Ethanol-induced Gastric Erosions Research Articles

Proanthocyanidin ameliorates against ethanol -induced gastric mucosal erosion by attenuating inflammatory response, oxidative stress and apoptosis in rats

Gastric ulcer is a common chronic disease in human digestive system. Massive alcohol drinking can lead to gastric ulcer. The gastroprotective effect and molecular mechanisms of Proanthocyanidin in a rat model of ethanol-induced gastric mucosal erosion were investigated.35 male rats were divided into five equal groups. Group 1 :( Control normal) rats received no drugs. Group 2:(Early ulcer) rats received absolute ethanol (0.5ml/100g rat) orally on empty stomach and sacrificed one hour later. Group 3 :(Early ulcer + proanthocyanidin protected) rats received proanthocyanidin orally (300mg/kg b.wt/day) for 3 weeks before ethanol administration then sacrificed after one hour. Group 4: (Late ulcer) rats received ethanol similar to group 2 and sacrificed after 21 days. Group 5: (Late ulcer + proanthocyanidin treated) rats first administered with ethanol (0.5ml/100g rat) and after one hour proanthocyanidin was administered for 21 days. A significant increase in stomach L-MDA concentration with marked decrease in CAT activity and GSH concentration were observed in gastric erosion -induced rats. However, a significant depletion of gastric L-MDA level and marked increase in CAT activity and GSH concentration were observed after Proanthocyanidin treatment when compared to ulcerated rats. A significant up-regulation of gene expression level of BAX, NF-κB and IL-1β with down-regulation of Bcl-2 gene were observed in stomach of gastric erosion -induced rats. However, a significant down regulation of BAX, NF-κB and IL-1β with up-regulation of Bcl-2 gene were observed after Proanthocyanidin treatment. Conclusively, Proanthocyanidin protects rat gastric mucosa against ethanol-induced gastric erosion via anti-inflammatory, anti- apoptotic and anti-oxidative mechanisms.

Effect of Saiboku-to, an Oriental Herbal Medicine, on gastric lesion induced by restraint water-immersion stress or by ethanol treatment.

The effect of saiboku-to on gastric lesions induced by restraint water-immersion stress and ethanol has been examined in rats. Thirty minutes after oral administration of saiboku-to, the rats were placed in restraint cages and immersed in water at 23 degrees C for 7 h, or orally administered 99.5% ethanol (1 mL) and placed in normal cages for 1 h. The stress for 7 h or the ethanol treatment for 1h induced erosion in the glandular area of the stomach. Histology showed that the surface epithelial cells were desquamated and part of the lamina propria mucosae was injured. The evaluation of lesion index, the cumulative length of the gastric lesion, on the gross appearance of the stomach, revealed that saiboku-to dose-dependently inhibited both the water-immersion stress-induced gastric erosion and ethanol-induced gastric erosion. To determine whether the anti-erosion effect of saiboku-to was because of a mild irritant effect, saiboku-to or 20% ethanol, which is known as a typical mild irritant, were given orally. After 30 min a strong irritant, 99.5% ethanol, was given orally. Histological examination was performed 30 min after administration of saiboku-to or the mild irritant, and 1 h after administration of the strong irritant. The mild irritant induced a reduction in surface epithelial cells 30 min after administration. Furthermore, the mild irritant protected the stomach against mucosal erosion produced by the strong irritant. Saiboku-to protected the strong irritant-induced erosion without producing mild irritation as observed in stomach treated with 20% ethanol. Pretreatment with saiboku-to also inhibited the decrease in the levels of hexosamine, gastric mucus glycoprotein, induced by the strong irritant. In pylorus-ligated rats, saiboku-to dose-dependently inhibited gastric acid secretion, a gastric aggressive factor. These results suggest that the anti-erosion effect of saiboku-to which is not a mild irritant, involves both inhibition of aggressive factors, such as gastric acid secretion, and augmentation of defensive factors, such as gastric mucus cells.

Protective effect of an orally administered, highly potent somatostatin analog (RC-121) against absolute ethanol-induced hemorrhagic erosions of the rat gastric mucosa

The cytoprotective effect of a highly potent somatostatin (SRIF) analog, RC-121 (H-D-Phe-C ys-Tyr-D-Trp-Lys-Val-Cy s-Thr-NH 2), was examined in the absolute ethanol-induced gastric erosion model in rat. This analog diminished the degree of gastric erosion by 50–55% when administered in i.p. doses of 2×10 −10−10 −8 g/100 g body weight, or in oral doses of 10 −8−2×10 −7 g/100 body weight. The orally active, highly potent SRIF analogs may be useful as therapeutic agents in the treatment of human peptic ulcer.

