Healing property of the Piper betel phenol, allylpyrocatechol against indomethacin-induced stomach ulceration and mechanism of action

AIM：To evaluate the protective activity of allylpyrocatechol （APC）, the major antioxidant constituent of Piper betel, against the indomethacin-induced stomach ulceration in the rat model and correlates with its antioxidative and mucin protecting properties.
METHODS： Male Sprague-Dawley rats were divided into five groups. Normal control rats （group Ⅰ ） were given the vehicle oral dose of gum acacia in distilled water （1 mL per rat）; ulcerated control and treated rats （groups Ⅱ-V） were given a single dose of indomethacin （30 mg/kg body wt.）; group Ⅱ rats were sacrificed 4 h after indomethacin administration; groups Ⅲ-Ⅴ rats were given the vehicle （1 mL per rat） or APC （2 mg/kg body wt.） or misoprostol （1.43 μg/kg body wt.） once daily by oral intubation for 7 d starting from 4 h after the indomethacin administration. After 7 d, the stomach tissues were excised for histological examination and biochemical analysis.
RESULTS： Treatment with APC （2 mg/kg body wt per day） and misoprostol （1.43 μg/kg body wt per day） for 7 d could effectively heal the stomach ulceration as revealed from the ulcer index and histopathological studies. Compared to the zero day ulcerated group, treatment with APC and misoprostol reduced the ulcer index by 93.4% and 85.4% respectively （P 〈 0.05）. Both APC and misoprostol accelerated ulcer healing observed in natural recovery （P 〈 0.05）, their respective healing capacities not being significantly different. The healing capacities of APC and misoprostol could be attributed to their antioxidant activity as well as the ability to enhance the rnucin content of the gastric tissues. Compared to the ulcerated untreated rats, those treated with APC and rnisoprostol showed near normal MDA levels, while the protein levels were 86% and 78% of the normal value respectively （P 〈 0.05）. Likewise, both APC and rnisoprostol increased the SOD, catalase, and rnucin levels significantly （P 〈 0.05）, the effect of APC being better.     

Does the African garden egg offer protection against experimentally induced ulcers?

ObjectiveTo evaluate the possible antiulcer effect of the African garden egg, Solanum aethiopicum (S. aethiopicum) (a domestic vegetable) experimentally in rats.MethodsA methanol extract of the plant fruit was prepared by maceration. Twenty five overnight fasted rats for each model were divided randomly into five groups of five rats. Groups 1, 2, 3, 4 and 5 received normal saline, extract dose levels of 100, 200 and 400 mg/kg and 100 mg/kg of ranitidine respectively. All administrations were given orally. For the indomethacin and aspirin models, ulcerogenic agents (indomethacin, 50 mg/kg and aspirin 200 mg/kg) were given thirty minutes after extract treatments and animals sacrificed 8 h later. The acidified ethanol model (ethanol 60% + 0.1 mol/L HCl) was given 1hr after extract treatment and animals sacrificed 1 h later. Ulcer index was checked and analysed with appropriate statistical tools.ResultsExtract of S. aethiopicum showed positive effect on all the models used. It produced higher ulcer inhibition than ranitidine in the indomethacin and acid-ethanol models. All the anti-ulcer effects of the extract at different doses were dose dependent but only in indomethacin model did it produce statistically significant (P<0.05) ulcer reduction in all doses compared to control.ConclusionsGarden egg, a readily cultivated crop vegetable possesses ulcer protective properties against ulcers induced experimentally making it a cheap source of natural anti-ulcer remedy.     

