The Effect of Metformin on Ethanol- and IndomethacinInduced Gastric Ulcers in Rats.

BACKGROUND: Previous studies found metformin as an effective agent to suppress oxidative stress, inflammation, and apoptosis in various inflammatory diseases. The present study investigated the effect of metformin against 2 experimental gastric injury models in rats, using macroscopical, histopathological, biochemical, and immunostaining studies. METHODS: After 24 hours of fasting, male Sprague-Dawley rats (280-400 g) (n = 8 per group) received indomethacin (80 mg/kg; indo ulcer group) or absolute ethanol (5 mL/kg; ethanol ulcer group) or vehicle orally by gavage. Metformin (500 mg/kg) was given orally for 3 days prior to indomethacin or ethanol challenge. Ranitidine (50 mg/kg) was given orally for 3 days before indomethacin or ethanol administration as a positive control. On day 3, the animals were euthanized 6 hours after indo or 1 hour after ethanol challenge. Gastric samples were used for macroscopic scoring, histopathological examinations, and biochemical assays. Trunk blood was collected for the assessment of interleukin-1ß level. RESULTS: In both ethanol ulcer and indo ulcer groups, metformin decreased the extent of gastric lesions macroscopically and microscopically, improved the high chemiluminescence levels, and the percentage of terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive apoptotic cells compared with untreated ulcer groups. Gastric blood flow analysis revealed significant increases in both metformin-treated ulcer groups compared to untreated ulcer groups. CONCLUSION: The findings of the present work demonstrated the gastroprotective effect of metformin against the development of gastric mucosal lesions induced by ethanol and indomethacin in non-diabetic, normoglycemic rats via its antioxidant and anti-apoptotic properties and partly from its ability to restore blood flow.

Potential Effect of 1,25 Dihydroxyvitamin D3 on Thioacetamide-Induced Hepatotoxicity in Rats.

BACKGROUND: 1,25 Dihydroxyvitamin D3 (1,25(OH)2D3) modulates inflammation and immune responses. Deficiency of 1,25(OH)2D3 was found to be associated with the risk of cancer, cardiovascular disease, osteoarthritis, infections, and autoimmune diseases. This study evaluated the effect of 1,25 dihydroxyvitamin D3 1,25(OH)2D3 on thioacetamide (TAA)-induced acute liver injury in rats. MATERIALS AND METHODS: Rats were treated with either saline or 1,25(OH)2D3 (0.30 µg/kg; orogastrically) for 15 d. Starting from day 13, TAA (200 mg/kg; intraperitoneally) was given for 3 d. On day 15, all rats were euthanized. Liver and blood samples were collected. RESULTS: TAA caused severe damage, increased lipid peroxidation with reductions in endogenous antioxidants, increased apoptosis, increased production of reactive oxygen species, and elevated inducible nitric oxide synthase (iNOS), and nuclear factor kappa B (NF-κB) expression in liver. Extent of damage was decreased by 1,25(OH)2D3 (P < 0.01). 1,25(OH)2D3 attenuated the increase in malondialdehyde (P < 0.01), increase in myeloperoxidase (P < 0.01), increase in chemiluminescence levels (P < 0.05) and apoptotic activity (P < 0.001). Elevated liver iNOS and NF-κB expression in TAA group was also reduced by 1,25(OH)2D3 (P < 0.001, for iNOS; P < 0.001, for NF-κB). TAA group revealed high serum aspartate transaminase and alanine transaminase (ALT) activities (P < 0.01, for aspartate transaminase; P = 0.08, for ALT) and reduced albumin levels (P < 0.01) compared with control. 1,25(OH)2D3 had no statistically significant effect on these parameters. CONCLUSIONS: 1,25(OH)2D3 provides protection against hepatic injury in a rat model of TAA-induced hepatotoxicity via suppression of inflammatory reaction, oxidative stress, and apoptosis.

The effect of 1,25 dihydroxyvitamin D3 on HCl/Ethanol-induced gastric injury in rats.

