sitagliptin-phosphate and Reperfusion-Injury

Sitagliptin, an oral glucose-lowering agent, has been found to produce cardiovascular protection possibly via anti-inflammatory and anti-atherosclerotic activities of glucagon-like peptide-1 receptor (GLP-1). The aim of this study was to investigate whether sitagliptin protected the kidney function from acute ischemia-reperfusion (IR) injury in rats.. Adult male SD rats were categorized into 4 groups: sham control, IR injury, IR+sitagliptin (300 mg/kg) and IR+sitagliptin (600 mg/kg). Acute renal IR injury of both kidneys was induced by clamping the renal pedicles for 1 h. The drug was orally administered at 1, 24 and 48 h after acute IR. Blood samples and 24-h urine were collected before and at 72 h after acute IR. Then the rats were sacrificed, and the kidneys were harvested for biochemical and immunohistochemical studies.. Acute IR procedure markedly increased serum levels of creatinine and BUN and the ratio of urine protein to creatinine. The kidney injury score, inflammatory biomarkers (MMP-9, TNF-α and NF-κB) levels and CD68+ cells in IR kidneys were considerably increased. The expression of oxidized protein, reactive oxygen species (NOX-1, NOX-2) and apoptosis proteins (Bax, caspase-3, PARP) in IR kidneys was also significantly upregulated. All these pathological changes were suppressed by sitagliptin in a dose-dependent manner. Furthermore, the serum GLP-1 level, and the expression of GLP-1 receptor, anti-oxidant biomarkers (HO-1 and NQO-1 cells, as well as SOD-1, NQO-1 and HO-1 proteins), and angiogenesis markers (SDF-1α+ and CXCR4+ cells) in IR kidneys were significantly increased, and further upregulated by sitagliptin.. Sitagliptin dose-dependently protects rat kidneys from acute IR injury via upregulation of serum GLP-1 and GLP-1 receptor expression in kidneys.

Topics: Animals; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Kidney; Male; Pyrazines; Rats; Rats, Sprague-Dawley; Receptors, Glucagon; Reperfusion Injury; Sitagliptin Phosphate; Triazoles; Up-Regulation

Twisting of the spermatic cord is considered a popular problem in the urological field, which may lead to testicular necrosis and male infertility. Sitagliptin, a glucose-lowering agent, proved to have a vindicatory function in myocardial and renal ischaemia/reperfusion (I/R), but its role in testicular I/R has not yet been studied. The current work investigates its capability to recover the testicular I/R injury with shedding more light on the mechanism of its action. Four groups were used: sham, sham pretreated with sitagliptin, I/R and sitagliptin/I/R-pretreated groups. The outcomes proved that I/R significantly decreased the serum testosterone, with a major increase in oxidative, inflammatory and nitrosative stress, along with a reduction in testicular vascular endothelial growth factor-A level with marked germinal cell apoptosis. However, pretreatment with sitagliptin significantly reversed the profound testicular I/R damaging effects, on the basis of its antioxidant, anti-inflammatory and anti-apoptotic activities with the ability of recuperation of the testicular vascularity.

Topics: Animals; Cholesterol; Dipeptidyl-Peptidase IV Inhibitors; Drug Evaluation, Preclinical; Male; Oxidative Stress; Rats; Reperfusion Injury; Sitagliptin Phosphate; Spermatogenesis; Testicular Diseases; Testis; Testosterone; Tumor Necrosis Factor-alpha; Vascular Cell Adhesion Molecule-1; Vascular Endothelial Growth Factor A

