The role of the cholinergic system in the memory-protecting effects of metformin in a model of scopolamine-induced memory impairment in aged rats.

PURPOSE: As the elderly population grows, the prevalence of dementia is also rapidly increasing worldwide. Metformin, an antidiabetic drug, has been shown to have ameliorative effects on impaired cognitive functions in experimental models. However, studies have generally used young animals. Additionally, although it has a major role in Alzheimer's disease (AD) and memory, literature information about the effects of metformin on the cholinergic system is limited. In this study, we investigated the effects of metformin on memory in a model of scopolamine-induced memory impairment in aged rats. We also examined the effects of metformin on the cholinergic system, which is very important in cognitive functions. METHODS: Metformin was administered orally to male Wistar rats (20-22 months old) at 100 mg/kg/day for three weeks. Morris water maze (MWM) tests were performed to assess spatial memory. Before the probe test of the MWM test, scopolamine was injected intraperitoneally at a dose of 1 mg/kg. After testing, animals were sacrificed, whole brains were removed, and hippocampus samples were separated for biochemical analysis. RESULTS: Impaired memory associated with scopolamine administration was reversed by metformin. In addition, metformin administration ameliorated scopolamine-induced changes in acetylcholine (ACh) levels, acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), and choline acetyltransferase (ChAT) activity. CONCLUSION: Our results show that metformin may have protective effects in a scopolamine-induced memory impairment model in aged animals by improving cholinergic function. Metformin shows promise in preventing dementia with its dual cholinesterase inhibition and ChAT activation effect.

Regional expression differences of SERT and TSPAN8 in hippocampus, cerebellum and cortex of wild-type young, adult and middle-aged rats.

Changes in gene expression with aging are associated with a decline in physical and cognitive abilities. Here, we investigated the changes in mRNA and protein expression of TSPAN8 and SERT in the different parts of the brain for different age group rats. Our protein analysis revealed that aging mainly triggers SERT gene expression in the cerebellum and hippocampus, showing that an increase in mRNA expression correlates with protein expression. For TSPAN8, age-dependent protein increase was observed in the hippocampus and highest expression was observed for adult and middle-aged rats.

Protective effects of p-coumaric acid against gentamicin-induced nephrotoxicity in rats.

The most important side effect of gentamicin (GM) is nephrotoxicity. p-Coumaric acid (PCA) is a phenolic compound that scavenges free radicals, reduces fibrosis, and tissue damage. This study investigates the protective effect of PCA on tissue damage and kidney function in gentamicin-induced nephrotoxicity (GIN). Thirty-five rats were separated into five groups and each group contained seven animals: control group, ethanol group, GM group, PCA group, and GM + PCA group. At the end of the seven-day treatment, the rats were sacrificed after blood and kidney tissue samples were taken. While serum urea, creatinine, and neutrophil gelatinase-associated lipocalin (NGAL) levels increased significantly in the GM group compared to the control, they showed a significant decrease in the GM + PCA group compared to the GM. Serum tumor necrosis factor-α (TNF-α) and tissue malondialdehyde (MDA) levels were significantly increased in the GM group compared to the control. While the tissue total oxidant status (TOS) and oxidative stress index (OSI) values of the GM group were significantly higher than the control, they showed a significant decrease in the GM + PCA group compared to the GM. In the histopathological examination, significant tubular necrosis and tubulointerstitial inflammation were detected in the proximal tubules in the GM group compared to the control, while a significant decrease was observed in the severity of these findings in the GM + PCA group compared to the GM. This study shows that PCA has biochemical and histopathological ameliorating effects on GIN in the rat model.

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.

Protective Effects of Quercetin on Necrotizing Enterocolitis in a Neonatal Rat Model.

INTRODUCTION: Necrotizing enterocolitis (NEC) is one of the major health problems of newborn period. To date, a large amount of chemicals have been tested for NEC and some showed limited beneficial effects. The research for better results still continues. This study aims to investigate the effects of quercetin (QE) on NEC treatment in rats. METHODS: Newborn rats were divided into control, NEC, and NEC + QE groups. In NEC and NEC + QE groups, experimental NEC was induced. NEC + QE group animals were also given QE. Weight changes of the animals were recorded, and serum total antioxidant status (TAS), total oxidant status (TOS), malondialdehyde (MDA), and glutathione (GSH) levels were measured. Histologic evaluation of the distal ileum and the terminal deoxynucleotidyl transferase dUTP nick end labeling staining were performed. RESULTS: A significant increase in the TAS levels was observed in NEC + QE group. Only NEC group exhibited significantly higher TOS and MDA levels and lower GSH levels. Rats in the NEC + QE group had better histopathology and less apoptosis than NEC group. CONCLUSION: QE is effective in enhancing antioxidant defense mechanism, limiting oxidative stress, reducing intestinal damage, and preventing NEC development.