This study evaluated ulceroprotective and antioxidant effect of 1,25 dihydroxyvitamin D3 against gastric damage in rats. Rats were treated intraperitoneally with either 1,25 dihydroxyvitamin D3 (0.25 µg/kg) or saline for 14 days. On day-15, the non-selective cyclooxygenase inhibitor indomethacin (10 mg/kg; subcutaneously), the inhibitor of sulfhydryl groups N-ethylmaleimide (10 mg/kg; intraperitoneally) or ATP-sensitive K+ channel blocker glibenclamide (10 mg/kg; orally) was given prior to 1,25 dihydroxyvitamin D3. Animals were euthanized at 60 min post ulcerogenic challenge (0.3 M HCl and 60% ethanol (0.2 mL; orally). Stomach and blood were collected for biochemical and histological evaluations. HCl/Ethanol group revealed severely damaged mucous and glandular epithelium with diffuse hemorrhage and inflammatory cell infiltration (microscopic score: 10.67 ±â€¯0.67 and ulcer index: 33.13 ±â€¯5.09). 1,25 dihydroxyvitamin D3 decreased the extent of damage (microscopic score: 6.80 ±â€¯0.02 and ulcer index: 19.00 ±â€¯4.34; p < 0.05), and the elevations in gastric malondialdehyde level (p < 0.001), myeloperoxidase activity (p < 0.001), nuclear factor-κB expression (p < 0.05), and apoptotic index (p < 0.05) following HCl/Ethanol challenge. Decreased gastric glutathione following HCl/Ethanol administration was restored by 1,25 dihydroxyvitamin D3 (p < 0.01). These findings demonstrated protection of the gastric mucosa against HCl/Ethanol-induced injury by 1,25 dihydroxyvitamin D3 via attenuation of inflammatory reaction, oxidative stress and apoptosis.

Inhibition of 5-lipoxygenase by zileuton in a rat model of myocardial infarction.

OBJECTIVE: The goal of the present study was to investigate the effects of 5-lipoxygenase (5-LOX) inhibition, alone and with cyclooxygenase (COX) inhibitors, on inflammatory parameters and apoptosis in ischemia/reperfusion (I/R)-induced myocardial damage in rats. For this purpose, zileuton, a selective and potent inhibitor of 5-LOX, resulting in suppression leukotriene production, was used. METHODS: Male Wistar rats (200-250 g; n=12 per group) were used in the study. I/R was performed by occluding the left coronary artery for 30 minutes and 2 hours of reperfusion of the heart. Experimental groups were I/R group, sham I/R group, zileuton (5 mg/kg orally, twice daily)+I/R group, zileuton+indomethacin (5 mg/kg intraperitoneally)+I/R group, zileuton+ketorolac (10 mg/kg subcutaneously)+I/R group, and zileuton+nimesulide (5 mg/kg subcutaneously)+I/R group. Following I/R, blood samples were collected to measure tumor necrosis factor alpha (TNF-α), and left ventricles were excised for evaluation of microscopic damage; malondialdehyde (MDA), glutathione, nuclear factor (NF)-κB assays; and evaluation of apoptosis. RESULTS: Left ventricle MDA in I/R group was higher compared to sham group; however, it did not show significant change with zileuton. Although tissue injury in I/R group was less severe in all treatment groups, it was not statistically significant. NF-κB H-score and apoptotic index, which were higher in I/R group compared to sham I/R, were decreased with application of zileuton (H-score: p<0.01; apoptotic index: p<0.001). Zileuton had no significant effect on increased serum TNF-α levels in I/R group. CONCLUSION: 5-LOX inhibition in rat myocardial infarction model attenuated increased left ventricle NF-κB expression and apoptosis and these actions were not modulated by COX inhibitors.

The role of cholinergic anti-inflammatory pathway in acetic acid-induced colonic inflammation in the rat.

