Protection by opioids against gastric lesions caused by necrotizing agents

The synthetic opioid met-enkephalin analog [D-Ala2, MePhe4, Met(0)5ol] enkephalin (DAMME) and the opiate morphine injected intraperitoneally to rats at doses of 0.5-2 and 5-20 mg/kg, respectively, showed a protective effect on gastric damage induced by oral administration of necrotizing agents (0.6 N HCl or 0.2 N NaOH solutions, 1 ml/rat). The protection was prevented by naltrexone (10 mg/kg s.c.), an opioid antagonist with long-lasting activity. Histological sections of mucosal samples from animals pretreated with morphine (10 mg/kg i.p.) and DAMME (1 mg/kg i.p.) showed less alteration of the columnar epithelium, with a normal glandular structure, than untreated rats. A mediation of prostaglandins is suggested, since indomethacin (10 mg/kg s.c.) significantly reduced the protective effects of opioids.     

Protection against alcohol-induced gastric mucosal injury by nitecapone.

1. The mechanism of gastric mucosal protection by an anticular agent, nitecapone, against injury was investigated in rats with and without indomethacin pretreatment. 2. Animals received intragastrically either a dose of nitecapone or vehicle alone, followed by ethanol given at various intervals up to 5 hr, and their gastric mucosa subjected to histologic and physicochemical assessment. 3. Ethanol caused extensive gastric hemorrhagic lesions which were essentially prevented by nitecapone at doses of 30 mg and higher per kg body weight. The maximal protection was achieved by 1.5 hr which persisted up to 4 hr and was not thwarted by indomethacin. 4. Physicochemical measurements revealed that nitecapone evoked 78% increase in mucus gel dimension, and showed 21% increase in phospholipids, and the content of sulfo-(22%) and sialomucins (72%). This was accompanied by 1.6-fold increase in mucus viscosity, 31% increase in H+ retardation capacity and 2.2-fold increase in hydrophobicity. 5. The results suggest that the gastroprotective action of nitecapone occurs through the enhancement of the physicochemical characteristics of mucus layer.     

胡椒碱抗实验性胃溃疡的作用

目的：研究胡椒碱抗大鼠或小鼠实验性胃溃疡的作用。方法：实验性胃溃疡是由应激、吲哚美辛、盐酸和幽门结扎引起,实验前5h ig胡椒碱。结果：胡椒碱25、50、100mg/kg能抑制大鼠或小鼠胃粘膜损伤,对应激性型胃粘膜损伤,抑制率分别为16．9％,36．0％,48．3％;吲哚美辛型胃粘膜损伤为4．4％,51．1％,64．4％;盐酸型胃粘膜损伤为19．2％,41．5％,59．6％;对幽门结扎型胃粘膜损伤为4．8％,11．9％,26．2％;胃液分泌减少;胃酸、胃蛋白酶活性降低。结论：胡椒碱具有抗实验性胃溃疡作用。     

Protection by paracetamol against various gastric irritants in the rat

Four nonsteroid anti-inflammatory drugs (NSAID), indomethacin, phenylbutazone, ibuprofen, and glafenine, caused erosions in the rat stomach in a dose-dependent manner. Paracetamol, which has been shown to protect against the gastric erosive activity of aspirin, reduced the gastric toxicity of indomethacin but was ineffective against the erosive activity of phenylbutazone and glafenine. Only the high erosion score of a large dose of ibuprofen was partly decreased by paracetamol. The gastric damaging effects of necrotizing concentrations of ethanol and sodium hydroxide were strongly reduced by paracetamol, but the erosive activity of hydrochloric acid was only slightly decreased by paracetamol. Thus, although paracetamol protected the gastric mucosa against various noxious agents, this drug was not able to protect against every type of gastric damage. Paracetamol might be protective by stimulating the biosynthesis of prostaglandins in the stomach wall.     

