Gastroprotective Effect of Rutin against Indomethacin‐Induced Ulcers in Rats

Abstract: Several reports have indicated that indomethacin‐induced gastropathy is mediated through generation of free radicals, neutrophil infiltration and disturbance in nitric oxide production. Rutin is a potent antioxidant flavonoid. Recently, rutin was reported to inhibit neutrophil infiltration and to modulate nitric oxide production in gastric mucosa. Therefore, the aim of this study was to investigate the protective effect of rutin against indomethacin‐induced gastric injury. Accordingly, four groups of rats were used. The first three groups were injected orally with vehicle, rutin (200 mg/kg) and indomethacin (48 mg/kg) respectively. The fourth group was injected with rutin 1 hr before indomethacin. Animals were killed after 6 hr of indomethacin administration. Gastric juice acidity and gastric injury were evaluated directly. Moreover, the activities of myeloperoxidase, superoxide dismutase and the contents of reduced glutathione, thiobarbituric acid reactive substance and total nitrite/nitrate (as a marker of nitric oxide production) were determined in mucosal tissues. Indomethacin increased gastric ulcer index, gastric myeloperoxidase activity, gastric acidity and thiobarbituric acid reactive substance contents compared with control. On the other hand, indomethacin decreased glutathione, nitrite/nitrate contents and superoxide dismutase activity. Histopathological examination of the stomachs of indomethacin‐treated rats revealed degenerative changes in gastric tissues. Pre‐treatment with rutin protected gastric tissues against indomethacin‐induced gastropathy as demonstrated from reduction in the ulcer index, attenuation of histopathological changes and amelioration of the altered oxidative stress and biochemical parameters. These results indicate that rutin has a protective effect against indomethacin‐induced gastropathy probably through inhibiting neutrophil infiltration, suppression of oxidative stress generation and replenishing nitrite/nitrate levels regardless of gastric acidity.     

LPS from Escherichia coli protects against indomethacin-induced gastropathy in rats--role of ATP-sensitive potassium channels

The effect of lipopolysaccharide (LPS) in gastric protection has not been elucidated, but ATP-sensitive potassium (K(ATP)) channels are known to be involved in gastric defense. We evaluated the effect of LPS administration on indomethacin-induced gastropathy, and the role of K(ATP) channels in this event. Rats received intravenous (i.v.) LPS administration. After 1/2, 6, 24 or 48 h, indomethacin was injected. 3H later, gastric damage and myeloperoxidase activity were determined. Another group received LPS and 5 h later, glibenclamide, diazoxide or glibenclamide plus diazoxide. After 1 h, the rats received indomethacin and 3 h later, gastric damage and myeloperoxidase activity were evaluated. LPS reduced dose dependently gastric damage and myeloperoxidase activity induced by indomethacin. Glibenclamide reversed this LPS effect on indomethacin-induced gastropathy. Glibenclamide plus diazoxide administration did not change this LPS effect. Thus LPS has a protective effect against indomethacin-induced gastropathy, probably through activation of K(ATP) channels.     

Effect of hesperidin and neohesperidin from bittersweet orange (Citrus aurantium var. bigaradia) peel on indomethacin-induced peptic ulcers in rats

Hesperidin and neohesperidin are the major flavanones isolated from bittersweet orange. It was recently reported that they have potent anti-inflammatory effects in various inflammatory models. In the present study, the effects of hesperidin and neohesperidin on indomethacin-induced ulcers in rats and the underlying mechanisms were investigated. Gastric ulcers were induced in rats with a single dose of indomethacin. The effects of pretreatment with hesperidin and neohesperidin were assessed in comparison with omeprazole as reference standard. Ulcer index, gene expression of gastric cyclooxygenase-2 (COX-2), tumor necrosis factor alpha (TNF-α), lipid peroxidation product, malondialdhyde (MDA), and reduced glutathione (GSH) content in stomach were measured. Furthermore, gross and histopathological examination was performed. Our results indicated that both hesperidin and neohesperidin significantly aggravated gastric damage caused by indomethacin administration as evidenced by increased ulcer index and histopathological changes of stomach.     

