Experimental Gastric Ulcer Models Research Articles

Comparative and combined studies on anti-ulcer effect of two plant extracts in experimental models of gastric ulcer in SD rats

Comparative and combined studies on anti-ulcer effect of two plant extracts in experimental models of gastric ulcer in SD rats

Comparative and combined studies on anti‑ulcer effect of two plant extracts in experimental models of gastric ulcer in SD rats

Objective: The present study was designed to carry out comparative and combined effect anti-ulcer studies of Ficus racemosa Linn. (Family: Moraceae) (Gular) fruit extract and Aegle marmelos (Linn.) Corr. (family: Rutaceae) root extract in various experimental models of ulcer. Materials and Methods: Gastro-protective studies were carried out with individual treatments of Ficus racemosa fruit extract (FRFE) and Aegle marmelos root extract (AMRE) and combination of both in four standard experimental models of ulcer like pylorus ligation (PL)-induced ulcers, Aspirin (ASP)-induced ulcers, Cold-restraint stress (CRS)-induced ulcers, and Ethanol (EtOH)- induced ulcers in SD rats. Gastric secretion parameters, gastric mucosal parameters and anti-oxidant parameters were estimated. Results: Both FRFE and AMRE have demonstrated the efficacy in different models of ulcer in the following order: PL-induced gastric ulcers > ASP-induced gastric ulcers > EtOH-induced gastric ulcers > CRS-induced gastric ulcers. Both have shown similar degree of efficacy in almost all the models. Results clearly implied that the three combinations A1-50 mg/kg (25 mg of FRFE + 25 mg of AMRE), A2-75 mg/kg (37.5 mg of FRFE + 37.5 mg of AMRE) and A3-100 mg/kg (50 mg of FRFE + 50 mg of AMRE) show significant anti-ulcer effect in CRS-induced ulcer model. Summary: Combination of both FRFE and AMRE have exhibited remarkable antiulcer effect at even lower doses of equal proportions (1:1) in comparison with individual treatment studies, which also have shown good efficacy but much higher doses are required. This study highlights the importance of combined herbal formulations that help to facilitate the efficacy as well as safety of drugs. Key words: Aegle marmelos, anti‑ulcer effect, Ficus racemosa, gastroprotection

Investigation of the Mechanisms Underlying the Gastroprotective Effect of Cymbopogon Citratus Essential Oil

Cymbopogon citratus is a medicinal plant popularly used in Brazil for the treatment of various diseases, and the research interest in this plant is justifiable because of its potential medicinal value in stomachache and gastric ulcer. This study was aimed to test the validity of this practice by using experimental models of gastric ulcer and to clarify the mechanisms of gastroprotection by C. citratus leaves essential oil (EOCC). EOCC was evaluated for the ability to protect the gastric mucosa against injuries caused by necrotizing agents (absolute ethanol and aspirin) in rodents. The results of this study revealed that EOCC posses a dose-independent anti-ulcer effect against the different experimental models. EOCC pretreatment depicted a higher preventive index in ethanol-(88%) and aspirin-induced (76%) acute ulceration. On pretreatment of mice with indomethacin, the cyclooxygenase inhibitor slightly suppressed the gastroprotective effect of EOCC (48.5%). Furthermore, EOCC gastroprotection was not attenuated in mice pretreated with L-NAME (85.2%), glibenclamide (100%), or yohimbine (79.7%), the respective inhibitors of nitric oxide synthase, K+ATP channel activation, and α2 receptors. These results confirmed the traditional use of C. citratus for the treatment of gastric ulcer. Thus, we provide the first evidence that EOCC reduces gastric damage induced by ethanol, at least in part, by mechanisms that involve endogenous prostaglandins.