Protective effects of escin against indomethacin-induced gastric ulcer in mice

Escin, a natural mixture of triterpenoid saponin isolated from the seed of the horse chestnut, is reported to have a potent antiulcer activity against ethanol-induced gastric mucosal lesions. This study investigated the possible mechanisms underlying the gastroprotective effect of escin against indomethacin-induced gastric ulcer in mice. Gastric ulceration was induced by a single intragastric administration of indomethacin (18?mg/kg). The mice underwent intragastric treatment with escin at doses of 0.45, 0.9 or 1.8?mg/kg. Gastric lesion was estimated morphometrically and histopathologically 6?h after the indomethacin administration. The antioxidative parameters in gastric mucosa were measured. Moreover, the activity of myeloperoxidase and the contents of TNF-α, P-selectin and VCAM-1 in gastric tissues were determined. The results showed that escin protected gastric tissues against indomethacin-induced gastropathy as demonstrated from a reduction in the ulcer index and an attenuation of histopathologic changes. Escin caused significant reductions of the contents of malondialdehyde, TNF-α, P-selectin, VCAM-1 and myeloperoxidase activity. The altered activities of superoxide dismutase, catalase and glutathione peroxidase in the stomach tissues were also ameliorated by escin treatment. The present study demonstrated that escin had a protective effect against indomethacin-induced gastric ulcer in mice, not only by virtue of its antioxidant potential, but also due to its anti-inflammatory effect.     

Protective effect of l-citrulline against ethanol-induced gastric ulcer in rats

We examined the protective effect of l-citrulline on ethanol-induced gastric ulcer in rats. Administration of l-citrulline at doses of 300, 600 and 900mg/kg body weight prior to ethanol ingestion protected the stomach from ulceration. The gastric lesions were significantly attenuated by all doses of l-citrulline as compared to the ethanol group. Pre-treatment with l-citrulline prevented the oxidative damage and the decrease of nitric oxide content as well as the increase of the myeloperoxidase activity. Consequently, significant changes observed included the attenuation in the elevation in total nitric oxide synthase activity and inducible nitric oxide synthase activity as well as the decrease in constitutive nitric oxide synthase activity in the gastric mucosa induced by ethanol. Analysis of serum cytokines of ethanol-induced rats showed a moderate decrease in interleukin-10 with considerable increase of interleukin-6 while l-citrulline inhibited the acute alteration of cytokines. These results suggested the gastroprotective effect of l-citrulline.     

Protective effect of tetrahydrocoptisine against ethanol-induced gastric ulcer in mice

Excessive alcohol consumption can lead to gastric ulcer and the present work was aimed to examine the protective effect of tetrahydrocoptisine (THC) in the model of ethanol-induced gastric ulcer in mice. Fasted mice treated with ethanol 75% (0.5 ml/100 g) were pre-treated with THC (10 or 20 mg/kg, ip), cimetidine (100 mg/kg, ip) or saline in different experimental sets for a period of 3 days, and animals were euthanized 4 h after ethanol ingestion. Gross and microscopic lesions, immunological and biochemical parameters were taken into consideration. The results showed that ethanol induced gastric damage, improving nitric oxide (NO) level, increased pro-inflammatory cytokine (TNF-α and IL-6) levels and myeloperoxidase (MPO) activity, as well as the expression of nuclear factor-κB (NF-κB) in the ethanol group. Pretreatment of THC at doses of 10 and 20 mg/kg bodyweight significantly attenuated the gastric lesions as compared to the ethanol group. These results suggest that the gastroprotective activity of THC is attributed to reducing NO production and adjusting the pro-inflammatory cytokine, inhibited neutrophil accumulation and NF-κB expression.     