Escin attenuates acute lung injury induced by endotoxin in mice

Endotoxin causes multiple organ dysfunctions, including acute lung injury (ALI). The current therapeutic strategies for endotoxemia are designed to neutralize one or more of the inflammatory mediators. Accumulating experimental evidence suggests that escin exerts anti-inflammatory and antiedematous effects. The aim of this study was to evaluate the effect of escin on ALI induced by endotoxin in mice. ALI was induced by injection of lipopolysaccharide (LPS) intravenously. The mice were given dexamethasone or escin before injection of LPS. The mortality rate was recorded. Tumor necrosis factor-α (TNF-α), interleukin 1β (IL-1β) and nitric oxide (NO) were measured. Pulmonary superoxide dismutase (SOD), glutathione peroxidase (GPx) activity, glutathione (GSH), malondialdehyde (MDA) contents, and myeloperoxidase (MPO) activity were also determined. The expression of glucocorticoid receptor (GR) level was detected by Western blotting. Pretreatment with escin could decrease the mortality rate, attenuate lung injury resulted from LPS, down-regulate the level of the inflammation mediators, including NO, TNF-α, and IL-1β, enhance the endogenous antioxidant capacity, and up-regulating the GR expression in lung. The results suggest that escin may have potent protective effect on the LPS-induced ALI by inhibiting of the inflammatory response, and its mechanism involves in up-regulating the GR and enhancing the endogenous antioxidant capacity.     

Tetramethylpyrazine ameliorates indomethacin-induced gastric ulcer in rats: Impact on oxidative,inflammatory, and angiogenic machineries

Available antiulcer medications reveal partial efficacy and numerous adverse reactions. Tetramethylpyrazine (TMP) was known for its potential antioxidant, anti-inflammatory and angiogenic properties. The aim of current study was to investigate the potential gastroprotective effect of TMP against indomethacin-induced gastric ulcer in rats with possible underlying mechanisms. TMP was tested at 3 doses (15, 30 & 60 mg/kg/d po) three days before indomethacin challenge (25 mg/kg ip). Gastric tissue was evaluated morphologically and histopathologically. Oxidative statuses were assessed via glutathione content (GSH), malondialdhyde (MDA) and catalase (CAT) activity, while TNFα and IL-6 were measured as inflammatory mediators. Gastric PGE2 was investigated in addition to vascular endothelial growth factor (VEGF). TMP was effective (at 30 and 60 mg/kg/d) in promoting mucus secretion and preventing histopathologic changes induced by indomethacin. Mechanistically, TMP significantly enhanced GSH content and CAT activity while reducing lipid peroxidation as expressed by MDA concentration. Moreover, TMP effectively reduced TNFα, IL-6 and intracellular adhesion molecule (ICAM-1) concentrations. On the other hand, TMP enhanced both COX-1 and PGE2 and encouraged angiogenesis via increasing VEGF expression. In conclusion, TMP possesses a protective effect against indomethacin-induced gastric ulcer. This could be explained – at least partly – by its antioxidant, anti-inflammatory and angiogenic effects.     

Protective effects of zinc in indomethacin-induced gastric mucosal injury: evidence for a dual mechanism involving lipid peroxidation and nitric oxide

BACKGROUND: Indomethacin causes gastric mucosal injury, although the pathogenesis is not fully understood. Zinc, is known to have gastroprotective effects in both humans and experimental animals. Aim: To determine (i) the protective effects of zinc in indomethacin-induced gastric mucosal injury in rats, and (ii) whether these cytoprotective effects are mediated by changes in gastric lipid peroxidation and/or nitric oxide synthase activity. METHODS: Gastric lesions were induced in rats by the intragastric administration of indomethacin. Morphological changes, lipid peroxidation (malondialdehyde levels) and nitric oxide synthase activity were determined in animals pre-treated with zinc sulphate and in controls. RESULTS: Indomethacin significantly increased malondialdehyde levels and decreased NOS activity. These effects were attenuated by pre-treatment with zinc (P < 0.005 and 0.0001, respectively). The protective effects of zinc were readily abolished in animals pre-treated with N-nitro-L-arginine methyl ester (L-NAME). Morphologically, indomethacin induced large areas of mucosal ulcerations, which were completely prevented by zinc pre-treatment. CONCLUSIONS: Zinc provides protection against indomethacin-induced gastric mucosal injury. These protective effects result from the inhibition of lipid peroxidation and the preservation of mucosal nitric oxide synthase.     