Sodium alginate ameliorates indomethacin-induced gastrointestinal mucosal injury via inhibiting translocation in rats

AIM:To investigate the effects of sodium alginate(ALNa)on indomethacin-induced small intestinal lesions in rats.METHODS:Gastric injury was assessed by measuring ulcerated legions 4 h after indomethacin(25 mg/kg)administration.Small intestinal injury was assessed by measuring ulcerated legions 24 h after indomethacin(10mg/kg)administration.AL-Na and rebamipide were orally administered.Myeloperoxidase activity in the stomach and intestine were measured.Microvascular permeability,superoxide dismutase content,glutathione peroxidase activity,catalase activity,red blood cell count,white blood cell count,mucin content and enterobacterial count in the small intestine were measured.RESULTS:AL-Na significantly reduced indomethacininduced ulcer size and myeloperoxidase activity in the stomach and small intestine.AL-Na prevented increases in microvascular permeability,superoxide dismutase content,glutathione peroxidase activity and catalase activity in small intestinal injury induced by indomethacin.AL-Na also prevented decreases in red blood cells and white blood cells in small intestinal injury induced by indomethacin.Moreover,AL-Na suppressed mucin depletion by indomethacin and inhibited infiltration of enterobacteria into the small intestine.CONCLUSION:These results indicate that AL-Na ameliorates non-steroidal anti-inflammatory drug-induced small intestinal enteritis via bacterial translocation.     

Evaluation of the antiulcer activity of Olax subscorpioidea Oliv. roots in rats

ObjectiveTo evaluate the antiulcer activity of the methanolic root extract of the plant Olax subscorpioidea in experimental rats.MethodsPhytochemical tests and acute toxicity tests were carried out on its methanolic root extract. Pre-treatments with three doses of the extract (200, 400 and 600 mg/kg body weight orally) and Sucralfate at 100 mg/kg orally were used for the various groups of rats. The indomethacin and ethanol models for experimental induction of ulcers in rats were used. Mean ulcer indices were measured and percentage inhibition was derived.ResultsPhytochemistry revealed presence of alkaloids, steroids, glycosides and terpenoids and the extract showed an LD₅₀ of 2 154 mg/kg in mice. Ulcer was produced in all the rats in both models with the extract showing potent antiulcer activity of ethanol model. There was no significant ulcer inhibition by any of the treatments compared to control group in the indomethacin model but the extract's antiulcer effect was dose-dependent (11.8%, 19.2%, 32.7%, P >0.05). The ulcer reduction in the ethanol model was significant ulcer reduction in the highest dose group and Sucralfate group compared to control group (79.3% and 82.9%, P < 0.05). However, the extract at all dosage showed a dose-dependent ulcer inhibition in this model.ConclusionThe above results suggest that the roots of Olax subscorpioidea possess antiulcer activity in experimental rats as claimed by traditional users.     

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

ObjectiveTo investigate the gastroprotective activity of hydroalcoholic extract leaves of Ficus religiosa (F. religiosa) in different experimental models of gastric ulcer in rats.MethodsThe 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.ResultsAdministration 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.ConclusionsThe results suggest that the leaves of the F. religiosa possess significant anti ulcer activity.     

Mitigation of indomethacin-induced gastric mucosal lesions by a potent specific type V phosphodiesterase inhibitor