The "cholinergic anti-inflammatory pathway" provides neurological modulation of cytokine synthesis to limit the magnitude of the immune response. This study aimed to evaluate the impact of the cholinergic anti-inflammatory pathway on the extent of tissue integrity, oxidant-antioxidant status and neutrophil infiltration to the inflamed organ in a rat model of acetic acid-induced colitis. Colitis was induced by intrarectal administration of 5% acetic acid (1ml) to Sprague-Dawley rats (200-250g; n=7-8 per group). Control group received an equal volume of saline intrarectally. The rats were treated with either nicotine (1mg/kg/day) or huperzine A (0.1mg/kg/day) intraperitoneally for 3 days. After decapitation, the distal colon was scored macroscopically and microscopically. Tissue samples were used for the measurement of malondialdehyde (MDA) and glutathione (GSH) levels, and myeloperoxidase (MPO) activity. Formation of reactive oxygen species was monitored by using chemiluminescence (CL). Nuclear factor (NF)-κB expression was evaluated in colonic samples via immunohistochemical analysis. Trunk blood was collected for the assessment of tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, IL-10, resistin and visfatin levels. Both nicotine and huperzine A reduced the extent of colonic lesions, increased colonic MDA level, high MPO activity and NF-κB expression in the colitis group. Elevation of serum IL-1ß level due to colitis was also attenuated by both treatments. Additionally, huperzine A was effective to reverse colitis-induced high lucigenin-enhanced CL values and serum TNF-α levels. Colitis group revealed decreased serum visfatin levels compared to control group which was completely reversed by nicotine. In conclusion, modulation of the cholinergic system either by nicotine or ACh esterase inhibition improved acetic acid-induced colonic inflammation as confirmed by macroscopic and microscopic examination and biochemical assays.

The effect of phosphodiesterase-5 inhibition by sildenafil citrate on inflammation and apoptosis in rat experimental colitis.

AIMS: To investigate the effect of sildenafil citrate (SIL) on the extent of tissue integrity, oxidant-antioxidant status and apoptosis in rats with colitis. MAIN METHODS: Colitis was induced by trinitrobenzenesulphonic acid (TNBS) in 40% ethanol (30 mg/ml; 0.8 ml) given intrarectally to Sprague-Dawley rats. Sildenafil (25 mg/kg/day) was administered after the induction of colitis and the treatment was continued for 7 days. Other groups received subcutaneously either N(G)-nitro- L-arginine methyl ester (l-NAME; 25 mg/kg) or N(G)-nitro-d-arginine methyl ester (d-NAME; 25 mg/kg) before SIL. After decapitation, the distal colon was scored and stored for the measurement of malondialdehyde (MDA) level, glutathione (GSH) content, myeloperoxidase (MPO) activity and apoptosis. Oxidant generation was monitored by using chemiluminescence (CL). Blood was collected for tumor necrosis factor (TNF)-α and interleukin (IL)-10 assays. KEY FINDINGS: The macroscopic lesion score of the colitis group was reduced by SIL (p < 0.01) and this effect was abolished by l-NAME (p < 0.01). Increase in colonic MDA along with a concomitant decrease in GSH of the colitis group was reversed by SIL (p < 0.01 and p < 0.001, respectively). l-NAME prevented the effect of SIL on GSH content (p < 0.001). Sildenafil also reduced the elevated MPO of the colitis group (p < 0.001) and this effect was reversed by L-NAME (p < 0.01). Increase in lucigenin CL and serum TNF-α levels in the colitis group were also prevented by SIL (p < 0.001 and p < 0.01, respectively). SIGNIFICANCE: Sildenafil is beneficial in TNBS-induced rat colitis partially by nitric oxide-dependent mechanisms via the maintenance of oxidant-antioxidant status, prevention of apoptosis, superoxide production and cytokine release.

Phosphodiesterase-5 inhibition by sildenafil citrate in a rat model of bleomycin-induced lung fibrosis.

Sildenafil, a selective and potent inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase (PDE)5, has a relaxant effect on the smooth muscle cells of the arterioles supplying the human corpus cavernosum acting via nitric oxide (NO)-dependent mechanism. This study aimed to investigate the possible protective effect of sildenafil citrate on the extent of tissue integrity, oxidant-antioxidant status and neutrophil infiltration to the inflamed organ in a rat model of bleomycin-induced lung fibrosis. Lung fibrosis was induced by intratracheal administration of 0.1 ml of bleomycin hydrochloride (5 mg/kg in 0.9% NaCl) under anesthesia to Sprague-Dawley rats (200-250 g; n = 7-8 per group). Control rats received an equal volume of saline intratracheally. In the treatment groups, the rats were treated with either sildenafil citrate (10 mg/kg per day; subcutaneously) or saline for 14 days. Another group of rats were administered subcutaneously with N(G)-nitro-l-arginine methyl ester (l-NAME; 20 mg/kg in 0.9% NaCl) 5 min after sildenafil injections. After decapitation, the lungs were excised and taken for microscopic evaluation or stored for the measurement of malondialdehyde (MDA) and glutathione (GSH) levels, and myeloperoxidase (MPO) activity, and for the assessment of apoptosis. Trunk blood was collected for the assessment of serum tumor necrosis factor (TNF)-alpha and interleukin (IL)-1beta levels. In the group with lung fibrosis, the lung tissue was characterized by microscopic lesions, increased lipid peroxidation with a concomitant reduction in GSH content, increased MPO activity and apoptosis. Serum TNF-alpha and IL-1beta levels were higher in the lung fibrosis group compared to control values. Sildenafil reversed tissue MDA levels, MPO activity and serum pro-inflammatory cytokine levels, and preserved GSH content although its effect on the extent of tissue lesion and apoptosis was not statistically significant. Treatment with l-NAME reversed the effect of sildenafil on GSH content. In conclusion, sildenafil citrate administration to rats with bleomycin-induced lung fibrosis seems to be beneficial via prevention of lipid peroxidation, cytokine production and/or release and neutrophil accumulation.