Gastroprotective and antioxidant effects of amiodarone on indomethacin-induced gastric ulcers in rats

Reactive oxygen species (ROS) have been implicated in the etiology of indomethacin-induced gastric mucosal damage. This study investigated amiodarone's protective effects against oxidative gastric mucosal damage induced by indomethacin. Amiodarone is a widely used antiarrhythmic agent. We have investigated alterations in the glutathione level, and the activities of antioxidative enzymes [superoxide dismutase, catalase, glutathione s-transferase glutathione reductase and myeloperoxidase], as markers for ulceration process following oral administration of amiodarone and ranitidine in rats with indomethacin-induced ulcers. In the present study we found that 1) amiodarone, lansoprazole and ranitidine reduced the development of indomethacin-induced gastric damages, at a greater magnitude for amiodarone and lansoprazole than for ranitidine; 2) amiodarone and ranitidine alleviated increases in the activities of catalase and glutathione s-transferase enzymes resulting from ulcers; 3) amiodarone and ranitidine ameliorated depressions in the glutathione level and the activities of superoxide dismutase and glutathione reductase enzymes caused by indomethacin administration; and 4) all doses of amiodarone amplified the myeloperoxidase activity resulting from indomethacin-induced gastric ulcers. The results indicate that the gastroprotective activity of amiodarone, which may be linked to its intrinsic antioxidant properties, cannot be attributed to its effect on myeloperoxidase activity.     

Escin attenuates cerebral edema induced by acute omethoate poisoning

Organophosphorus exposure affects different organs such as skeletal muscles, the gastrointestinal tract, liver, lung, and brain. The present experiment aimed to evaluate the effect of escin on cerebral edema induced by acute omethoate poisoning. Sprague-Dawley rats were administered subcutaneously with omethoate at a single dose of 60 mg/kg followed by escin treatment. The results showed that escin reduced the brain water content and the amount of Evans blue in omethoate-poisoned animals. Treatment with escin decreased the levels of tumor necrosis factor-alpha (TNF-α), matrix metalloproteinase-9 (MMP-9), cyclooxygenase-2 (COX-2), and prostaglandin E? (PGE?) in the brain. Escin also alleviated the histopathological change induced by acute omethoate poisoning. The findings demonstrated that escin can attenuate cerebral edema induced by acute omethoate poisoning, and the underlying mechanism was associated with ameliorating the permeability of the blood-brain barrier.     

Effects of escin on acute inflammation and the immune system in mice

Escin has been used extensively to treat chronic venous insufficiency, hemorrhoids, and edema resulting from cerebral ischemic damage, trauma or operation. However, no studies have looked at the anti-inflammatory properties of escin administered by intravenous injection, and it is still not clear whether escin has an effect on the immune system. This study seeks to investigate the time dependent anti-inflammatory properties of escin and its effect on the immune system. The anti-inflammatory effect of escin was observed in carrageenan-induced paw edema and acetic acid-induced capillary permeability in mice. The immunopharmacological effects of escin were evaluated by spleen index (SI), thymus index (TI), proliferative capacity of splenocytes (PS), lymphocyte count (LC), serum TNF-α levels, and phagocytic rate (PR) in mice. Escin treatment showed a significant anti-inflammatory effect, similar to that seen with dexamethasone treatment. However, the duration of the anti-inflammatory response was longer with escin treatment than with dexamethasone treatment. The results also demonstrated that escin had no significant effects on SI, TI, LC, PS, TNF-α levels, and PR. The findings suggest that escin is a potent anti-inflammatory drug with long-lasting anti-inflammatory effects and without any immunosuppressive effects.     