AIM: To investigate the gastroprotective effect of vardenafil against indomethacin-induced gastric damage.METHODS: Forty-eight female Wistar albino rats were randomly divided into 6 groups. Group 1 received saline only. Group 2 (indomethacin) received indomethacin.Rats in group 3 and 4 were pretreated with different doses of famotidine. Group 5 and 6 were pretreated with different doses of vardenafil. Rats in groups 3 to 6 received 25 mg/kg indomethacin 30 min after pretreatment. The animals were sacrificed 6 h later and their stomachs were opened. Gastric lesions were counted and measured. The stomach of each animal was divided in two parts for histopathological examinations and nitric oxide (NO) and malondialdehyde (MDA) assays, respectively.RESULTS: There were no gastric mucosal lesion in the saline group but all rats in the indomethacin group had gastric mucosal ulcerations (ulcer count; 6.25 ± 3.49,and mean ulcer area; 21.00 ± 12.35). Ulcer counts were diminished with famotidine 5 mg/kg (4.12 ± 2.47, P > 0.05), 20 mg/kg (2.37 ± 4.43, P < 0.05), vardenafil 2 mg/kg (4.37 ± 3.06), and vardenafil 10 mg/kg (1.25 ± 1.38, P < 0.05) compared to the indomethacin group.Gastric mucosal lesion areas were diminished with famotidine 5 mg/kg (8.62 ± 2.97, P < 0.001), famotidine 20 mg/kg (0.94 ± 2.06, P < 0.001), vardenafil 2 mg/kg (6.62 ± 5.87, P < 0.001), and vardenafil 10 mg/kg (0.75 ± 0.88, P < 0.001) compared to the indomethacin group. MDA levels were significantly higher in indomethacin group (28.48 ± 14.51), compared to the famotidine 5 mg/kg (6,21 ± 1.88, P < 0.05), famotidine 20 mg/kg (5.88 ± 1.60. P < 0.05), vardenafil 2 mg/kg (15.87 ± 3.93, P < 0.05), and vardenafil 10 mg/kg (10.97 ± 4.50,P < 0.05). NO concentration in gastric tissues of the famotidine groups were significantly increased ( P < 0.05),but the NO increases in the vardenafil groups were not statistically significant. Histopathology revealed diminished gastric damage for pretreatment groups compared to the indomethacin group ( P < 0.05).CONCLUSION: Vardenafil affords a significant dosedependent protection against indomethacin induced gastric mucosal lesions in rats.     

Mitigation of indomethacin-induced gastric mucosal lesions by a potent specific type Ⅴ phosphodiesterase inhibitor

AIM: To investigate the gastroprotective effect of vardenafil against indomethacin-induced gastric damage.METHODS: Forty-eight female Wistar albino rats were randomly divided into 6 groups. Group 1 received saline only. Group 2 (indomethacin) received indomethacin.Rats in group 3 and 4 were pretreated with different doses of famotidine. Group 5 and 6 were pretreated with different doses of vardenafil. Rats in groups 3 to 6 received 25 mg/kg indomethacin 30 min after pretreatment. The animals were sacrificed 6 h later and their stomachs were opened. Gastric lesions were counted and measured. The stomach of each animal was divided in two parts for histopathological examinations and nitric oxide (NO) and malondialdehyde (MDA) assays, respectively.RESULTS: There were no gastric mucosal lesion in the saline group but all rats in the indomethacin group had gastric mucosal ulcerations (ulcer count; 6.25 ± 3.49,and mean ulcer area; 21.00 ± 12.35). Ulcer counts were diminished with famotidine 5 mg/kg (4.12 ± 2.47, P > 0.05), 20 mg/kg (2.37 ± 4.43, P < 0.05), vardenafil 2 mg/kg (4.37 ± 3.06), and vardenafil 10 mg/kg (1.25 ± 1.38, P < 0.05) compared to the indomethacin group.Gastric mucosal lesion areas were diminished with famotidine 5 mg/kg (8.62 ± 2.97, P < 0.001), famotidine 20 mg/kg (0.94 ± 2.06, P < 0.001), vardenafil 2 mg/kg (6.62 ± 5.87, P < 0.001), and vardenafil 10 mg/kg (0.75 ± 0.88, P < 0.001) compared to the indomethacin group. MDA levels were significantly higher in indomethacin group (28.48 ± 14.51), compared to the famotidine 5 mg/kg (6,21 ± 1.88, P < 0.05), famotidine 20 mg/kg (5.88 ± 1.60. P < 0.05), vardenafil 2 mg/kg (15.87 ± 3.93, P < 0.05), and vardenafil 10 mg/kg (10.97 ± 4.50,P < 0.05). NO concentration in gastric tissues of the famotidine groups were significantly increased ( P < 0.05),but the NO increases in the vardenafil groups were not statistically significant. Histopathology revealed diminished gastric damage for pretreatment groups compared to the indomethacin group ( P < 0.05).CONCLUSION: Vardenafil affords a significant dosedependent protection against indomethacin induced gastric mucosal lesions in rats.     