Oxidative stress and inflammation play a key role in the development of hepatic ischemia reperfusion (HIR)-induced injury. Nuclear factor-erythroid 2-related factor-2 (Nrf-2) is a main regulator of numerous genes, encoding cytoprotective molecules including heme oxygenase-1 (HO-1). Sitagliptin (Sit) is an incretin enhancer acting via inhibition of dipeptidyl peptidase-4 (DPP-4) enzyme. This study was undertaken to investigate the ability of Sit to prevent the hepatic pathological changes of HIR induced injury and to modify Nrf-2 and its target HO-1.. Pringle's maneuver was used to induce total HIR in adult male rats that were randomly assigned into 4 groups. Group1 (sham-operated control), Group 2 (sham-operated + Sit-control group), Group 3 (HIR non-treated), and Group 4 (HIR + Sit). Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities together with hepatic contents of malondialdhyde (MDA), nitric oxide (NO) and reduced glutathione (GSH) and superoxide dismutase (SOD) activity were evaluated. Hepatic tissue mRNA of Nrf-2 and protein content of HO-1 along with histopathological examination and scoring of hepatic injury were performed.. Sit caused a significant reduction in ALT and AST activities together with attenuation of HIR-induced histopathological liver injury. Effect of Sit was associated with decreased hepatic level of MDA and NO with increased GSH level and SOD activity. Non-treated rats with HIR showed an increase in Nrf-2 mRNA expression and HO-1 content in hepatic tissue which was further increased by Sit treatment.. These results indicate that hepatoprotective activity of Sit against HIR is attributed at least in part to modulation of Nrf-2/ HO-1 signaling pathway.

Topics: Alanine Transaminase; Animals; Apoptosis; Aspartate Aminotransferases; Glutathione; Heme Oxygenase-1; Liver; Male; NF-E2-Related Factor 2; Oxidative Stress; Rats; Reperfusion Injury; Sitagliptin Phosphate; Superoxide Dismutase

Ischemia/reperfusion (IR) is the main cause of liver damage after transplantation. We evaluated the effect of sitagliptin (STG) on oxidative stress parameters in the rat liver under IR.. Rats were treated with STG (5 mg/kg) (S and SIR) or saline solution (C and CIR). Livers from CIR and SIR were subjected to ischemia (60 min) and reperfusion (24 h). During reperfusion, aminotransferases (ALT and AST) were determined in blood samples. Thiobarbituric acid reactive substances (TBARS), superoxide dismutase (SOD), catalase (CAT), paraoxonase-1 (PON1), glutathione peroxidase (GPx), and the mRNA expression of SOD1 were determined in liver homogenates after reperfusion. Different regions of livers were also histologically evaluated.. The PON1 activity was higher, and the TBARS level was lower in SIR than in CIR. There was an inverse relationship between TBARS and PON1 levels in the whole cohort. The GPx activity was lower in ischemic than in nonischemic groups regardless of the STG treatment. In SIR, the SOD1 activity was higher compared to that in CIR. In S, the expression of SOD1 mRNA was the highest of all examined groups and positively correlated with the SOD1 activity in the whole animal cohort. During IR aminotransferases, the activity in the drug-treated group was lower in all examined points of time. In drug-treated groups, the percentage of steatosis was higher than that in nontreated groups regardless of IR.. The protective effect of STG on the rat liver, especially its antioxidant properties, was revealed under IR conditions.

Topics: Animals; Gene Expression Regulation, Enzymologic; Liver; Male; Oxidative Stress; Oxidoreductases; Rats; Rats, Wistar; Reperfusion Injury; Sitagliptin Phosphate

The current study is focusing on the role of brain natriuretic peptide (BNP), a substrate of dipeptidyl peptidase-4 (DPP-4) enzyme, and its signaling survival pathway in the cardioprotective mechanism of sitagliptin, a DPP-4 inhibitor.. Pretreatment with sitagliptin provided significant protection against I/R injury as manifested by decreasing, percentage of infarct size, suppressing the elevated ST segment, reducing the increased cardiac enzymes, as well as DPP-4 activity and elevating both heart rate (HR) and left ventricular developed pressure (LVDP). However, the addition of either blocker to sitagliptin regimen reversed partly its cardioprotective effects. Although I/R increased BNP content, it unexpectedly decreased that of cGMP; nevertheless, sitagliptin elevated both parameters, an effect that was not affected by the use of the two blockers. On the molecular level, sitagliptin decreased caspase-3 activity and downregulated the mRNA levels of BNP, Bax, and Cyp D, while upregulated that of Bcl2. The use of either KT-5823 or 5-HD with sitagliptin hindered its effect on the molecular markers tested.. The results of the present study suggest that the cardioprotective effect of sitagliptin is mediated partly, but not solely, through the BNP/cGMP/PKG survival signaling pathway.