Protection against ethanol-induced gastric damage by drugs acting at the GABA-benzodiazepine receptor complex

The protective effects of drugs acting at the GABA-benzodiazepine receptor complex against ethanol-induced gastric damage in rats were investigated. Gastric lesions were induced by administration of 1 ml absolute ethanol orally to rats. Administration of clonazepam (0.625–2.5 mg/kg, IP), wich binds with high affinity to the benzodiazepine binding site of the GABA-benzodiazepine receptor complex, or Ro 5–3663 (2.5 or 5 mg/kg), wich binds to the piorotoxinin site of the receptor complex, protected against ethanol-induced gastric damage. The protective effect of clonazepam (1.25 mg/kg, IP) against ethanol-induced gastric damage was reversed, dose dependently, by the specific benzodiazepine antagonist, flumazenil (5–20 mg/kg, IP). This protective effect of clonazepam or Ro 5–3663 seems to be specific to ethanol-induced gastric damage, since neither drug protected against indomethacin-induced gastric damage. These results present for the first time evidence of the involvement of drugs acting at GABA-benzodiazepine receptors in protection against ethanol-induced gastric damage.     

l-Theanine healed NSAID-induced gastric ulcer by modulating pro/antioxidant balance in gastric ulcer margin

l-Theanine is a unique non-protein-forming amino acid present in tea [Camellia sinensis (L.) O. Kuntze]. In the present work, we evaluated the healing effect of l-theanine on NSAID (indomethacin)-induced gastric ulcer. Histology of the stomach tissues revealed maximum ulceration on the third day after indomethacin administration (18 mg/kg, single dose p.o.) which was accompanied by increased lipid peroxidation; protein carbonylation; Th1 cytokine synthesis, and depletion of thiol, mucin, prostaglandin (PG) E, Th2 cytokine synthesis; and total antioxidant status in mice. l-Theanine healed gastric ulcer at a dose of 10 mg/kg b.w. but aggravated the ulcerated condition at a higher dose of 40 mg/kg b.w. At 10 mg/kg b.w., l-theanine significantly alleviated the adverse oxidative effect of indomethacin through enhanced synthesis of PGE₂ by modulation of cyclo-oxygenase-1 and 2 [COX-1 and COX-2] expression, Th1/Th2 cytokine balance, and restoration of cellular antioxidant status at the gastric ulcer margin. The present study revealed for the first time the dose-dependent biphasic effect of a natural neuroprotective agent, l-theanine, on gastric ulcer disease.     

海藻提取物对小鼠酒精性胃溃疡的保护作用

目的 探究海藻提取物对乙醇诱导小鼠急性胃溃疡的保护作用及其作用机制.方法 将8周龄雌性健康BABL/c小鼠随机分为正常组、模型组、海藻提取物低剂量组(7.2 mg·kg-1 bw-1)、海藻提取物高剂量组(21.5 mg·kg-1 bw-1).预灌胃2周后,模型组和海藻提取物组灌胃10 mL·kg-1·bw-1 85％...     

The protective effect of liquorice components and their derivatives against gastric ulcer induced by aspirin in rats

Abstract— We have examined the protective effect of liquorice or its derivatives against gastric ulcer induced by aspirin. A granular mixture of aspirin alone and coated with liquorice or its derivatives including the deglycyrrhized form, a high glycyrrhized form, carbenoxolone, and enoxolone were studied. Aspirin coated with liquorice reduced the number and size of ulcers, reducing the ulcer index from 1·5±0·12 to 0·5 ± 0·12 and the incidence from 96% to 46%. Coating with derivatives was less effective (ulcer index, 0·70–0·94; incidence 62–76%).     

Protection by zinc sulphate against reserpine-induced ulceration and other gastric effects in the rat.

The effects of intraperitoneal pretreatment, 48 h beforehand, with zinc sulphate (22, 44 or 88 mg/kg) were studied on gastric ulceration, gastric secretion and changes in stomach wall mast cell counts induced after 4 h by reserpine (5 mg/kg) given intraperitoneally to intact (unoperated for pylorus occlusion) or pylorus-occluded rats. Zinc sulphate dose-dependently antagonised the gastric actions of reserpine by preventing ulceration in the ruminal and glandular segments of the stomach, reducing acid secretion, and inhibiting mast cell degranulation which occurred mainly in the glandular mucosal layer. The relationship between these findings and the action of zinc on gastric mast cell is discussed.     

