitive deficits by reducing inflammation and vascular dysfunction in rats.

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.

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.

The protective effect of metformin in scopolamine-induced learning and memory impairment in rats.

BACKGROUND: Alzheimer's disease (AD) is the most common neurodegenerative disease in the world. One of the most commonly prescribed oral antidiabetic drug, metformin, has been shown to have beneficial effects on restoring impaired cognitive function. In the present study, we investigated the effects of metformin on spatial memory in terms of alleviating scopolamine-induced learning and memory impairments in rats by using the Morris water maze (MWM) test and the modified elevated plus-maze (mEPM) test. Furthermore, we investigated the possible mechanisms of action of metformin in preventing cognitive dysfunction. METHODS: Male Wistar rats received metformin (50, 100, or 200 mg/kg/day) via gavage feeding for three weeks. Scopolamine was administered intraperitoneally before the probe step of the MWM test or the acquisition session of the mEPM test. RESULTS: The learning and memory impairment induced by scopolamine was reversed by metformin. In addition, metformin improved the level of phosphorylated AMP-activated protein kinase and cAMP responsive element binding protein. However, metformin pretreatment had no impact on inhibiting the scopolamine-induced changes in acetylcholine levels. Furthermore, metformin exerted its antioxidant effect by significantly reversing scopolamine-induced changes in malondialdehyde, total antioxidant status, and superoxide dismutase levels in the hippocampus. CONCLUSION: Our results indicate that one of the most commonly used antidiabetic drug, metformin, has the potential to prevent the development of dementia and be a novel therapeutic drug for the amelioration of cognitive dysfunction in AD.

Resveratrol prevents cognitive deficits by attenuating oxidative damage and inflammation in rat model of streptozotocin diabetes induced vascular dementia.

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-1ß expressions; serum SOD and NADPH oxidase levels and, hippocampal BDNF, TNF-α and IL-1ß 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-1ß, 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.