锌二氢卟吩e4的合成及初步抗胃溃疡活性和对急性肝损伤的保护作用

目的　研究锌二氢卟吩e₄(1)的合成及实验性抗溃疡活性和对急性肝损伤的保护作用。方法　蚕沙叶绿素粗品经酸碱降解反应制得二氢卟吩e₆(3),3经吡啶回流降解制得二氢卟吩e₄(2),2与醋酸锌络合制得1;并测定1对消炎痛诱发的大鼠胃溃疡的保护作用及对硫代乙酰胺、四氯化碳所致小鼠急性肝损伤的防治作用。结果　1为新化合物。生物活性实验结果表明,1能显著降低消炎痛诱发的大鼠胃溃疡指数和溃疡个数;能显著降低小鼠硫代乙酰胺或四氯化碳急性肝损伤后升高的SGPT活性。结论　1对消炎痛诱发的大鼠胃溃疡和硫代乙酰胺、四氯化碳所致小鼠急性肝损伤具有显著的保护作用。     

Escin attenuates cerebral edema induced by acute omethoate poisoning

Organophosphorus exposure affects different organs such as skeletal muscles, the gastrointestinal tract, liver, lung, and brain. The present experiment aimed to evaluate the effect of escin on cerebral edema induced by acute omethoate poisoning. Sprague-Dawley rats were administered subcutaneously with omethoate at a single dose of 60?mg/kg followed by escin treatment. The results showed that escin reduced the brain water content and the amount of Evans blue in omethoate-poisoned animals. Treatment with escin decreased the levels of tumor necrosis factor-alpha (TNF-α), matrix metalloproteinase-9 (MMP-9), cyclooxygenase-2 (COX-2), and prostaglandin E₂ (PGE₂) in the brain. Escin also alleviated the histopathological change induced by acute omethoate poisoning. The findings demonstrated that escin can attenuate cerebral edema induced by acute omethoate poisoning, and the underlying mechanism was associated with ameliorating the permeability of the blood–brain barrier.     

Gastroprotective effect of sumatriptan against indomethacin-, stress- and ethanol-induced gastric damage in male rats: Possible modulatory role of 5-hydroxytryptamine 1B/1D receptors and pro-inflammatory cytokines

The current study was aimed to investigate the beneficial effect of sumatriptan, a 5-hydroxytryptamine 1B/1D (5HT_1B/1D) receptor agonist, on gastric ulcer in rats via stimulating 5HT_1B/1D receptors and suppressing pro-inflammatory cytokines. Rats were allocated into three models of gastric ulcer: indomethacin (30 mg/kg, PO), water immersion restraint stress (WRS) and ethanol (5 ml/kg PO). Animals were administered with sumatriptan (0.01, 0.1, 0.3 and 1 mg/kg, i.p) 30 min before gastric ulcer induction. GR-127935 (0.01 mg/kg, i.p, a selective 5HT_1B/1D antagonist) was administered 30 min before sumatriptan (0.1 mg/kg) injection. Macroscopic assessments (J-score), ELISA analysis of tumour necrosis factor-alpha (TNF-α) and interleukin-1beta (IL-1β) and histopathological changes were performed on the rat's stomach tissues. Gastric ulcer induction in three models caused an increase in J-score, TNF-α, IL-1β and microscopic features. Sumatriptan (0.1 mg/kg) significantly improved gastric injury induced by indomethacin, WRS and ethanol through the reduction in the J-score, TNF-α, IL-1β and microscopic lesions. Concurrent administration of GR-127935 (0.01 mg/kg) with sumatriptan (0.1 mg/kg) reversed the gastroprotective effect of sumatriptan in three models. Sumatriptan possessed gastroprotective effects on indomethacin-, WRS- and ethanol-induced gastric damage in rats via the possible involvement of the 5HT_1B/1D receptors.     

Indomethacin-induced gastric ulceration in rats: Ameliorative roles of Spondias mombin and Ficus exasperata

Context: Spondias mombin Linn (Anacardiaceae) and Ficus exasperata Valh (Moraceae) are botanicals with known phytotherapeutic potentials in the traditional system of medicine in the world.

Objective: The objective of this study is to investigate the quantitative polyphenolic constituents and gastroprotective effects of aqueous leaf extracts of Spondias mombin and Ficus exasperata against indomethacin-induced gastric ulcer in rats.