Protective effect of Luffa acutangula extracts on gastric ulceration in NIDDM rats: role of gastric mucosal glycoproteins and antioxidants

ObjectiveTo study the comparative gastroprotective effect of Luffa acutangula methanolic extract (LAM) and aqueous extract (LAW) on type II diabetes rats.MethodsStreptozotocin (65 mg/kg, i.p.) along with nicotinamide (120 mg/kg, i.p.) was used to induce non insulin dependent diabetes mellitus (NIDDM) in rats. A daily oral dose of aspirin (200 mg/kg, i.p.) was administered for initial seven days to induce gastric ulcerations in the diabetic rats. LAM and LAW were administered orally in the doses of 100, 200 and 400 mg/kg once daily for 21 days. Glibenclamide and ranitidine were used as standards for comparing the antidiabetic and antiulcer effect respectively.ResultsLAM significantly (P<0.01) increased mucosal glycoprotein and antioxidant enzyme level in gastric mucosa of diabetic rats than LAW (P <0.05). LAM was efficient in reversing the delayed healing of gastric ulcer in diabetic rats close to the normal level. LAM exhibited better ulcer healing effect than glibenclamide and LAW, because of its both antihyperglycemic and mucosal defensive actions.ConclusionsThus, LAM is proved to be a better alternative for treating gastric ulcers co-occurring with diabetes.     

Cytoprotection mediated antiulcer effect of aqueous fruit pulp extract of Cucumis sativus

ObjectiveThe study was aimed to evaluate the gastroprotective potential of Cucumis Sativus fruit pulp aqueous extract (CSE) in gastric ulcerated rats.MethodsCytoprotective potential was evaluated via oral administration of CSE at the doses of 250, 500 & 1000 mg/kg three times in a day, for 5 days before the induction of ulcers in indomethacin and pyloric ligation induced ulcer model. Further, its effects were studied on various parameters volume of gastric juice, pH, free and total acidity, protein concentration, acid output in gastric juice, lipid peroxide (LPO), and activities of enzymic antioxidants-super oxide dismutase (SOD) and catalase (CAT) in gastric mucosa. The levels of hexose, hexosamine, sialic acid, fucose in gastric mucosa and gastric juice were also examined. The extent of healing was also determined with post administration of CSE at the same doses & dosage schedule in acetic acid induced model.ResultsIn indomethacin and pyloric ligation model, the pretreatment with CSE and ranitidine significantly reduced the lesion index, in comparison with control treated group (P < 0.05). The percentages of protection of ulcers were 25.8, 65.7, 80.6 & 93.8 for the treated groups of CSE and ranitidine whereas in pyloric ligation it was 31.26, 55.18, 93.26 & 95.51 respectively. In pyloric ligation model, CSE resulted in significant increase in pH, enzymic antioxidants i.e. SOD & CAT, with a significant decrease in volume of gastric juice, free and total acidity, protein & carbohydrate concentration and LPO levels. In acetic acid inducer model, treatment with Cucumis sativus (CSE) caused significant reduction in lesion index in when compared to control treated group, providing evidence for ulcer healing capacity of it. The presence of the flavonoids and polyphenols may be responsible for the gastroprotective effect of CSE.ConclusionsThe aqueous fruit pulp extract of Cucumis sativus (CSE) has a gastroprotective property.     

Effects of leminoprazole, omeprazole and sucralfate on indomethacininduced delayed healing of kissing gastric ulcers in rats