Gastric mucosal protection by acetazolamide derivatives: Role of carbonic anhydrase and sulfhydryls

Acetazolamide, a carbonic anhydrase inhibitor, prevents acute gastric hemorrhagic lesions induced by ethanol. We used acetazolamide and other carbonic anhydrase inhibitors to correlate their gastroprotective effects with the degree of inhibition of carbonic anhydrase. Since acetazolamide is a thiadiazole, we also investigated structurally related thiadiazoles that contain sulfhydryls to test the hypothesis that the protection against ethanol-induced gastric erosions is related to the presence of sulfhydryls. Dose-response studies with acetazolamide revealed that the protection did not correlate with the inhibition of carbonic anhydrase in the rat gastric mucosa. The carbonic anhydrase inhibitors sulfanilamide and ethoxzolamide, did not offer protection. Bismuthiol I, a thiadiazole with two sulfhydryls, was twice as protective as 2-amino-5-mercapto-1,3,4-thiadiazole with only one sulfhydryl group. We conclude that the protection by acetazolamide against ethanol-induced lesions is not related to the inhibition of carbonic anhydrase in the gastric mucosa. The gastroprotective effect of acetazolamide and its derivatives may be related to their content of sulfhydryls in an oxidized or reduced state.

Protection by metals against ethanol-induced gastric mucosal injury in the rat: Comparative biochemical and pharmacologic studies implicate protein sulfhydryls

Recent evidence suggests a role of endogenous sulfhydryls (SHs) in gastric “cytoprotection.” Because divalent metals bind to or oxidize SH groups, their effect on ethanol-induced gastric erosions was studied. For comparative biochemical studies the SH cysteamine, the glutathione depletor diethylmaleate, and SH alkylating agent N-ethylmaleimide (NEM) were also used. Rats pretreated with CdCl2, ZnCl2, or Cu(NO3)2 6 h before absolute ethanol showed a significant dose-dependent decrease in the mucosal lesions. Copper was effective in preventing the lesions up to 15 min before the ethanol. Iron and manganese were active at 30 min, but not at 6 h before the ethanol lesions. Indomethacin administration decreased the protection afforded by iron, manganese, and cadmium, but did not modify that by lead and copper. N-ethylmaleimide abolished the protection by iron, manganese, and cadmium, but did not affect the protection caused by lead and copper when given after the metals. However, when NEM was given before lead and copper, it diminished the protection. Secretory studies revealed that cadmium and zinc slightly inhibited gastric acid secretion, but a similar reduction of acid output by cimetidine did not decrease the ethanol-induced gastric erosions. Biochemical studies of endogenous SH showed that the protective metals and NEM decreased the glutathione concentration in the nonprotein fraction, whereas these metals diminished and NEM, which antagonizes mucosal protection, elevated the cysteine concentration in the protein fraction of the gastric mucosa. The common factor with the protective agents thus seems to be the blocking of protein SH by binding or oxidation by protective agents. These endogenous SHs may mediate cellular responses to injury.

Protection by metals against ethanol-induced gastric mucosal injury in the rat

Abstract Recent evidence suggests a role of endogenous sulfhydryls (SHs) in gastric cytoprotection. Because divalent metals bind to or oxidize SH groups, their effect on ethanol-induced gastric erosions was studied. For comparative biochemical studies the SH cysteamine, the glutathione depletor diethylmaleate, and SH alkylating agent N-ethylmaleimide (NEM) were also used. Rats pretreated with CdCl 2 , ZnCl 2 , or Cu(NO 3 ) 2 6 h before absolute ethanol showed a significant dose-dependent decrease in the mucosal lesions. Copper was effective in preventing the lesions up to 15 min before the ethanol. Iron and manganese were active at 30 min, but not at 6 h before the ethanol lesions. Indomethacin administration decreased the protection afforded by iron, manganese, and cadmium, but did not modify that by lead and copper. N -ethylmaleimide abolished the protection by iron, manganese, and cadmium, but did not affect the protection caused by lead and copper when given after the metals. However, when NEM was given before lead and copper, it diminished the protection. Secretory studies revealed that cadmium and zinc slightly inhibited gastric acid secretion, but a similar reduction of acid output by cimetidine did not decrease the ethanol-induced gastric erosions. Biochemical studies of endogenous SH showed that the protective metals and NEM decreased the glutathione concentration in the nonprotein fraction, whereas these metals diminished and NEM, which antagonizes mucosal protection, elevated the cysteine concentration in the protein fraction of the gastric mucosa. The common factor with the protective agents thus seems to be the blocking of protein SH by binding or oxidation by protective agents. These endogenous SHs may mediate cellular responses to injury.

Effects of somatostatin on ethanol-induced gastric erosions in the rat: role of mast cells.