Gastroprotective effects of essential oil from Protium heptaphyllum on experimental gastric ulcer models in rats

Peptic ulcers are a common disorder of the entire gastrointestinal tract, its etiology has not been completely elucidated. The basic physiopathological of peptic ulcers result from an imbalance between some endogenous aggressive factor and cytoprotective factors. The treatment of this disease is usually done with antacids or proton pump, but are currently being used plants derivated compounds. We evaluated the gastroprotective properties and its possible mechanisms of action of the essential oil from Protium heptaphyllum (Aubl.) Marchand, Burseraceae (BB). The formation of ulcers, were evaluated in three experimental models, through the induction of gastric lesions by ethanol, nonsteroidal anti-inflammatory drugs and acetic acid. The mechanisms of action were evaluated through the pylorus ligature experiment, western blot, GSH, GR, SOD, GPx, MDA and MPO activities. BB significantly inhibited the formation of ulcers induced by the three different models, increased the GSH and GR levels and maintained the same levels of SOD and GPx of the sham group, inhibited MPO and MDA, did not produce significant modification in gastric juice content and showed increased COX-2 and EGF. BB exerts its gastroprotective activity, possibly, by increasing COX-2 and EGF expression and due to its possible antioxidant property.

English

  Absolute alcohol, stress, pyloric ligation and others are well-rounded experimental gastric ulcer models widely used to evaluate the anti-ulcer activity of drugs (Wang et al., 2007; Zhang et al., 2007; Huang et al., 2004; Oyagi et al., 2010). In the model evaluation process, ulcer index is a more important indicator. So in this experiment, the absolute alcohol gastric ulcer model is taken as an example to discuss a model of gastric ulcer index, which can be used as a new method to calculate the reduction of the systematic errors that exist in the experiment. The oral ethanol approach was used to establish an absolute alcohol gastric ulcer model, and impose certain medication, while traditional methods and the establishment of grayscale image analysis methods were used for calculating its ulcer index respectively, before comparing the differences between the two methods. Grayscale image analysis methods and traditional methods have significant correlation (r = 0.819, P＜0.01) and similarity (r = 0.951). A grayscale image analysis method not only proves to be a more scientific approach to measure rat gastric ulcer area, but also provide a new method to evaluate drug efficacy to some extent.   Key words: Gastric ulcer, ulcer index, gray-scale image analysis, image J.

Effects of a Polysaccharide Fraction from the Roots of Bupleurum falcatum L. on Experimental Gastric Ulcer Models in Rats and Mice

Effects of an acidic polysaccharide fraction, BR-2, from the roots of Bupleurum falcatum L., on HCl-ethanol, ethanol and water immersion stress-induced gastric lesions in mice and pylorus-ligated ulcers in rats have been studied. Oral administration of BR-2 at doses of 50 to 200 mg kg-1 inhibited the formation of the gastric lesions induced by necrotizing agents such as HCl-ethanol and ethanol, in a dose dependent manner. This protective effect was observed after oral, intraperitoneal, and subcutaneous administration of BR-2 (25-100 mg kg-1). BR-2 also inhibited the formation of gastric ulcers which were induced by water immersion stress or pylorus-ligation. Prostaglandin E2 in gastric juice from rats and in gastric mucosa from mice was not influenced by oral administration of BR-2. The protective action of BR-2 against HCl-ethanol-induced gastric lesions was not abolished by pretreatment with indomethacin (20 mg kg-1, i.p.). The amount of alcian blue binding to mucosa also increased after administration of BR-2 (100 mg kg-1, p.o.); however, the amount of hexosamine and N-acetylneuraminic acid in mucosa did not change significantly.

Study of anti ulcer activity of Ficus religiosa L. on experimentally induced gastric ulcers in rats

Objective To investigate the gastroprotective activity of hydroalcoholic extract leaves of Ficus religiosa ( F. religiosa) in different experimental models of gastric ulcer in rats. Methods The hydroalcoholic extract leaves of F. religiosa were studied at two dose levels (250 and 500 mg/kg, oral) in rats against absolute ethanol (0.2 mL oral), aspirin (200 mg/kg) and pyloric ligation induced gastric ulcer. Ranitidine (50 mg/kg, oral) was used as a standard drug. Mean ulcer indices and oxidative stress were measured. Phytochemical tests and acute toxicity tests were also carried out. Results Administration of F. religiosa to rats significantly decreased the ulcer index value when compared with the control treated group. Ranitidine (50 mg/kg, oral) also produced a significant decrease the ulcer index value when compared with the control treated group. Phytochemical analysis revealed the presence of tannins, sterols, saponins, flavonoids, carbohydrates and proteins. Conclusions The results suggest that the leaves of the F. religiosa possess significant anti ulcer activity.