Gastroprotective effect of cirsilineol against hydrochloric acid/ethanol-induced gastric ulcer in rats

This study was designed to evaluate the gastroprotective activity of cirsilineol in hydrochloric acid (HCl)/ethanol-induced gastric ulcer model. Cirsilineol was administered at the doses of 20 and 40 mg/kg in HCl/ethanol-induced rats. The gastroprotective ability was verified by determining the ulcer score, total acidity, hemoglobin, inflammatory cytokines, lipid peroxides, and enzymatic antioxidants superoxide dismutase (SOD) and catalase (CAT) in gastric tissue and serum biochemical analysis. The results showed a favorable increase in the hemoglobin level, antioxidant enzymes (SOD and CAT), restored electrochemical balance (carbon dioxide & anion gap) while a noticeable decrease in ulcer index, total acidity, lipid peroxides, inflammatory cytokines (interleukin-1 beta [IL-1β], IL-6, and tumor necrosis factor alpha) in rats treated with the cirsilineol. The serum biochemical analysis on liver markers (alkaline phosphatases, alanine aminotransferase, and aspartate aminotransferase), kidney markers (urea, creatinine, albumin, globulin, total protein), and lipid profile (triglyceride, high-density lipoprotein, total cholesterol) were attenuated by cirsilineol treatment in rats. Histopathology showed enhanced gastric protection and preserved the integrity of gastric mucosa upon cirsilineol administration. These results ultimately suggest that cirsilineol has gastroprotective effects that prevent the development of gastric ulcer.     

Protection by polaprezinc, an anti-ulcer drug, against indomethacin-induced apoptosis in rat gastric mucosal cells

Polaprezinc [N-(3-aminopropionyl)-L-histidinato zinc] (PZ), an anti-ulcer drug, is a chelate compound consisting of zinc and L-carnosine. PZ has been shown to prevent gastric mucosal injury. In the present study, we investigated the inhibitory effect of PZ on indomethacin (IND)-induced apoptosis in a rat gastric mucosal cell line, RGM1. Pretreatment with PZ suppressed caspase-3 activation and subsequent apoptosis in the cells exposed to 500 microM IND in a dose-dependent manner, and 50 microM PZ exhibited the maximum inhibitory effect. Among PZ subcomponents, zinc but not L-carnosine played a pivotal role in this antiapoptotic function. PZ did not affect mitochondrial cytochrome c release upstream of caspase-3 activation in the IND-induced apoptotic signal pathway. Treatment with 500 microM IND evidently produced reactive oxygen species (ROS) in RGM1 cells. However, PZ did not scavenge ROS in IND-treated cells. Moreover, N-acetylL-cysteine, a potent antioxidant, inhibited ROS generation but did not suppress apoptosis in RGM1 cells exposed to IND. These observations demonstrate a novel pharmacological action of PZ; i.e., that PZ, and in particular its zinc subcomponent, inhibits apoptosis via inhibition of caspase-3 activation but not antioxidant activity.     

Protection against aspirin-induced human gastric mucosal injury by bosentan, a new endothelin-1 receptor antagonist