Topics: Animals; bcl-2-Associated X Protein; Carbazoles; Cardiotonic Agents; Caspase 3; Cyclic GMP; Cyclophilins; Decanoic Acids; Dipeptidyl Peptidase 4; Hemodynamics; Hydroxy Acids; Male; Natriuretic Peptide, Brain; Peptidyl-Prolyl Isomerase F; Proto-Oncogene Proteins c-bcl-2; Rats; Reperfusion Injury; Signal Transduction; Sitagliptin Phosphate

This study investigated the effect of sitagliptin prophylactic treatment on intestinal I/R rat model and explored the possible underlying mechanism.. Forty-five male Sprague-Dawley rats were randomly assigned to 3 groups: Sham group (operation without clamping), I/R group (operation with clamping) and sitagliptin pretreated group (300 mg/kg/day; p.o.) for 2 weeks before I/R insult. Intestinal I/R was performed by clamping the superior mesenteric artery for 30 min, followed by 60 min reperfusion after removal of clamping. At the end of the experimental period, all rats were sacrificed for histopathological, biochemical, PCR and western blot assessment.. Pretreatment with sitagliptin remarkably alleviated the pathological changes induced by I/R in the jejunum, suppressed upregulated NF-κB, TNF-α, IL-1βand MPO caused by I/R. Moreover, sitagliptin decreased the Bax/Bcl-2 ratio and accordingly suppressed apoptotic tissue damage as reflected by a caspase-3 level reduction in rat intestine subjected to I/R injury. Interestingly, sitagliptin could obviously increase the active GLP-1 level and GLP-1 receptor mRNA expression in the jejunum of I/R rats. This was associated with the augmentation of the cAMP level and enhancement of PKA activity. Simultaneously, sitagliptin treatment was able to increase the protein expression levels of phosphorylated PI3K and Akt.. Sitagliptin has shown protective effects against intestinal I/R injury in rats through reduction of intestinal inflammation and apoptosis. The molecular mechanisms may be partially correlated with activation of cAMP/PKA and PI3K/Akt signaling pathway by the GLP-1/GLP-1 receptor.

Topics: Animals; Apoptosis; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Gene Expression Regulation; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Hypoglycemic Agents; Inflammation; Inflammation Mediators; Intestinal Diseases; Intestinal Mucosa; Intestines; Male; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Sitagliptin Phosphate

A correlation between the level of asymmetric dimethylarginine (ADMA) - the inhibitor of the nitric oxide (NO) synthesis - and the liver function and survival after a liver transplantation has been reported.. The aim of this study was to evaluate the effect of sitagliptin -the inhibitor of dipeptidyl peptidase-4 (DPP-4) - on the NO-ADMA-dimethylarginine dimethylaminohydrolase (DDAH) pathway in rat livers subjected to ischemia/reperfusion (IR).. The rats received sitagliptin (5 mg/kg, per os - p.o.) (groups: S - livers not subjected to IR procedure, and SIR - livers subjected to IR procedure) or a saline solution (groups: C - livers not subjected to IR procedure, and CIR - livers subjected to IR procedure) for 14 days; following this, livers in the SIR and CIR groups were subjected to ischemia (60 min) and reperfusion (24 h). Aminotransferases were measured before the surgery; additionally, the arginine (ARG), ADMA and symmetric dimethylarginine (SDMA) levels were estimated just before ischemia and during reperfusion (at 0.5, 4 and 24 h). After IR, citrulline, the DDAH activity, mRNA for type 1 DDAH (DDAH1), and arginine methyltransferase type 1 (PRMT1) were determined.. The increase in the initial level of ARG/ADMA0 (A/A) ratio in group S compared to group C verged on statistical significance. At 0.5 and 4 h of reperfusion, the highest concentration of ADMA was found in group CIR. At those time points, the ARG level and the A/A ratio were decreased in groups CIR and SIR as compared to groups C and S, respectively. The alanine transaminase (ALT) activity was lower in the sitagliptin-treated group than in the non-treated one. The DDAH and citrulline levels were reduced in group CIR as compared to group C, but were greater in group SIR as compared to group S. The PRMT1 mRNA expression was higher in groups CIR and SIR, compared to groups C and S, respectively.. The increased A/A ratio suggests a protective effect of sitagliptin on livers not subjected to IR. Changes in the DDAH activity and the PRMT1 mRNA expression also imply the protective activity of sitagliptin during IR.