We have examined whether or not repeated treatment with indomethacin delays the healing of kissing gastric ulcers induced in rats. The effects of leminoprazole, omeprazole and sucralfate on any delay in ulcer healing caused by indomethacin were also determined in relation to myeloperoxidase activity. Kissing gastric ulcers were induced by luminal application of an acetic acid solution. Indomethacin significantly delayed ulcer healing in a dose-dependent manner. Leminoprazole and omeprazole decreased the size and depth of ulcers, the healing of which was delayed by indomethacin, while sucralfate only decreased the ulcer depth. Histological studies showed that indomethacin inhibited tissue contraction and regeneration of the ulcerated mucosa. Leminoprazole and omeprazole prevented the inhibition of these parameters. The myeloperoxidase (MPO) activity of the ulcer portion in animals treated with indomethacin was markedly higher than in the control group. Both leminoprazole and omeprazole, but not sucralfate, significantly reduced MPO activity in contrast to the control value (in the presence of indomethacin). There was a significant relationship between the ulcerated area and myeloperoxidase activity. These results suggested that: (i) leminoprazole and omeprazole prevent the indomethacin-induced delay in ulcer healing by promoting tissue contraction and regeneration of the ulcerated mucosa; (ii) sucralfate prevents the indomethacin-induced delay in ulcer healing via the promotion of the formation of granulation tissue; and (iii) MPO activity will be useful to biochemically ensure the healing state of ulcers.     

Mitigation of indomethacin-induced gastric mucosal lesions by a potent specific type Ⅴ phosphodiesterase inhibitor

AIM: To investigate the gastroprotective effect of vardenafil against indomethacin-induced gastric damage.METHODS: Forty-eight female Wistar albino rats were randomly divided into 6 groups. Group 1 received saline only. Group 2 (indomethacin) received indomethacin.Rats in group 3 and 4 were pretreated with different doses of famotidine. Group 5 and 6 were pretreated with different doses of vardenafil. Rats in groups 3 to 6 received 25 mg/kg indomethacin 30 min after pretreatment. The animals were sacrificed 6 h later and their stomachs were opened. Gastric lesions were counted and measured. The stomach of each animal was divided in two parts for histopathological examinations and nitric oxide (NO) and malondialdehyde (MDA) assays, respectively.RESULTS: There were no gastric mucosal lesion in the saline group but all rats in the indomethacin group had gastric mucosal ulcerations (ulcer count; 6.25 ± 3.49,and mean ulcer area; 21.00 ± 12.35). Ulcer counts were diminished with famotidine 5 mg/kg (4.12 ± 2.47, P > 0.05), 20 mg/kg (2.37 ± 4.43, P < 0.05), vardenafil 2 mg/kg (4.37 ± 3.06), and vardenafil 10 mg/kg (1.25 ± 1.38, P < 0.05) compared to the indomethacin group.Gastric mucosal lesion areas were diminished with famotidine 5 mg/kg (8.62 ± 2.97, P < 0.001), famotidine 20 mg/kg (0.94 ± 2.06, P < 0.001), vardenafil 2 mg/kg (6.62 ± 5.87, P < 0.001), and vardenafil 10 mg/kg (0.75 ± 0.88, P < 0.001) compared to the indomethacin group. MDA levels were significantly higher in indomethacin group (28.48 ± 14.51), compared to the famotidine 5 mg/kg (6,21 ± 1.88, P < 0.05), famotidine 20 mg/kg (5.88 ± 1.60. P < 0.05), vardenafil 2 mg/kg (15.87 ± 3.93, P < 0.05), and vardenafil 10 mg/kg (10.97 ± 4.50,P < 0.05). NO concentration in gastric tissues of the famotidine groups were significantly increased ( P < 0.05),but the NO increases in the vardenafil groups were not statistically significant. Histopathology revealed diminished gastric damage for pretreatment groups compared to the indomethacin group ( P < 0.05).CONCLUSION: Vardenafil affords a significant dosedependent protection against indomethacin induced gastric mucosal lesions in rats.     