Gastric antiulcer, antisecretory and cytoprotective properties of celery (Apium graveolens) in rats

In the present investigation, an ethanol extract of celery [Apium graveolens L. (Apiaceae/Umbelliferae)], at doses of 250 and 500 mg/kg body weight, was evaluated for antigastric ulcer activity using various experimental gastric ulcer models in rats. Ulcers were induced by indomethacin, cytodestructive agents (80% ethanol, 0.2 M NaOH and 25% NaCl) and cold restraint stress. Gastric secretory studies were undertaken by using pylorus ligation (Shay rat model). In addition to gastric wall mucus (GWM), non-protein sulfhydryl (NP-SH) and malondialdehyde (MDA) were also estimated in gastric tissues after 80% ethanol treatment. Pretreatment of celery extract produced dose-dependent reduction in all experimentally induced gastric lesions. Ethanol (80%) decreased the levels of GWM, NP-SH and increase in MDA concentration in gastric tissue. Celery extract showed the ability to significantly replenish the ethanol-induced depleted levels of GWM and gastric mucosal NP-SH. The gastric mucosal MDA level was also significantly lowered in extract pretreated rats. The celery extract showed stomach protection against the models used for ulcerogenesis. Results were further confirmed by using histopathological assessment. The phytochemical screening showed the presence of various chemical constituents such as flavonoids, tannins, volatile oils, alkaloids, sterols and/or triterpenes. Acute toxicity test revealed no deleterious or toxic symptoms or mortality over a period of 14 days. However, the LD50 was found to be 7.55 g/kg, and showed a large margin of safety. The results suggest that Apium graveolens extract significantly protects the gastric mucosa and suppresses the basal gastric secretion in rats, possibly through its antioxidant potential.

Effects of an essential oil from the bark of Croton cajucara Benth. on experimental gastric ulcer models in rats and mice.

Croton cajucara Benth. (Euphorbiaceae) is widely used in Amazonian folk medicine for the treatment of a wide range of gastrointestinal symptoms. The essential oil from its bark was investigated for acute toxicity in mice and for its ability to prevent the formation of ulceration of the gastric mucosa in different models of experimentally induced gastric ulcer in mice and rats. When previously administered orally at a dose of 100 mg kg(-1), the essential oil significantly reduced (P < 0.01) the gastric injury induced by hypothermic restraint stress (48%), indomethacin (47%), ethanol (86%) and pylorus ligature models (87%) in rats. In the HCl/ethanol-induced gastric ulcer model in mice, at oral doses of 100 and 200 mg kg(-1), the essential oil from C. cajucara significantly reduced (P < 0.01) the formation of gastric lesions by 52% and 67%, respectively, when compared with the control group. In rats submitted to pylorus ligature, the essential oil given orally increased the volume of gastric juice when compared with the control group (P < 0.01). When the essential oil (100 mg kg(-1)) was administered intraduodenally to mice, significant modifications were found in gastric parameters such as pH and total acid content after oil treatment. We observed significant changes (P < 0.01) in gastric juice parameters such as an increase in volume and a decrease in gastric acidity (pH and total acid content). The acute toxicologic effects of the essential oil from C. cajucara were assessed in mice. The LD50 values were 9.3 g kg(-1) by the oral route and 680 mg kg(-1) by the intraperitoneal route. The good yield of essential oil obtained from dried C. cajucara bark (1%) as well as its anti-ulcerogenic activity and low toxicity suggest that pharmacological studies of this substance as a potential new anti-ulcerogenic drug are warranted.