Topics: Amidohydrolases; Animals; Arginine; Cytarabine; Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; Ischemia; Liver; Nitric Oxide; Protein-Arginine N-Methyltransferases; Rats; Reperfusion Injury; Sitagliptin Phosphate

Results regarding protective effects of dipeptidyl peptidase 4 (DPP4) inhibitors in renal ischaemia-reperfusion injury (IRI) are conflicting. Here we have compared structurally unrelated DPP4 inhibitors in a model of renal IRI.. IRI was induced in uninephrectomized male rats by renal artery clamping for 30 min. The sham group was uninephrectomized but not subjected to IRI. DPP4 inhibitors or vehicle were given p.o. once daily on three consecutive days prior to IRI: linagliptin (1.5 mg·kg. Plasma-active glucagon-like peptide type 1 (GLP-1) increased threefold to fourfold in all DPP4 inhibitor groups 24 h after IRI. Plasma cystatin C, a marker of GFR, peaked 48 h after IRI. Compared with the placebo group, DPP4 inhibition did not reduce increased plasma cystatin C levels. DPP4 inhibitors ameliorated histopathologically assessed tubular damage with varying degrees of drug-specific efficacies. Renal osteopontin expression was uniformly reduced by all DPP4 inhibitors. IRI-related increased renal cytokine expression was not decreased by DPP4 inhibition. Renal DPP4 activity at study end was significantly inhibited in the linagliptin group, but only numerically reduced in the prolonged/dose-adjusted sitagliptin group. Active GLP-1 plasma levels at study end were increased only in the prolonged/dose-adjusted sitagliptin treatment group.. In rats with renal IRI, DPP4 inhibition did not alter plasma cystatin C, a marker of glomerular function, but may protect against tubular damage.

Topics: Adamantane; Animals; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Dose-Response Relationship, Drug; Kidney; Linagliptin; Male; Molecular Structure; Nitriles; Pyrrolidines; Rats; Rats, Wistar; Reperfusion Injury; Sitagliptin Phosphate; Structure-Activity Relationship; Vildagliptin

This study was designed to investigate the protective effects of sitagliptin on renal damage induced by renal ischemia reperfusion (I/R) in rats. For this, rats were randomly divided into four groups (n = 8): (1) sham group, in which the rats only underwent right nephrectomy; (2) right nephrectomy and left kidney ischemia (1 h) and reperfusion (24 h) group (I/R); (3) 5 mg/kg sitagliptin administrated group, per-oral once a day for two weeks; (4) 5 mg/kg sitagliptin administrated group, per-oral once a day for two weeks before left kidney I/R (n = 8). Sitagliptin-treated rats that underwent renal I/R demonstrated significant decrease in the serum urea nitrogen and creatinine and also, lipid peroxidation, total oxidant status and malondialdehyde level in the renal tissue when compared to the renal I/R group. Additionally, reduced glutathione, glutathione peroxidase, superoxide dismutase, catalase and total antioxidative capacity were significantly increased after renal I/R in sitagliptin-treated rats. Our histopathological findings were in accordance with these biochemical results. In sum, in the current study all of our results indicated that sitagliptin treatment ameliorated renal damage induced by renal I/R in rats.