Halofuginone has a beneficial effect on gentamicin-induced acute nephrotoxicity in rats.

The aim of this study was to investigate the putative beneficial effect of halofuginone on gentamicin-induced nephrotoxicity in rats. Sprague-Dawley rats were treated with gentamicin sulphate (GEN; 80 mg/kg) or saline intraperitoneally (i.p.) for 7 days. Halofuginone was administered (0.1 mg/kg/day; i.p.) following GEN or saline injections. Blood and urine samples were collected to measure the renal function tests. Kidneys were excised for histological evaluation and for the measurement of malondialdehyde (MDA), glutathione (GSH), myeloperoxidase (MPO) activity, and chemiluminescence (CL). Halofuginone treatment to animals with GEN-induced renal injury caused a significant decrease in serum blood urea nitrogen level and reduced the elevated MDA, GSH content, and MPO activity. It was also effective in reversing the elevated CL values of rats with GEN-induced nephrotoxicity and preserving renal morphology, as examined microscopically. In conclusion, halofuginone was beneficial in GEN-induced acute nephrotoxicity. The mechanism could be attributed, at least in part, to decreased tissue leukocyte infiltration and reactive metabolite production.

The effect of sildenafil, a phosphodiesterase-5 inhibitor, on acetic acid-induced colonic inflammation in the rat.

BACKGROUND AND AIM: Sildenafil, a selective and potent inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase (PDE)5, has a relaxant effect on the smooth muscle cells of the arterioles supplying the human corpus cavernosum acting via nitric oxide (NO)-dependent mechanism. This study aimed to investigate the possible protective effect of sildenafil citrate on the extent of tissue integrity, oxidant-antioxidant status and neutrophil infiltration to the inflamed organ in a rat model of acetic acid-induced colitis. METHODS: Colitis was induced by intrarectal administration of 1 mL of 5% acetic acid to Sprague-Dawley rats (200-250 g; n = 7-8/group). Control rats received an equal volume of saline intrarectally. In treatment groups, the rats were treated with either sildenafil citrate (5 mg/kg/day; subcutaneously) or saline for 3 days. After decapitation, distal colon was weighed and scored macroscopically and microscopically. Tissue samples were used for the measurement of malondialdehyde (MDA) and glutathione (GSH) levels, myeloperoxidase (MPO) activity, and oxidant production. Trunk blood was collected for the assessment of serum tumor necrosis factor (TNF)-alpha and interleukin (IL)-1beta levels. RESULTS: In the colitis group, the colonic tissue was characterized by lesions, increased lipid peroxidation with a concomitant reduction in GSH content, increased MPO activity and oxidant production. Serum TNF-alpha and IL-1beta levels were higher in the colitis group compared to control values. Sildenafil reversed these inflammatory parameters nearly back to control values. CONCLUSIONS: Sildenafil citrate administration to rats with acetic acid-induced colitis seems to be beneficial via prevention of lipid peroxidation, oxidant generation, cytokine production and neutrophil accumulation.

Hyperbaric oxygen therapy is as effective as dexamethasone in the treatment of TNBS-E-induced experimental colitis.