Amifostine (Wr-2721) Prevents Indomethacin-Induced Gastric Damage in Rats: Role of Non-Protein Sulfhydryl Groups and Leukocyte Adherence

This study was designed to evaluate the protective effect of amifostine on indomethacin-induced gastric damage, and the role of increased gastric non-protein sulfhydryl groups (NP-SH) and decreased leukocyte adherence in this event. Wistar rats were pretreated with amifostine (10, 30, or 90 mg/kg intraperitoneal (i.p.) or subcutaneous (s.c.)) or saline. After 30 min, the rats received indomethacin (20 mg/kg, by gavage) and were then killed 3 hr later. Macroscopic and microscopic gastric damage, concentration of gastric NP-SH, prostaglandin E2 (PGE2), and mesenteric leukocyte adherence (intravital microscopy) were assessed. Amifostine prevented significantly (P < 0.05), macroscopic or microscopic, indomethacin-induced gastric damage, and increased gastric NP-SH, in a dose-dependent manner, with a maximal effect at a dose of 90 mg/kg. Subcutaneous, but not i.p., amifostine administration decreased (P < 0.05) the indomethacin-induced increase in leukocyte adherence. Indomethacin-induced PGE2 depletion was not reversed by amifostine. Amifostine has a protective effect against indomethacin-induced gastropathy by increasing gastric NP-SH and decreasing leukocyte adherence.     

Bilateral adrenalectomy worsens gastric mucosal lesions induced by indomethacin in the rat. Role of enhanced gastric motility

The mechanism by which bilateral adrenalectomy worsens indomethacin-induced gastric lesions was investigated in rats. In sham-operated rats subcutaneously administered indomethacin produced gastric lesions at doses of 10 mg/kg body wt or greater, in association with lowering of blood glucose levels. In a parallel study, indomethacin induced gastric hypermotility at the same dose levels but had no effect on acid output or mucosal blood flow even at 25 mg/kg body wt. Adrenalectomy (2 wk) itself significantly reduced the blood glucose levels (approximately 50%) and markedly potentiated the ulcerogenic and motility responses caused by indomethacin; the ED50 values dropped to approximately 10 times lower than those in sham-operated rats. Both acid output and mucosal blood flow were significantly reduced by adrenalectomy, but these values were increased after indomethacin treatment (3 mg/kg body wt). The ulcerogenic and motility responses caused by indomethacin were significantly reduced by acute infusion of glucose (25% wt/wt, 1.2 ml/h) intravenously in both sham-operated and adrenalectomized rats, and by subcutaneous administration of hydrocortisone acetate (10 mg/kg body wt for 2 wk) in the latter group. When the motility and the ulcer score were determined in the same animals, a highly significant relationship was found between these two factors in both sham-operated and adrenalectomized rats. These results suggest that (a) the increased gastric motility may be a key element in the pathogenesis of indomethacin-induced lesions and in the mechanism for aggravation of the lesions and in the mechanism for aggravation of the lesions by adrenalectomy, and (b) abrasion of adrenal glands by inducing hypoglycemia may sensitize the system to indomethacin and increase gastric motility.     

Evaluation of gastric anti–ulcer activity of methanolic extract of Cayratia trifolia in experimental animals

ObjectiveTo evaluate the gastric anti-ulcer activity of methanolic extract of Cayratia trifolia L. (MECT) (Vitaceae) leaves in experimental animals.MethodsMECT was investigated in pylorus ligation and ethanol induced ulcer models in Wistar rats. In both models, the common parameter determined was ulcer index. MECT at doses of 250, 500 mg/kg (p.o.) was used to determine whether it could produce significant inhibition of the gastric lesions induced by pylorus ligation and ethanol.ResultsThe extract (250 and 500 mg/kg) showed significant (P<0.05) reduction in gastric volume and ulcer index as compared to the control in both of the two models.ConclusionsIt can be concluded that MECT possesses antiulcerogenic as well as ulcer healing properties, which might be due to its antisecretory activity.     