Topics: Animals; Dipeptidyl-Peptidase IV Inhibitors; Disease Models, Animal; Female; Kidney; Random Allocation; Rats; Rats, Wistar; Reperfusion Injury; Sitagliptin Phosphate

Ischemic stroke is a major macrovascular complication of diabetes mellitus. Sitagliptin, a dipeptidyl peptidase-IV inhibitor, was recently shown to improve cognitive functions in diabetic rats; hence the present study was conducted to evaluate its protective effect against transient ischemia-reperfusion (I/R) in diabetic animals.. Diabetes was induced by streptozotocin (40 mg/kg). Six weeks later, cerebral I/R was induced by bicommon carotid occlusion for 15 min followed by 1h reperfusion. Sitagliptin (250 mg/kg; p.o.) was administered daily during the last 2 weeks before I/R.. The drug alleviated hippocampal injury inflicted by diabetes and/or I/R injury where it suppressed nuclear factor kappa (NF-κ)B, and consequently the downstream inflammatory cytokines tumor necrosis factor-α and interleukin-6. In parallel, the anti-inflammatory cytokine interleukin-10 was elevated. Antioxidant potential of sitagliptin was depicted, where it reduced neutrophil infiltration, lipid peroxides and nitric oxide associated with replenished reduced glutathione. Decline of excitatory amino acid glutamate content is a main finding which is probably mediated by the NF-κB signaling pathway as well as improved oxidant status. Sitagliptin exerted an anti-apoptotic effect as reflected by the reduction of the mitochondrial matrix component cytochrome -C and the key downstream executioner caspase-3. Histopathological examination corroborated the biochemical data.. These findings suggest that sitagliptin is endowed with neuroprotective properties which are probably mediated by its antioxidant, anti-inflammatory, and anti-apoptotic mechanisms and hence may provide a novel agent for the management of ischemic stroke in diabetics.

Topics: Animals; Brain Ischemia; Caspase 3; Cytochromes c; Diabetes Complications; Diabetes Mellitus, Experimental; Hippocampus; Hypoglycemic Agents; Interleukin-10; Male; Neuroprotective Agents; Neutrophil Infiltration; Pyrazines; Rats; Rats, Wistar; Reperfusion Injury; Sitagliptin Phosphate; Triazoles

The purpose of this study is to investigate the effects and the underlying mechanisms of sitagliptin pretreatment on myocardial injury and cardiac function in myocardial ischemia/reperfusion (I/R) rat model. The rat model of myocardial I/R was constructed by coronary occlusion. Rats were pretreated with sitagliptin (300 mg/kg/day) for 2 weeks, and then subjected to 30 min ischemia and 2h reperfusion. The release of lactate dehydrogenase (LDH) and creatine kinase-MB (CK-MB), cardiac function and cardiomyocyte apoptosis were evaluated. The levels of malondialdehyde (MDA), glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD) in heart and glucagon-like peptide-1 (GLP-1) level in plasma were measured. Western blot analysis was performed to detect the target proteins of sitagliptin. Our results showed that sitagliptin pretreatment decreased LDH and CK-MB release, and MDA level in I/R rats. More importantly, we revealed for the first time that sitagliptin pretreatment decreased cardiomyocyte apoptosis while increased the levels of GSH-Px and SOD in heart. Sitagliptin also increased GLP-1 level and enhanced cardiac function in I/R rats. Furthermore, sitagliptin pretreatment up-regulated Akt(serine473) and Bad(serine136) phosphorylation, reduced the ratio of Bax/Bcl-2, and decreased expression levels of cleaved caspase-3 and caspase-3. Interestingly, the above observed effects of sitagliptin were all abolished when co-administered with GLP-1 receptor antagonist exendin-(9-39) or PI3K inhibitor LY294002. Taken together, our data indicate that sitagliptin pretreatment could reduce myocardial injury and improve cardiac function in I/R rats by reducing apoptosis and oxidative damage. The underlying mechanism might be the activation of PI3K/Akt signaling pathway by GLP-1/GLP-1 receptor.

Topics: Animals; Apoptosis; Body Weight; Cardiotonic Agents; Creatine Kinase, MB Form; Disease Models, Animal; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucose; Glutathione Peroxidase; Heart; Heart Ventricles; L-Lactate Dehydrogenase; Male; Malondialdehyde; Myocytes, Cardiac; Organ Size; Pyrazines; Rats; Rats, Sprague-Dawley; Receptors, Glucagon; Reperfusion Injury; Sitagliptin Phosphate; Superoxide Dismutase; Triazoles