INTRODUCTION: Hyperbaric oxygen (HBO) has been demonstrated to be useful as an adjunctive therapy for Crohn's disease. In the present study, HBO was tested as a treatment for trinitrobenzenesulfonic acid-ethanol (TNBS-E)-induced distal colitis, and its effects were compared with dexamethasone therapy. METHODS: A total of 48 Sprague-Dawley rats were separated into six groups: the control, and those treated with vehicle, TNBS-E, HBO, dexamethasone, or combined HBO + dexamethasone. The HBO treatment group was exposed to 100% HBO at 2 ATM for 75 min twice daily at 6-h intervals in a HBO chamber, both on the day of colitis induction and 3 days thereafter. Treatment with intraperitoneal dexamethasone twice daily was started 1 h before the induction of colitis and was continued for 7 days in the dexamethasone group. The rats were decapitated 8 days after the induction of colitis, and the colonic tissue wet weight, macroscopic and microscopic lesion score, and tissue myeloperoxidase (MPO) activity were determined. RESULTS: HBO therapy decreased the activity of experimental colitis measured by the tissue wet weight, macroscopic score, microscopic score, and MPO activity. The dexamethasone treatment significantly reduced the colitis activity as determined by the tissue MPO activity and wet weight. There were also decreases in the macroscopic and microscopic activity scores with the dexamethasone therapy; however, these changes were not statistically significant. The combined therapy with HBO and dexamethasone provided no additional benefit over HBO therapy alone. CONCLUSION: HBO therapy can be a valuable therapeutic option in treatment of patients with inflammatory bowel disease. HBO therapy in the refractory patients deserves further, larger clinical studies.

Protective role of adrenomedullin in burn-induced remote organ damage in the rat.

Clinical and experimental research findings suggest that a local burn insult produces oxidant-induced organ changes as evidenced by increased lipid peroxidation in lung, liver and gut. Adrenomedullin (AM), a potent vasodilator, was originally isolated from pheochromocytoma cells, and has been identified in other tissues. In this study, we investigated the potential role of AM in burn-induced remote organ damage in rats. Sprague-Dawley rats (250-300 g) were treated with either AM (100 ng/kg, subcutaneously) or saline 10 min before burn insult which covers 30% of total body surface area and were decapitated 24 h after the burn insult. Trunk blood was collected and analyzed for liver and kidney functions and for determination of TNF-alpha levels. The liver, lung and kidney samples were taken for histologic evaluation and for measurement of malondialdehyde (MDA) level, myeloperoxidase (MPO) activity and chemiluminescence levels. The data revealed that AM treatment resulted in a significant protection in tissues tested against burn injury via suppression of lipid peroxidation, tissue neutrophil infiltration, oxidant generation and via decreasing circulating levels of the pro-inflammatory cytokine TNF-alpha. AM treatment was also effective in attenuating hepatic and kidney dysfunction due to burn injury, suggesting that peripherally AM administration may protect the tissues against burn-induced injury.

Alpha-lipoic acid modulates gut inflammation induced by trinitrobenzene sulfonic acid in rats.

BACKGROUND AND AIM: Alpha-lipoic acid (ALA) has been shown to combat oxidative stress by quenching a variety of reactive oxygen species. It is involved in the regeneration of exogenous and endogenous antioxidants, chelation of metal ions, and repair of oxidized proteins. This study aimed to evaluate the potential beneficial effect of ALA on trinitrobenzenesulfonic acid (TNBS)-induced gut ileitis and colitis in rats. METHOD: After 48 h of fasting, Sprague-Dawley rats underwent a laparotomy under ether anesthesia. TNBS solution 30 mg/mL in 40% ethanol (1 mL) was injected into the lumen, 10 cm proximal to the ileocolonic junction to induce ileitis or intrarectally 8 cm proximal to the anal sphincter to induce colitis. ALA (25 mg/kg intraperitoneally, twice a day) was given after induction of inflammation and continued for 3 days. All animals were decapitated 3 days after induction of the inflammation. The mucosal lesions of the ileum and colon were scored macroscopically and microscopically. Samples were taken for the measurement of malondialdehyde (MDA) and glutathione (GSH) levels, tissue-associated myeloperoxidase (MPO) activity and luminol- or lucigenin-enhanced chemiluminescence (CL). RESULTS: Macroscopic scores, morphological changes and increased tissue lipid peroxidation with a concomitant reduction in GSH of the ileitis or colitis groups were all reversed by treatment with ALA. ALA treatment was also effective in improving tissue MPO activity and CL values, which were elevated in untreated ileitis or colitis groups. CONCLUSION: ALA is beneficial in TNBS-induced gut inflammation in rats via suppression of neutrophil accumulation, preservation of endogenous glutathione and inhibition of reactive oxidant generation.

