Protective effect of teprenone against acute gastric mucosal lesions induced by compound 48/80, a mast cell degranulator, in rats

The protective effect of teprenone, an anti-ulcer drug, against acute gastric mucosal lesions was examined in rats with a single intraperitoneal injection of compound 48/80 (0.75 mg/kg). Teprenone (50, 100, or 200 mg/kg) was orally administered 0.5 h before compound 48/80 treatment. Administered teprenone prevented gastric mucosal lesion development found at 3 h after compound 48/80 treatment dose-dependently, although no dose of teprenone affected the decreased gastric mucosal blood flow and increased serum serotonin and histamine concentrations found at 3 h after the treatment. Increases in the activities of myeloperoxdiase (an index of neutrophil infiltration) and xanthine oxidase and the content of thiobarbituric acid reactive substances (an index of lipid peroxidation) and decreases in the contents of hexosamine (a marker of gastric mucus) and adherent mucus occurred in gastric mucosal tissues at 3 h after compound 48/80 treatment. Administered teprenone dose-dependently attenuated all these changes found at 3 h after compound 48/80 treatment. These results indicate that orally administered teprenone protects against compound 48/80-induced acute gastric mucosal lesions in rats possibly through its stimulatory action on gastric mucus synthesis and secretion and its inhibitory action on neutrophil infiltration and enhanced lipid peroxidation in the gastric mucosal tissue.     

Anti-ulcer effect of tea catechin in rats

Oral administration of tea catechin dose-dependently prevented absolute ethanol-induced (50, 100, 200 mg/kg) or restraint plus water immersion stress-induced acute gastric mucosal injury (300, 400 mg/kg) in rats. When the effect of test compound was evaluated on the 15th day after acetic acid injection to rats, repeated oral administration of tea catechin (25, 50, 100 mg/kg twice daily) dose-dependently accelerated the healing of acetic acid-induced chronic gastric ulcers. Tea catechin (10(-5)-10(-1) g/100 ml) concentration-dependently scavenged superoxide anions in vitro. Tea catechin (100, 200 mg/kg orally) markedly inhibited the increase in thiobarbituric acid-reactive substances in the injured mucosa of rats treated with 50% ethanol. Tea catechin (50, 100 mg/kg twice orally, daily) markedly inhibited the increase in content of thiobarbituric acid-reactive substances in the ulcerated region of acetic acid-induced gastric ulcers on the 7th and 15th days. In addition, at 50, 100 and 200 mg/kg orally, it dose-dependently prevented the decrease in gastric mucosal hexosamine content induced by absolute ethanol, although it failed to inhibit the basal gastric acid secretion. These results suggest that tea catechin may primarily protect gastric mucosa from acute gastric mucosal injury and promote the healing of chronic gastric ulcers by its antioxidant activity and gastric mucus-increasing actions.     

Effect of gefarnate on acute gastric mucosal lesion progression in rats treated with compound 48/80, a mast cell degranulator, in comparison with that of teprenone

We have reported that teprenone (geranylgeranylacetone), an anti-ulcer drug, prevents acute gastric mucosal lesion progression in rats treated once with compound 48/80 (C48/80), a mast cell degranulator, possibly by suppressing mucus depletion, neutrophil infiltration, and oxidative stress in the gastric mucosa. Herein, we examined the preventive effect of gefarnate (geranyl farnesylacetate), an anti-ulcer drug, on acute gastric mucosal lesion progression in rats treated once with C48/80 (0.75 mg/kg, i.p.) in comparison with that of teprenone, because the chemical structure and anti-ulcer action of gefarnate are similar to those of teprenone. Gefarnate (50, 100 or 200 mg/kg) administered orally at 0.5 h after C48/80 treatment, at which time gastric mucosal lesions appeared, reduced progressive gastric mucosal lesions at 3 h dose-dependently. At 3 h after C48/80 treatment, the gastric mucosa had decreased adherent mucus and hexosamine contents and increased myeloperoxdiase (an index of neutrophil infiltration) and xanthine oxidase activities and thiobarbituric acid reactive substances (an index of lipid peroxidation) content. Post-administered gefarnate attenuated all these changes dose-dependently. These preventive effects of gefarnate were similar to those of teprenone at a dose of 200 mg/kg. Post-administered gefarnate did not affect the increases in serum serotonin and histamine concentrations and the decrease in gastric mucosal blood flow at 3 h after C48/80 treatment like teprenone. These results indicate that orally administered gefarnate prevents acute gastric mucosal lesion progression in C48/80-treated rats possibly by suppressing mucus depletion, neutrophil infiltration, and oxidative stress in the gastric mucosa like teprenone.     