Somatostatin (S) inhibits hemorrhagic gastric erosions produced by ethanol. In this study we compared the dose-dependent effects of linear (reduced) and cyclic (oxidized) S with respect to mast cell degranulation. The gastric mucosal injuries were more inhibited by linear S than by cyclic S. But linear S aggravated injury at a certain dose (10(-7) mol/rat). Mucosal mast cell degranulation correlated significantly with the area of hemorrhagic mucosal lesions (r = 0.91). Both cytoprotection as well as aggravation potency of S may be connected to gastric mucosal mast cell activity in the rat.

Dose-dependent effects of linear and cyclic somatostatin on ethanol-induced gastric erosions: the role of mast cells and increased vascular permeability in the rat

Somatostatin prevents hemorrhagic gastric erosions produced by ethanol. In this paper we describe studies with linear (reduced) and cyclic (oxidized) synthetic somatostatin-14 in the rat model of ethanol-induced gastric mucosal injury. The linear form of somatostatin was more potent at concentrations of 10 −9 to 10 −8 mol per rat than the cyclic isomere. However, at a concentration of 10 −7 mol per rat i.p. injection of linear somatostatin significantly ( P < 0.01) enhanced gastric erosions caused by the alcohol. The area of hemorrhagic mucosal lesions correlated significantly ( r = −0.846) with mast cell depletion in the gastric mucosa of the animals. Increased vascular permeability and mast cell degranulation were also observed after intradermal injection of linear or cyclic somatostatin. The ‘cytoprotective’ as well as the aggravating potency of linear somatostatin may be connected to gastric mucosal mast cell activity in the rat.

Protective properties of colloidal bismuth subcitrate on gastric mucosa.

Colloidal bismuth subcitrate (CBS), PGE2, sucralfate, and cimetidine have been investigated for their mucosal protective effects in the ethanol-induced gastric erosion model in rats; moreover, to gain an insight into the mechanisms of action of CBS, its ability to stimulate the synthesis of gastric mucosal PGE2 was determined. Although less potent than PGE2 at inhibiting ethanol-induced gastric lesions, CBS was about 4 times more potent than sucralfate. Cimetidine displayed only very weak protective activities. CBS showed a time-dependent inhibition of ethanol-induced lesions. Complete protection was observed 15 min after treatment with CBS and partial protection was observed at 8 h, although no protection was found at 16 h. CBS increased the potential of rat gastric mucosa to synthesize PGE2 in a dose-dependent way. Up to 3-fold increases above the basal levels were found. Peak synthesis of PGE2 occurred 15 min after CBS and elevated levels were still found after 4 h. It is concluded from these studies that CBS produces potent gastric protection towards ethanol-induced injury in the rat. CBS also considerably increases the ability of rat gastric mucosa to synthesize PGE2 which may be an underlying biochemical mechanism for its protective properties on the gastric mucosa.

Role of the Adrenal Cortex in Gastric Mucosal Protection by Prostaglandins, Sulfhydryls, and Cimetidine in the Rat

To investigate the possible role of hormones in gastric mucosal protection, the effect of prostaglandin F2 beta, dimercaprol, or cysteamine on ethanol-induced gastric erosions, and of cimetidine on gastric erosions caused by aspirin was studied in intact, adrenalectomized, medullectomized, ovariectomized, or thyroidectomized rats. Cimetidine was administered at a low dose that did not inhibit hydrogen ion secretion. Adrenalectomized animals failed to exhibit the usual mucosal protective response to prostaglandin F2 beta, sulfhydryls, or cimetidine. Ovariectomy or thyroidectomy did not influence mucosal protection with these agents. The inhibition by total adrenalectomy of mucosal protection was not reversed by large intragastric doses or by parenteral administration of prostaglandin F2 beta. Adrenal medullectomy alone significantly diminished (by approximately one-third) ethanol-induced gastric mucosal injury; prostaglandin F2 beta or sulfhydryl drugs produced significant additional protection. Replacement therapy with glucocorticoids (triamcinolone, corticosterone) but not with mineralocorticoids (deoxycorticosterone, 9 alpha-fluorocortisol) restored the cytoprotective effect of prostaglandin F2 beta and sulfhydryls in adrenalectomized rats. The generation of prostaglandin E2- and prostaglandin I2-like activity in the gastric mucosa was unaltered by adrenalectomy. These studies suggest a permissive role for glucocorticoids in gastric mucosal protection induced by prostaglandins, sulfhydryls, and cimetidine.

Sulfhydryl compounds may mediate gastric cytoprotection.

Ethanol induces hemorrhagic gastric erosions and causes a dose-dependent decrease in the concentration of nonprotein sulfhydryl compounds in rat gastric mucosa. Sulfhydryl-containing drugs protect rats from ethanol-induced gastric erosions, whereas sulfhydryl blocking agents counteract the mucosal cytoprotective effect of prostaglandin F2 beta. These observations suggest that endogenous nonprotein sulfhydryls may mediate prostaglandin-induced gastric cytoprotection and that sulfhydryl drugs may have potential for preventing or treating hemorrhagic gastric erosions.