Evaluation of the effects of dexketoprofen trometamol on knee joint: an in vivo & in vitro study.

BACKGROUND & OBJECTIVES: Intra-articular (ia) injections of local anaesthetics and non-steroidal anti-inflammatory drugs (NSAID's) are simple and efficient to ensure post-operative analgesia but some of these have toxic effects on the synovium and cartilage. Dexketoprofen is recently introduced S-enantiomer of ketoprofen with a better analgesic and side effect profile. This study was done to evaluate the possible toxic effects of dexketoprofen trometamol on knee joint cartilage and symovium in vitro and in vivo. METHODS: Forty one Sprague-Dawley rats were anaesthetized by ketamine. Dexketoprofen trometamol (0.25 ml) was injected into the right knee joint of the 35 rats and 0.25 ml serum physiologic into the left knee joint of the same animals. Six rats were sham operated. Thirty five animals were randomly divided into five equal groups. Seven animals were sacrified at 24th, 48th hours and 7th, 14th, and 21 st days of the injections. Haematoxylin eosin stained sections from the knee joints were evaluated for the signs of inflammation according to five point scale. Primary chondrocytes were isolated from the articular cartilages of rats for in vitro studies. Cells were exposed to 0.25 ml dexketoprofen trometamol or 0.25 ml dexketoprofen medium mixture at 1:1 ratio for 15, 30, 45 and 60 min. Cell viability was determined by 3-(4, 5- dimethylthiazole-2-yl)-2.5-diphenyl tetrazolium bromide (MTT) assay, 24, 48 and 72 h after drug treatment. RESULTS: No significant histopathologic differences were found between dexketoprofen trometamol and physiologic serum (control) applied joints at all time intervals in in vivo study. Cell proliferation in dexketoprofen trometamol treated chondrocytes was inhibited for all time intervals compared to control. In dexketoprofen-medium mixture groups significant differences were only seen 24 h after the 30 and 45 min application of medium: drug mixture. INTERPRETATION & CONCLUSIONS: Intra-articular application of dexketoprofen trometamol into the rat knee joints did not cause significant histopathological changes, but its in vitro application in primary chondrocyte culture caused significant cytotoxicity. The effects of dexketoprofen at different concentrations need to be further investigated in culture of rat and human chondrocytes.

Subsequent alterations in the contractile property of the vas deferens according to duration of spermatic cord torsion.

OBJECTIVE: To determine whether twisting of the ipsilateral vas deferens results in alteration of its contractility. DESIGN: Experimental study. SETTING: University animal lab. ANIMAL(S): 24 male Wistar rats. INTERVENTION(S): All the rats in the experimental groups underwent spermatic cord torsion. Durations of torsion were 45 minutes, 3 hours, and 24 hours in groups 2, 3, and 4, respectively. In groups 2 and 3, subgroups b were created to evaluate late effects using in vitro pharmacological techniques. MAIN OUTCOME MEASURE(S): The contractility of the vas deferens was evaluated in groups 1, 2a, 3a, and 4 right after and in groups 2b and 3b 48 hours after the initial operation. RESULT(S): Group 4 and subgroups 2b and 3a had significantly diminished responses compared with the control group, whereas in subgroups 2a and 3b, the responses to noradrenaline and to single-pulse field stimulation were not significantly different. CONCLUSION(S): The impairment of contractility with the twisting of the vas deferens might be another factor responsible for subfertility, particularly that related to sperm transport. The unfavorable late change in short duration of torsion may be the result of either ischemia and reperfusion injury or sympathetic overactivation in the acute period of torsion.

Antidepressant-like effects of echo-planar magnetic resonance imaging in mice determined using the forced swimming test.

Echo-planar magnetic resonance imaging (EP-MRI), which is novel variant of MRI, is thought to have antidepressant properties in humans and animal models. Using the forced swimming test (FST), we investigated which monoaminergic system in mice is affected by EP-MRI. The short- and long-term effects of EP-MRI on immobility time in the FST and motor activity within a locomotor activity cage were examined. Two groups of mice underwent 20 min of EP-MRI in an MR scanner (Siemens, 1.5 T Symphony) either 23.5 or 1 h before the start of the second session of the FST. In both groups, the immobility duration in the FST was reduced, similar to effective antidepressant drug treatments. Climbing behavior in the 1-h group and swimming behavior in the 23.5-h group increased significantly, similar to that seen after the administration of desipramine (a noradrenaline reuptake inhibitor) and sertraline (a selective serotonin reuptake inhibitor), respectively. The findings support the hypothesis that EP-MRI has an antidepressant-like effect. We suggest that the antidepressant-like effect begins in the early period with noradrenaline systems and is maintained in the late period with serotonin systems.