Preventive effect of teprenone on stress-induced gastric mucosal lesions and its relation to gastric mucosal constitutive nitric oxide synthase activity.

Recently, we demonstrated that teprenone, an anti-ulcer agent, exerts protective and preventive actions against water immersion restraint (WIR) stress-induced gastric mucosal lesions in rats both by inhibiting neutrophil infiltration into the gastric mucosal tissue and by preserving gastric mucus synthesis and secretion. In rats with WIR stress we have also found a decrease in gastric mucosal constitutive nitric oxide synthase (cNOS) activity and a drastic increase in gastric mucosal inducible nitric oxide synthase (iNOS) activity. The decrease in gastric mucosal cNOS activity is closely related to an increase in neutrophil infiltration into the gastric mucosa and a decrease in the level of gastric mucus. In this study of WIR-stressed rats, therefore, we examined whether the inhibitory actions of teprenone on neutrophil infiltration and decreases in mucus synthesis and secretion in the gastric mucosa of rats are related to the change in gastric mucosal cNOS activity during the development of gastric mucosal lesions. Pre-administration of teprenone (200 mg kg-1) prevented the decrease in gastric mucosal cNOS activity with attenuations of neutrophil infiltration into gastric mucosal tissues and decreased levels of gastric mucosal hexosamine, an index of gastric mucin, and adherent mucus in rats with 3 or 6 h of WIR stress. These preventive effects of teprenone on the gastric mucosal neutrophil infiltration and the decrease in gastric mucus levels in rats with WIR stress were completely reversed with inhibition of gastric mucosal cNOS activity by co-administration of NG-monomethyl L-arginine (L-NMMA), a non-selective NOS inhibitor. These results suggest that the inhibitory actions of teprenone on neutrophil infiltration and decreases in mucus synthesis and secretion in the gastric mucosa of rats with WIR stress are closely related to the maintenance of cNOS activity in the gastric mucosal tissue.     

Preventive effect of teprenone on acute gastric mucosal lesion progression in compound 48/80-treated rats

The preventive effect of teprenone (6,10,14,18-teramethyl-5,9,13,17-nonadecatetaene-2-one), an anti-ulcer drug, on acute gastric mucosal lesion progression was examined in rats with a single intraperitoneal (i.p.) injection of compound 48/80 (0.75 mg/kg). Teprenone (20, 100 or 200 mg/kg), which was orally administered 0.5 h after compound 48/80 treatment at which time gastric mucosal lesions appeared, prevented gastric mucosal lesion development at 3 h after the treatment dose-dependently. Gastric mucosal tissues of compound 48/80-treated rats showed increases in myeloperoxidase (an index of neutrophil infiltration) and xanthine oxidase activities and thiobarbituric acid reactive substances (an index of lipid peroxidation) content and decreases in Se-glutathione peroxidase activity and hexosamine and vitamin E contents at 3 h after the treatment. Post-administered teprenone attenuated all these changes dose-dependently. These results indicate that teprenone prevents acute gastric mucosal lesion progression in compound 48/80-treated rats possibly by suppressing gastric mucus depletion, neutrophil infiltration and oxidative stress in the gastric mucosal tissue.     

Effects of the new anti-ulcer agent KB-5492 on experimental gastric mucosal lesions and gastric mucosal defensive factors, as compared to those of teprenone and cimetidine.