BACKGROUND: Gastric ulceration induced by aspirin and by non-steroidal anti-inflammatory drugs (NSAIDs) is a major clinical problem. The mechanism of injury is unclear. There is evidence that NSAID-induced injury may cause endothelin activation. Endothelin-induced vasoconstriction has been shown to be capable of causing gastric ulceration. AIM: To investigate whether acute gastroduodenal injury induced in humans by aspirin can be prevented by the endothelin-1 antagonist, bosentan. METHODS: Eighteen healthy volunteers each received 5 x 900 mg aspirin every 12 h on three separate occasions (with either placebo, bosentan 700 mg or misoprostol 400 mg). Treatment order was randomized by Latin square design. Subjects were endoscoped and erosions counted before and 90 min after the first and last dose of aspirin. Plasma concentrations of bosentan were measured up to 5 h post-dose. RESULTS: There was a significant reduction in the mean number of erosions in the aspirin plus bosentan and aspirin plus misoprostol groups after the first dose of aspirin, compared with controls (aspirin plus placebo) (P<0.05). This was not sustained after the fifth dose of aspirin in the aspirin plus placebo and aspirin plus bosentan groups, but was still present in the aspirin plus misoprostol group. The mean plasma concentration of bosentan measured 3.5 h post-dose fell from 4510 (95% CI: 2791-6230) ng/mL after the 1st dose to 2508 (95% CI: 1733-3283) ng/mL after the 5th dose (P = 0.02). CONCLUSION: Endothelin receptor antagonism by bosentan can protect the gastric mucosa against aspirin damage. After five doses, bosentan levels fell, possibly because of enzyme induction, and protection was no longer evident. Further investigation is needed to assess whether higher doses would be effective.     

Protection against thallium hepatotoxicity by silymarin

The effect of silymarin (100 mg/kg i.p.) on the biochemical indicators of liver damage induced by thallium (10 mg/kg p.o.) was studied in rats. The production of malondialdehyde and the content of reduced glutathione in the liver were measured as indicators of lipid peroxidation. Thallium intoxication increased the serum activities of glutamic pyruvic transaminase, gamma-glutamyl transpeptidase, alkaline phosphatase and the liver concentration of triglycerides. Thallium decreased the activity of alkaline phosphatase and increased that of gamma-glutamyl transpeptidase in the liver cell membrane. It also abolished the membrane activity of Na+/K+ ATPase. Lipid peroxidation was enhanced by thallium as malondialdehyde production was increased and the content of reduced glutathione was decreased in the liver. Silymarin completely prevented all these changes. It is suggested that thallium toxicity is due, at least in part, to the promotion of lipid peroxidation. The membrane stabilizing effect of silymarin observed in this and in other models of liver toxicity is due to some antioxidant property, possibly related to its ability to scavenge free oxygen radicals.     

Protection against diisopropylfluorophosphate intoxication by meptazinol

The protective action of meptazinol against diisopropylfluorophosphate (DFP) was evaluated in mice which were not receiving any other therapy and in preparations of electric eel AChE and horse serum BuChE. Meptazinol injected subcutaneously in mice produced a dose-dependent reduction in the mortality resulting from a LD99.1 (8 mg/kg sc) of DFP administered later. The effectiveness of protection was inversely correlated to the time between meptazinol and DFP administrations. Under these conditions, the ED50s (95% confidence limits) of meptazinol given 15, 30, and 60 min before poisoning were 7.2 (6.4-8.1), 15.8 (13.7-18.2), and 28 (23.5-33.3) mg/kg, respectively, while full protection (100% of survivors) was obtained with 15, 30, and 60 mg/kg drug doses, respectively. Meptazinol was completely ineffective against DFP-induced lethality when administered 3 min after the poison. The protective ratio of 30 mg/kg meptazinol injected 15 min before DFP was 5.0. Pretreatment of mice with 15, 30, and 60 mg/kg meptazinol 15 min before DFP (8 mg/kg) increased brain AChE activity in DFP-treated mice from 5 +/- 0.5% to 16.2 +/- 2.5%, 42.5 +/- 4%, and 81.2 +/- 4% of control values, respectively, while it failed to increase plasma BuChE activity. Finally, concentrations of meptazinol ranging between 0.1 and 10 microM were found to afford complete protection of eel AChE against irreversible inhibition by 40 microM DFP. By contrast, horse serum BuChE was not protected against the same inhibitor by concentrations of meptazinol up to 1 mM. It is concluded that protection against DFP intoxication by meptazinol is most probably due to its protective action toward AChE.