Analgesic and anti—inflammatory activities of the ethanol extract of the leaves of Helianthus Annus in Wistar rats

ObjectiveTo investigate the anti-inflammatory and analgesic effects of the ethanol extract of leaves of Helianthus annus L. (H. annus) in acclimatized Wistar rats.MethodsIt was undertaken using the albumin induced paw edema model of inflammation as well as both the hotplate and tail immersion analgesic test methods. Doses of the extract tested in experimental rats were 0.5 g/kg, 2 g/kg and 4 g/kg while negative and positive control rats received distilled water and indomethacin respectively.ResultsIt was shown that treatment with the tested doses of the extract effectively inhibited paw edema induced by egg albumin. This effect was comparable if not better than the observations made in rats treated with 10 mg/kg of indomethacin orally. Treatment with the extract was also observed to have significantly increased the mean tolerance time of rats to thermal noxious stimuli compared to control animals that had distilled water and appeared to be more effective than 10 mg/kg of indomethacin treatment.ConclusionsThese observations confirmed the presence of a strong anti-inflammatory and anti-noiciceptive activity in the ethanol extract of the leaves of H. annus and therefore validated the folkloric use of the leaves of this plant in treatment of pro-inflammatory, post traumatic situations.     

EP4 agonist alleviates indomethacin-induced gastric lesions and promotes chronic gastric ulcer healing

AIM: To investigate EP4-selective agonist effect on indomethacin-induced gastric lesions and on the spontaneous healing of chronic gastric ulcers. METHODS: In a mouse model of gastric bleeding with high dose of indomethacin (20 mg/kg), an EP4-selective agonist was administered orally. Stomach lesions and gastric mucous regeneration were monitored. In a mouse model of chronic gastric ulcer induced by acetic acid, EP4 agonist effect on the healing of chronic gastric ulcer was evaluated in the presence or absence of low dose indomethacin (3 mg/kg). In cultured human gastric mucous cells, EP4 agonist effect on indomethacininduced apoptosis was assessed by flow cytometry. RESULTS: The EP4-selective agonist reduced high dose indomethacin-induced acute hemorrhagic damage and promoted mucous epithelial regeneration. Low-dose indomethacin aggravated ulcer bleeding and inflammation, and delayed the healing of the established chronic gastric ulcer. The EP4 agonist, when applied locally, not only offset indomethacin-induced gastric bleeding and inflammation, but also accelerated ulcer healing. In the absence of indomethacin, the EP4 agonist even accelerated chronic gastric ulcer healing and suppressed inflammatory cell infiltration in the granulation tissue. In vitro , the EP4 agonist protected human gastric mucous cells from indomethacin-induced apoptosis. CONCLUSION: EP4-selective agonist may prevent indomethacin-induced gastric lesions and promote healing of existing and indomethacin-aggravated gastric ulcers, via promoting proliferation and survival of mucous epithelial cells.     

Ulcer healing properties of different extracts of Origanum majorana in streptozotocin-nicotinamide induced diabetic rats

ObjectiveThe aim of the present investigation was to evaluate the ulcer healing properties of different extracts of Origannum majorana, viz., hydrodistilled volatile oil (OMO), methanolic (OMM) and aqueous extract (OMW) in streptozotocin-nicotinamide induced diabetic rats.MethodsAll the extracts were administered in different doses (100, 200 and 400 mg/kg, p.o.) to investigate the ulcer healing potential. Streptozotocin (STZ; 65 mg/kg, i.p.) along with nicotinamide (120 mg/kg, i.p.) was used to induce non-insulin dependent diabetes mellitus in rats. Aspirin (200 mg/kg, i.p.) was administered for initial 7 d to induce gastric ulcerations in the diabetic rats. Various biochemical markers of blood and tissue origin were estimated to compare the ulcer healing potential of these extracts.ResultsThe OMO and OMM exhibited dose dependent significant (P<0.01) ulcer healing property than the OMW. Additionally, the antidiabetic property of OMO and OMM was better than OMW.ConclusionThe OMO and OMM of Origanum majorana leaves can prove to be beneficial in the concomitant treatment of gastric ulcers and diabetes.     