Chronic treatment with fluoxetine and sertraline prevents forced swimming test-induced hypercontractility of rat detrusor muscle.

Serotonin (5-hydroxytryptamine, 5-HT) reuptake inhibitors represent important targets for the development of new treatments for detrusor overactivity and urinary incontinence. The present study was undertaken to investigate the effects of the forced swimming test (FST) on the contractile response of isolated rat detrusor muscle and to examine the effects of in vivo treatments of fluoxetine and sertraline on altered detrusor muscle contractility. Fluoxetine (20 mg/kg ip) and sertraline (10 mg/kg ip) were administered once a day for 14 days. Rats were exposed to the FST on the 15th day. After the test, detrusor muscles were removed and placed in organ baths, and the contraction responses induced by carbachol, potassium chloride (KCl) and electrical field stimulation (EFS) were recorded. The contractile responses of detrusor muscle strips to carbachol and electrical field stimulation were found to be increased at all carbachol doses and frequencies, respectively. FST also increased the contractile responses to KCl, which is used to test the differences in postreceptor-mediated contractions. The hypercontractile responses of detrusor strips to carbachol, EFS and KCl were abolished by treatment with both fluoxetine and sertraline. These treatments also decreased the immobility duration in the FST consistent with an antidepressant-like effect in this test. The results of this study provide the first evidence that FST increases contractility of the rat detrusor muscle, and this hypercontractility was abolished by chronic treatments of fluoxetine and sertraline at antidepressant doses by decreasing the postreceptor-mediated events.

Possible role of sildenafil in inhibiting rat vas deferens contractions by influencing the purinergic system.

AIM: To evaluate the effect of sildenafil, a selective inhibitor of cyclic guanosine monophosphate (cGMP)-selective type 5 phosphodiesterase, on isolated rat vas deferens and its connections with the purinergic system. METHODS: Epididymal and prostatic portions of isolated vas deferens were placed in organ baths containing Krebs' solution. Contractions were induced by noradrenaline (NA), adenosine triphosphate (ATP), alpha,beta-methylene ATP and electrical field stimulation (EFS). The effect of sildenafil on the contractions was compared with suramin and Evans blue (EB). RESULTS: NA, ATP, alpha,beta-methylene ATP and EFS caused contractions in both portions of vas deferens. NA-induced contractions were unaffected by sildenafil and suramin but potentiated by EB. ATP-induced contractions were non-competitively inhibited in both portions by sildenafil and suramin but potentiated by EB. alpha,beta-methylene ATP-induced contractions were unaffected by sildenafil but were inhibited in both portions by suramin and EB. EFS-induced contractions were inhibited by sildenafil and suramin while potentiated by EB. CONCLUSION: Sildenafil inhibited the contractions in both portions of vas deferens, as did suramin. We have suggested that purinergic system has a role in this antagonism and it seems to be mediated by an ATP-dependent mechanism instead of a receptor interaction.

Effect of sildenafil on anxiety in the plus-maze test in mice.

Several studies have shown a role of nitric oxide/cyclic guanosine monophosphate signaling pathway in the regulation of anxiety. The effects of the phosphodiesterase (PDE) 5 inhibitors on anxiety are not fully understood. The aim of present study was to investigate the possible role of sildenafil, an inhibitor of cyclic GMP-specific phosphodiesterase, on anxiety in the plus-maze test in mice. Sildenafil at a dose of 0.5 mg/kg had no significant effect on the behavior in the plus-maze test but at doses of 1 and 3 mg/kg induced an anxiogenic effect. The combination of sildenafil (1 mg/kg, i.p.) and methylene blue (1 mg/kg, i.p.) abolished the anxiogenic-like effect of sildenafil. The combination of sildenafil (1 mg/kg, i.p.) and L-arginine (50 mg/kg, i.p.) decreased the percentage of time spent in open arms compared to saline-treated group. Diazepam at a dose of 2 mg/kg significantly increased the percentage of time spent in open arms (p < 0.05). Sildenafil at a dose of 3 mg/kg and the combination of L-arginine (50 mg/kg, i.p.) and sildenafil (1 mg/kg, i.p.) significantly decreased the locomotor activity (p < 0.05). These results suggest that a nitric oxide-cGMP pathway seems to play an important role in sildenafil-induced anxiogenic-like effect.