Study of total alkaloids from Rhizoma Coptis Chinensis on experimental gastric ulcers

To study the effects of total alkaloids (TA) extracted from Rhizoma Coptis Chinensis on experimental gastric ulcer models. Four kinds of experimental ulcer models were established respectively by water-immersion stress, intragastric ethanol, acetic acid erosion, and pylorus ligation. The anti-ulcer effects of TA were evaluated, and compared with that of berberine (Ber) and cimetidine (Cim). TA showed significant inhibitory effects on ulcerative formation induced by water-immersion stress, intragastric ethanol, and pylorus ligation in dose-dependent manner, and showed therapeutic effect on acetic acid erosion-inducing ulcer, in comparison with the control group. The anti-ulcer activity of Ber was less than TA containing equal content of Ber. TA significantly reduced the free acidity, total acidity and total acid output, but didn't affect the gastric juice volume, gastric pepsin activity, adherent mucus quantity of stomach wall and free mucus dissolving in gastric juice. The suppressive activities of TA on gastric acid secretion didn't occur when it was administered into dodecadactylon at a dose of 360 mg/kg wt. Moreover, when compared with Cim, the inhibitory effect of TA on gastric acid secretion isn't proportional to the inhibitory effects on the formation of the 4 kinds of experimental ulcers. TA is a potent candidate in therapeutic drugs for treating gastric ulcer. Its anti-ulcer effective components and mechanism is not only related to Ber and inhibition of gastric acid, but also to other ingredients of TA and mechanism so far unknown.

Gastroprotective and anti-inflammatory effects of resin from Protium heptaphyllum in mice and rats

The natural resin collected from the trunk wood of Protium heptaphyllum is used in folk medicine to treat inflammatory conditions and to hasten wound repair. In the search of new potential anti-inflammatory agents with gastroprotective property, the present study evaluated its effects in experimental models of gastric ulcer and inflammation. In mice, the resin (200 and 400 mg/kg) significantly attenuated the gastric damage induced by ethanol or acidified ethanol (HCl/ethanol), in a manner similar to N-acetyl- l-cysteine (NAC), a replenisher of sulfhydryls. Unlike NAC the resin failed to restore the ethanol-induced depletion of non-protein sulfhydryl content, indicating a different mechanism of gastroprotection. However, in 4-h pylorus-ligated rats, the resin significantly reduced the total acidity without much change in gastric secretory volume. In rats, at similar doses the resin did not modify the hind-paw edema induced by carrageenan, but effectively reduced the formation of cotton pellet-induced granuloma, suggesting its inhibitory effect on collagen formation but not on acute edema. Furthermore, the vascular permeability increase induced by acetic acid was significantly reduced in mice that received 400 mg/kg resin. The resin demonstrated no overt toxicity in mice up to an oral dose of 5 g/kg. Phytochemical analysis revealed the presence of α- and β-amyrins as principal triterpenoid constituents of resin, which were previously described to have anti-ulcer property. These findings indicate the potential gastroprotective and anti-inflammatory property of P. heptaphyllum resin and further support its popular use in gastrointestinal disorders.

Effects of sea buckthorn ( Hippophaë rhamnoides L.) seed and pulp oils on experimental models of gastric ulcer in rats

Oils from sea buckthorn ( Hippophaë rhamnoides L.) seeds and berries have traditionally been used in the treatment of disorders of skin and mucosa in China. Compared with the negative control, oral administration of CO 2-extracted seed and pulp oils, 7.0 ml · kg −1 · day −1 significantly reduced ulcer formation in water-immersion ( P<0.05) and reserpine-induced ( P<0.01) models in rats. In addition, administration of the two oils, 3.5 ml · kg −1· day −1, significantly reduced the index of pylorus ligation-induced gastric ulcer ( P<0.05) and sped up the healing process of acetic acid-induced gastric ulcer ( P<0.01). The results suggested that the CO 2-extracted sea buckthorn seed and pulp oils have both preventive and curative effects against experimental gastric ulcers in rats.