Gastric motility is an important factor in the pathogenesis of indomethacin-induced gastric mucosal lesions in rats

Effects of atropine, cimetidine, and 16,16-dimethyl prostaglandin E₂ (16,16-dmPGE₂) on indomethacin-induced gastric lesions were investigated in rats by correlating their effects on gastric acid and HCO^}-₃ secretion and motility. Subcutaneously administered indomethacin (25 mg/kg) produced gastric mucosal lesions within 4 hr. In parallel studies, an equivalent dose of indomethacin inhibited gastric HCO^}-₃ secretion, and stimulated gastric motor activity measured as intraluminal pressure recordings, whereas acid secretion was unaffected. The lesions induced by indomethacin were significantly prevented by three agents: cimetidine (100 mg/kg), which reduced acid secretion; atropine (1 mg/kg), which reduced acid secretion and gastric motility; and 16,16-dmPGE₂ (10 g/kg), which reduced acid secretion and motility and increased gastric HCO^– ₃ secretion. If acid (150 mM HCl) was infused into the stomach (1.2 ml/hr) during indomethacin treatment, only the latter two agents significantly prevented the formation of gastric lesions in response to indomethacin. Since only the effect on gastric motility was common to these two agents (atropine and 16,16-dmPGE₂), the increased gastric motility may be an important pathogenetic factor in indomethacin-induced gastric lesions. The presence of acid as well as a deficiency of endogenous PGs may be prerequisite for later extension of the lesions but cannot account for the induction of mucosal lesions in rats following administration of indomethacin.     

Prevention and healing of experimental indomethacin-induced gastric lesions: effects of ebrotidine, omeprazole and ranitidine

BACKGROUND: Ebrotidine is a new H2 receptor antagonist that potentiates the gastric mucosal barrier. AIM: To compare ebrotidine with other anti-secretory drugs in the prevention and healing of indomethacin-induced gastric lesions. METHODS: Three different models of indomethacin-induced gastric lesions were used. (1) Fasted rat model: indomethacin was intra-gastrically administered in rats pre-treated with different doses of the anti-secretory drugs. (2) Re-fed rat model: rats orally treated with different doses of anti-secretory drugs had free access to chow pellets and were then treated with parenteral indomethacin. (3) Healing model: either oral or parenteral anti-secretory drugs were given after indomethacin administration. Computer-assisted analysis of the area of damage was expressed as ulcer index. Gastric secretion was evaluated in the pylorus-ligated rat model. RESULTS: Inhibition of acid secretion was in the order omeprazole > ebrotidine = ranitidine. Ebrotidine at the highest dose used (100 mg/kg) and omeprazole, but not ranitidine, significantly prevented indomethacin-induced corpus (fasted rat) and antrum (re-fed rat) gastric lesions. In the ulcer healing model, oral administration of omeprazole and both ranitidine and ebrotidine at the highest dose used improved the ulcer index. The parenteral administration of these drugs had a lesser effect than the oral route and was in the order ebrotidine > omeprazole > ranitidine. CONCLUSIONS: Ebrotidine is effective in both the prevention and healing of indomethacin-induced experimental gastric lesions. In these models, the effect of ebrotidine is comparable to omeprazole and more effective than ranitidine.     

Effects of free radical scavengers on indomethacin-induced aggravation of gastric ulcer in rats

Effects of treatment with free radical scavengers in the healing process of acetic acid-induced gastric ulcer on the ulcer aggravation induced by indomethacin were investigated. Gastric ulcers were produced on the anterior wall of the stomach of male Sprague-Dawley rats by submucosal injection of 20% acetic acid. To investigate the role of oxygen radicals, rats with gastric ulcer were treated with scavengers for six weeks and then treated with indomethacin (1 mg/kg/day). While superoxide dismutase (10,000 units/kg/day) did not affect the ulcer area after indomethacin treatment, allopurinol (50 mg/kg/day) slightly inhibited the increase in ulcer area. Dimethyl sulfoxide (1% solution,ad libitum) produced a significant decrease in size of the ulcer after indomethacin treatment. Increased lipid peroxides in the gastric mucosa after indomethacin treatment decreased significantly in the rats of the dimethyl sulfoxide and allopurinol groups. These results indicate that lipid peroxidation mediated by oxygen radicals plays an important role in the mechanism of ulcer aggravation induced by indomethacin.