This study tested the hypothesis that exendin-4 and sitagliptin can effectively protect kidney from acute ischemia-reperfusion (IR) injury.. Adult SD-rats (n = 48) equally divided into group 1 (sham control), group 2 (IR injury), group 3 [IR + sitagliptin 600 mg/kg at post-IR 1, 24, 48 hr)], and group 4 [IR + exendin-4 10 μm/kg at 1 hr after procedure] were sacrificed after 24 and 72 hrs (n = 6 at each time from each group) following clamping of bilateral renal pedicles for 60 minutes (groups 2-4).. Serum creatinine level and urine protein to creatinine ratio were highest in group 2 and lowest in group 1 (all p < 0.001) without notable differences between groups 3 and 4. Kidney injury score, expressions of inflammatory biomarkers at mRNA (MMP-9, TNF-α, IL-1β, PAI-1), protein (TNF-α, NF-κB and VCAM-1), and cellular (CD68+) levels in injured kidneys at 24 and 72 hr showed an identical pattern compared to that of creatinine level in all groups (all p < 0.0001). Expressions of oxidized protein, reactive oxygen species (NOX-1, NOX-2), apoptosis (Bax, caspase-3 and PARP), and DNA damage marker (γH2AX+) of IR kidney at 24 and 72 hrs exhibited a pattern similar to that of inflammatory mediators among all groups (all p < 0.01). Renal expression of glucagon-like peptide-1 receptor, and anti-oxidant biomarkers at cellular (GPx, GR) and protein (NQO-1, HO-1, GPx) levels at 24 and 72 hr were lowest in group 1, significantly lower in group 2 than in groups 3 and 4 (all p < 0.01).. Exendin-4 and sitagliptin provided significant protection for the kidneys against acute IR injury.

Topics: Animals; Biomarkers; Creatinine; Exenatide; Inflammation; Kidney; Male; Oxidative Stress; Peptides; Proteinuria; Pyrazines; Rats; Rats, Sprague-Dawley; Real-Time Polymerase Chain Reaction; Reperfusion Injury; Sitagliptin Phosphate; Triazoles; Venoms

This study was designed to investigate the possible effect of sitagliptin on renal damage induced by renal ischemia reperfusion (I/R) in diabetic rats. T2DM in rats was induced by the administration of nicotinamide (230 mg/kg, i.p.), 15 min prior to a single dose of streptozotocin (65 mg/kg, i.v.). In vivo renal I/R was performed in both T2DM and normal rats. Each protocol comprised ischemia for 30 min followed by reperfusion for 24h and a treatment period of 14 days before induction of ischemia. Sitagliptin treated diabetic rats that underwent renal I/R demonstrated significant decrease in the serum concentrations of aspartate aminotransferase (p < 0.01), urea nitrogen (p < 0.01) and creatinine (p < 0.001) compared to renal I/R in diabetic rats. Lipid peroxidation, xanthine oxidase activity, myeloperoxidase activity and nitric oxide level in renal tissue were significantly (p < 0.05, p < 0.001, p < 0.01, p < 0.05 respectively) decreased after renal I/R in sitagliptin treated rats compared to diabetic rats. Antioxidant enzymes like glutathione (p < 0.05), glutathione peroxidase (p < 0.001), superoxide dismutase (p < 0.05) and catalase (p < 0.001) were significantly increased after renal I/R in sitagliptin treated diabetic rats compared to non treated diabetic rats. The typical DNA laddering was observed when renal I/R performed in diabetic rats, which indicates cell apoptosis. Sitagliptin treated rats demonstrated a decrease in DNA fragmentation and apoptosis. Furthermore, renal histopathology preserved in sitagliptin treated rats verified protection against renal I/R in diabetes. The results of present investigation established sitagliptin treatment attenuated renal damage induced by renal I/R in diabetic rats.

Topics: Animals; Apoptosis; Catalase; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; DNA Fragmentation; Female; Glutathione; Glutathione Peroxidase; Kidney; Kidney Diseases; Lipid Peroxidation; Male; Oxidative Stress; Peroxidase; Pyrazines; Rats; Rats, Wistar; Reperfusion Injury; Sitagliptin Phosphate; Superoxide Dismutase; Triazoles; Xanthine Oxidase