Montelukast reduces ischaemia/reperfusion-induced bladder dysfunction and oxidant damage in the rat.

The present study aimed to investigate the possible beneficial effects of the cysteinyl leukotriene-1 receptor antagonist montelukast on contractility and oxidant damage after ischaemia/reperfusion (I/R) of rat urinary bladder. The abdominal aorta of Sprague-Dawley rats was occluded to induce I/R. Montelukast (10 mg kg(-1)) or saline was administered intraperitoneally before I/R. In the sham-operated group, the abdominal aorta was left intact and the animals were treated with montelukast or saline. After decapitation, the bladder was removed and the tissue was either used for functional studies or stored for biochemical assays. In the I/R group, the isometric contractile responses of the bladder strips to carbachol (10(-8)-10(-4) M) were lower than those of the control group and were reversed by treatment with montelukast. Lipid peroxidation and myeloperoxidase activity of the bladder tissues in the I/R group were greater than in the sham-operated group. Montelukast treatment in the I/R group decreased these parameters compared with I/R alone. Similarly, the significant decrease in tissue glutathione level in the I/R group compared with controls was also prevented by montelukast. Treatment with montelukast almost completely reversed the low contractile responses of rat urinary bladder to carbachol and prevented oxidative tissue damage following I/R.

The effect of alpha-melanocyte stimulating hormone on gentamicin-induced acute nephrotoxicity in rats.

The effect of alpha-melanocyte stimulating hormone (alpha-MSH) was investigated on gentamicin-induced acute renal injury in rats. Sprague-Dawley rats (200-250 g; n = 8-10) were treated with gentamicin sulphate (GEN; 80 mg kg(-1)) or saline intraperitoneally for 7 consecutive days. alpha-MSH was administered at a dose of 25 microg rat(-1) day(-1) following GEN or saline injections. On day 8, all animals were decapitated. Trunk blood and 24 h urine were collected to measure the serum creatinine levels, blood urea nitrogen (BUN) levels and to calculate the creatinine clearance values. The kidneys were excised for histological evaluation and for the measurement of malondialdehyde (MDA) levels, glutathione (GSH) contents and myeloperoxidase (MPO) activity. Treatment with alpha-MSH reduced the severity of the renal lesions microscopically, decreased MDA content and MPO activity and restored GSH in kidney samples. However, it did not restore the impaired renal function tests due to GEN challenge. In conclusion, alpha-MSH treatment has a beneficial effect on GEN-induced acute nephrotoxicity, as confirmed by histological evaluation and biochemical assays; but it does not improve GEN-induced renal dysfunction. The mechanism of the protective effect could be attributed, at least in part, to decreased tissue leukocyte infiltration and thus, to decreased oxygen-derived reactive metabolite production.

Simvastatin attenuates cisplatin-induced kidney and liver damage in rats.

Statins have anti-inflammatory effects that are not directly related to their cholesterol-lowering activity. This study aimed to investigate the effect of simvastatin on the extent of tissue damage in cisplatin-induced nephrotoxicity and hepatotoxicity. The rats received a single intravenous injection of 2.5mgkg(-1) cisplatin. Other groups received either simvastatin (1mgkg(-1)) or the vehicle (ethanol:saline) intraperitoneally for 10 days beginning 5 days prior to cisplatin injection. All animals were decapitated 5 days after cisplatin administration. Trunk blood was collected and analyzed for blood urea nitrogen (BUN), creatinine, alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH), albumin, and total bilirubin levels. The urine samples were used for the calculation of creatinine clearance levels. The kidney and liver samples were stored for the measurement of malondialdehyde (MDA) and glutathione (GSH) levels, myeloperoxidase (MPO) activity and collagen content or were processed for histopathological examinations. Formation of reactive oxygen species in tissue samples was monitored by using chemiluminescence method. Simvastation reduced the extent of both kidney and liver damage and preserved both kidney and liver functions (p<0.01-0.001). Increase in liver MDA level with a concomitant reduction in GSH in the cisplatin group was attenuated by simvastatin treatment (p<0.05-0.01). Increase in tissue collagen content and chemiluminescence levels in the kidney and liver samples of the cisplatin group was also reversed by simvastatin (p<0.001). In conclusion, simvastatin is beneficial in cisplatin-induced kidney and liver dysfunction and organ damage in rats via prevention of lipid peroxidation and tissue fibrosis, preservation of antioxidant glutathione, and suppression of neutrophil infiltration.