Anti-gastric Ulcer and Cytoprotective Properties of Caralluma arabica

In the present study, a 10% ethanolic extract of Caralluma arabica, at the doses of 200 and 400 mg/kg, was evaluated for the antigastric ulcer activity using experimental gastric ulcer models induced by phenylbutazone or indomethacin and 80% ethanol or 0.2N NaOH, and cold restraint stress. Some experiments were carried out to study the effects of C. arabica extract on gastric acid secretion in pyloric ligationinduced ulcer and gastric wall mucin production. The 10% ethanolic extract of C. arabica produced a dose-dependent reduction in all experimentally induced gastric lesions used in the present study. The cytoprotective activity of C. arabica in ethanol-induced ulcer was completely abolished by pretreatment with indomethacin. Induction of gastric ulcer reduced gastric wall production of mucin to 50.8% of its initial value. This reduction was completely prevented by pretreatment with C. arabica extract. C. arabica extract significantly reduced total gastric acidity (from 22.4 ± 1.5 to 9.2 ± 1.6 mEq/L) and volume of gastric secretions (from 9.98 ± 0.7 to 2.03 ± 0.2 ml). Results of the present study reveal that the C. arabica extract protects gastric mucosal cells against experimental gastric mucosal damage. This effect confirms results of other studies on Caralluma species and seems to be mediated by multi-mechanisms including increased gastric production of prostaglandins and mucin and reduced gastric acidity.

Prospects for future development in the pharmacology of gastric ulcer models and of gastric acid secretion in experimental animals

Prospects for future development in the field of gastrointestinal pharmacology were briefly discussed on the base of the present progress in our own research on animal models of gastric ulcer and the mechanism of gastric acid secretion. We established a few novel methods to induce extensive ulceration restricted to the gastric antral area in rats by a combination of drug-induced vagal stimulation with necrotizing agents or anti-inflammatory drugs, as well as with ammonia in relation to the etiological role of Helicobacter pilori. In these models, it was found that the gastric antral area become sensitive to mucosal aggression under vagal stimulation and refeeding after starvation and that the mucosal primary afferent nervous system was involved in the integration of gastric mucosal defense mechanisms. Among many experimental gastric ulcer models, the gastric antral ulcer is important for future study because of its unique analogy with human ulcer in its location of incidence and pathology. We also established methods to measure gastric acid secretion in the isolated gastric mucosa or whole stomach of rat or mouse, as well as acid secretion in anesthetized rats. By using these methods, the signal transduction route of vagus nerve stimulation to parietal cells was studied. The importance of mediation of enterochromaffin cells in gastric acid secretion was clearly confirmed. In the studies on receptor mechanisms in the central nervous system regulating gastric acid secretion, critical roles of GABA, barbiturate, glutamate, neurosteroids and opioid receptors were clarified. From these results, several remaining problems were suggested and these must be resolved in future research.

Effect of amylin in various experimental models of gastric ulcer

Subcutaneous administration of amylin (20 to 40 μg/kg) prevented, in a dose-dependent manner, reserpine- and serotonin-induced gastric damage, but the anti-ulcer effect was not present when lesions were induced by pylorus ligation. The protective effect of amylin was inhibited by pretreatment with capsaicin as well as CGRP-(8-37), a calcitonin gene-related peptide (CGRP) and amylin receptor antagonist, and was significantly reduced by domperidone, a dopamine D 2 receptor antagonist, or neostigmine, an inhibitor of acetylcholinesterase. Our data suggest that the gastroprotective activity of amylin in some experimental models of gastric ulcers involves capsaicin-sensitive fibers and CGRP receptors. Moreover, the peptide interferes, at least in part, with the dopaminergic and parasympathetic systems.

Anti-ulcer activity and mode of action of the polysaccharide fraction from the leaves of Panax ginseng.