Materials and methods: Ulceration was induced by a single oral administration of indomethacin (30?mg/kg body weight (b.w.)). Ulcerated rats were orally administered with esomeprazole (a reference drug) at a dose of 20?mg/kg body weight, and Spondias mombin and Ficus exasperata at a dose of 100 and 200?mg/kg b.w. once daily for 21 d after ulcer induction. Gastric secretions and antioxidant parameters were thereafter evaluated.

Results: The significantly increased (p?<?0.05) ulcer index, gastric volume, malondialdehyde level, and pepsin activity by indomethacin were effectively reduced by 65.40, 36.47, 45.71, and 53.79%, respectively, following treatment with F. exasperata at 200?mg/kg b.w. S. mombin at this regimen also attenuated these parameters by 71.70, 46.62, 50.16, and 55.73%. Moreover, the extracts significantly increase the reduced activity of superoxide dismutase as well as pH and mucin content in the ulcerated rats.

Discussion and conclusion: These findings are indicative of gastroprotective and antioxidative potentials of the extracts which is also evident in the degree of % inhibition against ulceration. The available data in this study suggest that the extracts proved to be capable of ameliorating indomethacin-induced gastric ulceration and the probable mechanisms are via antioxidative and proton pump inhibition.     

Pro-ulcer effects of resveratrol in mice with indomethacin-induced gastric ulcers are reversed by l-arginine

Background and purpose:

Although resveratrol is currently being evaluated in pre-clinical studies as a potential cancer chemopreventive agent and cardiovascular stress-releasing compound, treatment with resveratrol severely delays healing of pre-existing gastric ulcers. Resveratrol treatment can also induce endothelial NOS (eNOS) expression. Here, we have attempted to modulate NO production via eNOS in order to alleviate the pro-ulcer effects of resveratrol.

Experimental approach:

Gastric ulcers were induced in mice with a single dose of indomethacin. The effects of pretreatment with l-arginine on the pro-ulcer effects of resveratrol in these mice were then assessed. We measured ulcer damage scores (DS), myeloperoxidase (MPO) activity, generation of prostaglandin E₂ (PGE₂) and NO, along with a gene expression study.

Key results:

Resveratrol significantly aggravated damage from indomethacin-induced gastric ulcers, and delayed healing, as shown by increased DS and MPO activity. The mRNA for cyclooxygenase (COX)-1, but not that for COX-2, was inhibited by resveratrol treatment, with reduced synthesis of PGE₂ by gastric tissue. However, resveratrol treatment induced eNOS gene expression and shifted the eNOS/iNOS balance. l-Arginine given before resveratrol in mice with indomethacin-induced ulcers significantly increased tissue NO synthesis and improved ulcer healing.

Conclusions and implications:

Exogenous l-arginine increased NO formation via raised levels of eNOS induced by resveratrol and protected against the pro-ulcer effects of resveratrol. Therefore, l-arginine might be useful for alleviation of the pro-ulcer side effects of resveratrol in patients.     

Endothelium protectant and contractile effects of the antivaricose principle escin in rat aorta

The triterpene saponin escin is the active component of the extract of seeds of Aesculus hippocastanum used in the treatment of chronic venous insufficiency. Escin is also used experimentally to increase membrane permeability in isolated cells. Since endothelial dysfunction is postulated to be involved in venous insufficiency, the possible endothelium-protectant effect of escin was explored in rat aortic rings, a model widely used to study such effects with cardiovascular agents. Escin enhanced endothelium-dependent relaxation induced by acetylcholine when such relaxation had been reduced by exposure to the superoxide ion generator pyrogallol. This effect was attributed to enhanced nitric oxide production by endothelial nitric oxide synthase, a calcium-dependent enzyme, activated by the increased endothelial cell permeability to calcium induced by escin. Another effect of escin thought to contribute to its therapeutic activity is its ability to produce venous contraction. The compound was found to induce concentration-related contraction also in rat aortic rings. This response was partially inhibited by removal of the endothelium or by preincubation with indomethacin, and was completely abolished by incubation in a calcium-free perfusion fluid. Contraction was considered to be due mainly to the aforementioned effect on calcium permeability, with some mediation by release of endothelial vasoconstrictor prostanoids. It was concluded that, in rat aorta, escin possesses an endothelium-protectant action and a direct contractile effect. The former could contribute to its beneficial effect in the treatment of venous insufficiency, while the latter could constitute a limiting side effect.     