Gastric protection by alpha-melanocyte-stimulating hormone against ethanol in rats: involvement of somatostatin.

The proopiomelanocortin-derived tridecapeptide alpha-melanocyte-stimulating hormone (alpha-MSH) is a neuropeptide that exerts broad anti-inflammatory actions in mammals. This study aimed to investigate the effect of alpha-MSH on ethanol-induced gastric ulcer in rats and to evaluate the involvement of endogenous somatostatin in the actions of the peptide. The rats received 1 mL 75% ethanol or saline orally. alpha-MSH was given (25 micro g/rat; i.p.) alone or following the somatostatin antagonist cyclo-(7-aminoheptanoyl-PH-E-d-Trp-Lys-THR) (10 microM/kg; i.p.) administration. Gastric lesions were scored macroscopically and microscopically following decapitation at 30 min after ethanol challenge. Gastric malondialdehyde (MDA) level, myeloperoxidase (MPO) activity and mast cell counts were assessed. Ethanol-induced gastric hemorrhagic lesions were characterized by increased gastric MDA level, MPO activity and mast cell counts. alpha-MSH treatment decreased the extent of tissue injury and reversed tissue MDA level, MPO activity and mast cell counts. The effect of the peptide on the severity of gastric lesions, MDA level and MPO activity was reversed by the somatostatin antagonist. In conclusion, alpha-MSH is beneficial in a rat model of gastric ulcer via mechanisms which partly involve the endogenous somatostatin.

The beneficial effect of resveratrol on rat bladder contractility and oxidant damage following ischemia/reperfusion.

OBJECTIVE: The present study aimed to investigate the possible beneficial activities of resveratrol (3,5,4'-trans-trihydroxystilbene), a natural phytoalexin, on contractility and oxidant damage after ischemia/reperfusion (I/R) of the rat urinary bladder. MATERIALS AND METHODS: The abdominal aorta of Sprague-Dawley rats was occluded for 60 min to induce ischemia and then allowed 60 min of reperfusion. Resveratrol (10 mg/kg) or saline was administered intraperitoneally 15 min before ischemia and immediately before reperfusion. In the sham-operated group, the abdominal aorta was left intact and the animals were treated with resveratrol or saline. The bladder samples were either used for functional studies or stored for biochemical assays. RESULTS: In the I/R group, the isometric contractile responses of the bladder strips to carbachol (CCh; 10(-8)-10(-4) mol/l) were lower than those of the control group and were reversed by treatment with resveratrol. Histological evaluation revealed loss of urothelial cells, detachment and loss of urothelial cells and local ulcerated areas and severe inflammatory cell infiltration in the untreated I/R group, and regeneration of luminal mucosa and a significant decrease in the density of the inflammatory cell population in the resveratrol-treated I/R group. Lipid peroxidation and the myeloperoxidase activity of the bladder tissues in the I/R group were higher than in the sham-operated group. Resveratrol treatment in the I/R group decreased these parameters compared with I/R alone. Similarly, the significant decrease in tissue glutathione level in the I/R group compared with controls was also prevented by resveratrol. CONCLUSION: Treatment with resveratrol almost completely reversed the low contractile responses of the rat urinary bladder to CCh and prevented oxidative tissue damage following I/R.

Effects of statins on experimental colitis in normocholesterolemic rats.