The effects of a weakly acidic polysaccharide fraction, GL-4, from the leaves of Panax ginseng C. A. Meyer on various experimental gastric ulcer models in mice and rats have been studied. Oral administration of GL-4 at doses of 50 to 200 mg/kg inhibited the formation of the gastric lesions induced by necrotizing agents such as HCl/ethanol and ethanol in a dose-dependent manner. This protective effect was observed not only upon oral but also upon subcutaneous administration of GL-4 (50-100 mg/kg). GL-4 also inhibited the formation of gastric ulcers which were induced by water immersion stress, indomethacin, or pylorus-ligation. The contents of prostaglandin E2 in the gastric juice from rats were not influenced by oral administration of GL-4. The protective action of GL-4 against HCl/ethanol-induced gastric lesions was not abolished by pretreatment with indomethacin. When GL-4 (100 mg/kg, p.o.) was administered into pylorus-ligated rats, both gastric acidity and pepsin activity in the gastric juice decreased significantly.

Zinc acexamate reduces gastric damage induced by platelet-activating factor

We have t≐sted the ability of zinc acexamate (ZAC) to prevent platelet- activating-factor (Paf) induced gastric damage in rats. Lesions were characterized by a vascular congestion affecting the entire mucosa, oedema, haemorrhage and frequent necrosis of the more superficial areas. The gastric damage appearing after Paf was accompanied by degranulation of gastric mast cells. Leukocytes were often seen at the submucosal level. Oral pretreatment with ZAC reduced in a dose-dependent manner both gastric damage and mast cell degranulation observed after Paf. ZAC administered orally at a dose of 100 mg kg −1 statistically inhibited (p < 0.01) gastric damage and mast cell degranulation. ZAC did not affect the hypotension induced by Paf confirming that gastric damage and hypotension appearing in rats after Paf administration are two independent phenomena. The present findings indicate that the inhibitory effect of ZAC upon gastric lesions induced by Paf may be related to the different protective actions exhibited by this zinc compound in a wide variety of experimental models of gastric ulcer.

Anti‐ulcerogenicity of the flavonoid fraction from Dittrichia viscosa (L.) W. Greuter in rats

AbstractThe anti‐ulcer activity of extracts from Dittrichia viscosa (L.) W. Greuter by means of different experimental gastric ulcer models was investigated. The results of this report indicate that the antiulcerogenic effect of Dittrichia viscosa lies mainly in its flavonoid fraction (the etheral extract, 1,14%), which afforded the predominant flavonoid, quercetin. This flavonol exercised a significant curative effect mainly in prolonged treatment of induced ulcers in rats.

Gastric antral and fundic mucosal protein, DNA and RNA changes in different experimental ulcer models

The changes in gastric (fundic and antral) mucosal protein, DNA and RNA content, have been investigated in different experimental gastric ulcer models of rat. It seems that indomethacin and stress (restraint) ulcer formation were followed by a predominant fundic (oxyntic cell area) mucosal DNA increase, while in the antral mucosa this phenomenon was connected to a significant RNA increase. The observed changes of the RNA/DNA ratio in the fundic mucosa were interpreted as a sign of accelerated cell renewal. The authors conclude that during ulceration the regenerative processes concomitantly take place.

Studies on the biotransformation and anti-ulcer effects of 2-(nicotinoylaminoethanesulfonylamino)pyridine

Investigations were made of 2-(nicotinoylaminoethanesulfonylamino)pyridine (NTP), a new compound with anti-ulcer effects, to clarify the relationship between its biotransformation and pharmacological effects. The effect of NTP was investigated by using two types of experimental gastric ulcer models in rats. The anti-ulcer effect was revealed to be an action of NTP itself. In order to study the biotransformation of NTP, a quantitative analysis method by HPLC was established. When NTP was orally administered to rabbits, 2-(aminoethanesulfonylamino)pyridine (TP), which is a metabolite of NTP, appeared in plasma and lymph. When NTP was orally administered to rabbits to investigate its distribution in organs, a massive amount of NTP and TP appeared in various organs within 7 hr after administration. We conclude that the pharmacological effect of NTP appears to be associated mainly with the unchanged substance.