Indomethacin, but not Helicobacter pylori, inhibits adaptive relaxation in isolated guinea-pig stomach

Nonsteroidal anti-inflammatory drugs (NSAIDs) and Helicobacter pylori (H. pylori) are major factors in gastritis and peptic ulcer However, the role of NSAIDs and H. pylori infection in dyspepsia remains unclear. Gastric adaptive relaxation may be related to the pathogenesis of functional dyspepsia because the response is often disturbed in dyspeptic patients. In this study, we investigated the effects of indomethacin or H. pylori water extracts on gastric adaptive relaxation. This experiment was performed using the modified method of Desai et al. Isolated guinea-pig stomach in an organ bath was monitored for intragastric pressure and volume. Adaptive relaxation was induced by gastric luminal distention. The effects of indomethacin and H. pylori on gastric relaxation were tested in this system. Indomethacin (> 1 x 10(-5) M) significantly inhibited adaptive relaxation. Indomethacin (> 3 x 10(-6) M) induced gastric relaxation in a dose-dependent fashion. However, aspirin at a concentration sufficient for cyclooxygenase (COX)-1 inhibition did not induce gastric relaxation. Preincubation with N-nitro-L-arginine methyl ester, a nitric oxide (NO)-synthase inhibitor, inhibited indomethacin-induced gastric relaxation. Adaptive relaxation was not affected by H. pylori water extracts. In conclusion, indomethacin inhibited adaptive relaxation via prior gastric relaxation. NO production, but not COX-1 inhibition, may be involved in this effect of indomethacin. H. pylori water extracts may not have direct effects on adaptive relaxation. Inhibition of adaptive relaxation may be one of the major mechanisms underlying NSAID-induced dyspepsia.     

Gastroprotective activity of isopulegol on experimentally induced gastric lesions in mice: investigation of possible mechanisms of action

The present study investigated whether isopulegol, a monoterpene present in essential oils of several aromatic plants, would be able to promote some gastroprotective effect and also verified the possible mechanisms involved in this action. For this study, ethanol- and indomethacin-induced gastric ulcer models in mice and histopathological assessment were used. The roles of NO, sulfhydryls (glutathione, GSH), ATP-sensitive K⁺ channels (K_ATP channels), and prostaglandins were also investigated. Isopulegol exhibited a dose-related gastroprotective effect against ethanol-induced lesions, while the pretreatment with glibenclamide and indomethacin [but not with N(G)-nitro-l-arginine methyl ester] were able to reverse this action. The pretreatment with isopulegol also restored GSH levels to normal levels and exhibited dose-related gastroprotective effect against indomethacin-induced ulcer. The results suggested that isopulegol presents significant gastroprotective effects in both ethanol- and indomethacin-induced ulcer models, which appear to be mediated, at least in part, by endogenous prostaglandins, K_ATP channel opening, and antioxidant properties.     

Protective effect of cromakalim and diazoxide, and proulcerogenic effect of glibenclamide on indomethacin-induced gastric injury.