OBJECTIVE: The results of previous studies suggest that statins have a direct anti-inflammatory effect that is not directly related to their cholesterol-lowering activity. The aim of this study was to investigate the effect of simvastatin (SIM) and fluvastatin (FLU) on trinitrobenzene sulfonic acid (TNBS)-induced colonic inflammation in rats. MATERIAL AND METHODS: The drugs were given for 3 days (0.1 and 1 mg/kg day-1; intraperitoneally) after induction of colitis. The lesions in the distal colon were scored at the macroscopic and microscopic level. Tissue malondialdehyde (MDA) and glutathione (GSH) levels, myeloperoxidase (MPO) activity and collagen content were assessed and formation of reactive oxygen species and peroxynitrite was monitored by chemiluminescence (CL) assay. Trunk blood was collected for the measurement of serum tumor necrosis factor (TNF)-alpha level. RESULTS: Treatment with SIM reduced the lesion score of the colitis group at macroscopic level (p<0.05), but there was no effect of treatment with FLU. The increase in colonic MDA level of the colitis group was reduced by both drugs at all doses (p<0.05-0.001). The decrease in GSH and the an increase in MPO activity in the colitis group were reversed by SIM at all doses (p<0.01), but FLU had no effect. An increase in colonic lucigenin CL value in the colitis group was reduced by SIM and FLU at all doses (p<0.001) and an increase in peroxynitrite ratio in the colitis group showed a significant reduction in SIM-treated groups; FLU reduced this effect at a dose of 1 mg/kg (p<0.01). An increase in tissue collagen content and serum TNF-alpha level in the colitis group was reversed by both drugs at all doses (p<0.001). CONCLUSIONS: SIM and FLU seemed to be beneficial in a TNBS-induced rat colitis model through the prevention of lipid peroxidation, superoxide generation, cytokine production and neutrophil accumulation.

Resveratrol reduces renal and lung injury caused by sepsis in rats.

UNLABELLED: Resveratrol (3,5,4'-trans-trihydroxystilbene), a natural phytoalexin, has various pharmacological effects, including anti-inflammatory properties via inhibition of oxidation, leukocyte priming, and expression of inflammatory mediators. The present study was aimed to investigate the possible beneficial activities of resveratrol on lung and kidney damage in a rat model of sepsis. MATERIALS AND METHODS: Sepsis was induced to Sprague-Dawley rats of both sexes (200-250 g) by cecal ligation and perforation. The rats were treated with resveratrol (30 mg/kg; i.p.) or saline after induction of sepsis and at 16 h. Twenty-four hours after the sepsis-induction, all rats were decapitated. Blood was collected for the measurement of tumor necrosis factor-alpha level and lactate dehydrogenase activity. Lung and kidney samples were taken for histological assessment and for the measurement of malondialdehyde, glutathione level, myeloperoxidase activity, and collagen content. RESULTS: Sepsis caused a significant increase in malondialdehyde levels, myeloperoxidase activity, and collagen content of the lung and kidney tissues with a concomitant reduction in glutathione levels. Microscopic examination revealed severe destruction of regular morphology in both lung and kidney tissues. Serum tumor necrosis factor-alpha and lactate dehydrogenase levels also were higher in rats with sepsis compared to those of the sham group. Resveratrol treatment reversed these biochemical parameters and preserved tissue morphology as evidenced by histological evaluation. CONCLUSIONS: Resveratrol, a phenolic compound, reduces sepsis-induced remote organ injury, at least in part, through its ability to balance oxidant-antioxidant status, to inhibit neutrophil infiltration and to regulate the release of inflammatory mediators.

The effect of angiotensin-converting enzyme inhibitors on experimental colitis in rats.

The present study was aimed to investigate the effect of ACE inhibition on trinitrobenzene sulphonic acid (TNBS)-induced colonic inflammation in rats by using captopril and lisinopril. In treatment groups, the rats were treated with ACE inhibitors, captopril or lisinopril (0.1 and 1 mg/kg/day; intraperitoneally). The drugs were given 5 min after induction of colitis and the treatment was continued for 3 days. Three days after the induction of colitis, all rats were decapitated. The distal colon was weighed and the mucosal lesions were scored at both macroscopical at microscopic levels. Malondialdehyde (MDA) and glutathione (GSH) levels, myeloperoxidase (MPO) activity and collagen content were assessed in tissue samples. Formation of reactive oxygen species in colonic samples was monitored by using chemiluminescence technique. Serum TNF-alphalevel was assessed in trunk blood. Captopril treatment was found to be beneficial in all parameters, except colonic glutathione content. On the other hand, although stimulation of lipid peroxidation and increase in serum TNF-alpha level were successfully prevented by lisinopril, the morphology of the lesions remained unchanged. In conclusion, sulphydryl and non-sulphydryl ACE inhibitors, captopril and lisinopril do not seem to be similarly effective in TNBS-induced colitis model at least at the doses tested in our study.