We investigated the influences of the K+ channel opening drugs cromakalim and diazoxide and their blocker, glibenclamide, in indomethacin-induced gastric injury in rats. Cromakalim (0.1 and 0.3 mg/kg) and diazoxide (10 and 30 mg/kg) produced dose-dependent gastroprotection at doses that were also effective on the cardiovascular system. Glibenclamide reversed their gastroprotective effects and aggravated indomethacin-induced gastric damage by its own. Cromakalim (10(-9)-10(-5) M) and diazoxide (10(-9)-10(-4) M) relaxed noradrenaline pre-contracted gastric arteries (94.59+/-1.58% and 93.86+/-2.99%, respectively). Their relaxant effects were inhibited by glibenclamide (10(-5) M) but not by indomethacin (10(-5) M) and LG-nitro-L-arginine (10(-4) M). Cromakalim (0.1 and 0.3 mg/kg) did not change gastric mucosal blood flow but increased the gastric mucosal vascular conductance in anaesthetized rats as measured by the hydrogen gas clearance technique. Indomethacin increased myeloperoxidase activity in the gastric mucosa, an effect which was reversed by cromakalim and diazoxide. Glibenclamide abolished their effects on myeloperoxidase activity and, alone, increased this parameter. Additionally, indomethacin caused infiltration of neutrophils which was reduced by cromakalim and diazoxide in a glibenclamide sensitive manner. The effects of cromakalim and diazoxide on mucosal myeloperoxidase activity, neutrophil infiltration and gastric injury correlated with each other. The effects of diazoxide (30 mg/kg) and glibenclamide (10 mg/kg) on blood glucose level were not correlated with their effects on gastric injury. Taken together, K+ channel opening drugs show misoprostol-like protective effects in indomethacin-induced gastric injury which seems to be related to modulation of neutrophil function.     

Effect of nimesulide, rofecoxib and celecoxib on gastric tissue glutathione level in rats with indomethacin-induced gastric ulcerations

Glutathione (GSH) is a tripeptide and a superoxide radical scavenger and it protects thiol protein groups required for maintaining the integrity of cell against oxidation. GSH is present in the stomach at high concentrations and plays an important role in maintaining the integrity of the gastric mucosa. We investigated whether oral administration of nimesulide, rofecoxib and celecoxib, selective COX-2 inhibitors, changed GSH level in the gastric tissue of indomethacin-treated rats. Thirty albino Wistar rats were used in this study. Animals were randomly assigned to five groups as follows: control group received only distilled water (group I). Nimesulide at a dose of 100 mg/kg (group II), rofecoxib at a dose of 25 mg/kg (group III) and celecoxib at a dose of 100 mg/kg (group IV) were intragastrically administered 5 min before indomethacin (25 mg/kg) treatment. Equal volume of distilled water was given to the indomethacin-administered group (group V). Indomethacin was administered intragastrically. Gastric tissue mean GSH level was significantly higher in nimesulide-given rats than in rofecoxib- and celecoxib-treated groups, there was not any significant difference between the nimesulide and control groups. Our study showed that although nimesulide prevented the indomethacin-induced gastric ulcers completely, rofecoxib and celecoxib did not prevent the indomethacin-induced ulcer formation. In conclusion, we propose that nimesulide exerts a prophylactic effect on the indomethacin-induced gastric ulcers by enhancing gastric GSH level.     

Role of cannabinoid CB1 receptors and tumor necrosis factor-alpha in the gut and systemic anti-inflammatory activity of SR 141716 (rimonabant) in rodents

(1) We investigated the effect of the cannabinoid CB1 receptor antagonist, SR 141716, on indomethacin-induced small intestine inflammation and Escherichia coli lipopolysaccharide (LPS)-induced plasma TNF-alpha (TNF) release in comparison to the cannabinoid CB2 receptor antagonist, SR 144528, in rodents. (2) In rats, indomethacin induced significant ulcer formation in the small intestine; this was accompanied by an increase in tissue TNF levels and myeloperoxidase (MPO) activity. SR 141716 prevented the ulcers and the rise in TNF levels (ID50 3.3, 0.4 mg kg-1, respectively) and MPO activity. SR 144528 prevented intestinal ulcers only. (3) The effect of SR 141716 against indomethacin-induced ulcers and increase of plasma TNF levels after LPS was also studied in wild-type and CB1 receptor knockout mice. Indomethacin induced intestinal ulcers in mice, but not tissue TNF production and MPO activity. SR 141716 reduced the ulcers to a similar extent in wild-type and CB1 receptor knockout mice. In rats and wild-type mice, but not in CB1 receptor knockout mice, SR 141716 inhibited the LPS-induced increase in plasma TNF levels. (4) These findings provide evidence that the indomethacin model of intestinal lesions differs in rat and mouse and support the existence of several mechanisms for the antiulcer activity of SR141716, the most important involving the inhibition of TNF production. The potent anti-inflammatory activity of SR141716 in rodents indicated its potential therapeutic interest in chronic immune-inflammatory diseases.