Effects of KB-5492, a new anti-ulcer agent, on various experimental gastric mucosal lesions and mucosal defensive factors in rats were compared with those of teprenone and cimetidine. KB-5492 administered orally at 12.5-200 mg/kg inhibited water-immersion stress- and indomethacin-induced gastric mucosal lesions in a dose-dependent manner with ED50 values of 46 and 27 mg/kg, respectively, indicating that KB-5492 was more potent than teprenone but less potent than cimetidine. KB-5492, administered orally at 12.5-100 mg/kg, also inhibited ethanol-induced gastric mucosal lesions in a dose-dependent manner with an ED50 of 23 mg/kg, so KB-5492 was 3 times more potent than teprenone, whereas cimetidine produced no obvious inhibition. In addition, KB-5492, administered orally at 25 and 50 mg/kg twice daily for 10 consecutive days, significantly accelerated the healing of acetic acid-induced gastric ulcers more potently than teprenone and cimetidine. KB-5492 at anti-ulcer doses significantly increased gastric mucosal blood flow in normal anesthetized rats and inhibited the reduction of gastric mucosal hexosamine content induced by aspirin, but did not affect gastric acid secretion in pylorus-ligated rats. These results indicate that KB-5492 has potent and broad anti-ulcer properties, which are probably exerted by its enhancement of gastric mucosal defensive factors through increasing gastric mucosal blood flow and/or retaining gastric mucus, and not by its inhibition of gastric acid secretion.     

Effects of the new anti-ulcer agent 12-sulfodehydroabietic acid monosodium salt on healing of acetic acid-induced gastric ulcers in rats

The macroscopic and microscopic effects of 12-sulfodehydroabietic acid monosodium salt (TA-2711, CAS 86408-72-2) on the healing of acetic acid-induced gastric ulcers in rats were compared with those of sucralfate and carbenoxolone. Test compounds were given orally twice a day for 10 consecutive days from the day after the injury with glacial acetic acid. TA-2711 (50 and 100 mg/kg) dose-dependently decreased the macroscopic ulcer index (mm2). In addition, at a dose of 100 mg/kg, this drug decreased the length of mucosal defect in the ulcerated region and increased the mucosal regeneration index estimated by microscopic observation. Furthermore, the mucosa surrounding the ulcerated area and the regenerated epithelium in the TA-2711 administered group contained more PAS (periodic acid-Schiff)-positive material than those in the control group. On the other hand, neither sucralfate nor carbenoxolone (100 mg/kg) showed any significant effects on ulcer healing.     

Effects of MCI-727, a new antiulcer agent, on various gastric and duodenal lesions in experimental animals

Effects of a new antiulcer drug, MCI-727, on gastric and duodenal lesions, gastric secretion and gastric motility were studied in comparison with cimetidine and teprenone. MCI-727 dose-dependently (3-100 mg/kg, p.o. or i.d.) inhibited the development of acute gastric or duodenal lesions such as pyrolus ligation-, water-immersion stress-, indomethacin-, HCl-, HCl-ethanol-induced gastric lesions and cysteamine-induced duodenal lesions in rats and histamine-induced duodenal lesions in guinea pigs. These antiulcer effects exceeded those of cimetidine or teprenone. Repeated administration of MCI-727 (0.3-3 mg/kg/day, p.o., for 10 days) significantly promoted the spontaneous healing of acetic acid-induced chronic gastric ulcers. Concerning gastric acid secretion, MCI-727 selectively inhibited tetragastrin-stimulated acid secretion without effecting basal acid secretion and acid secretion by other stimuli. Cimetidine and teprenone inhibited acid secretion in several cases. MCI-727 and teprenone had inhibitory effects on gastric motility, although cimetidine had no effect. These results suggest that MCI-727 has a wide spectrum of antiulcer activity, and its mode of antiulcer action is different from that of cimetidine or teprenone.     

Influence of aging on gastric ulcer healing activities of the antioxidants alpha-tocopherol and probucol

In the present study, we compared the effects of alpha-tocopherol and probucol, antioxidants, on the healing of acetic acid-induced gastric ulcers in 8-, 48- and 96-week-old rats. The repeated oral administration of alpha-tocopherol (16 mg/kg twice daily) and probucol (1000 mg/kg twice daily) for 14 consecutive days markedly accelerated the gastric ulcer healing in 48- and 96-week-old rats as well as 8-week-old ones. The ulcer healing effects of both drugs were not significantly different among the rats at three different ages. The superoxide dismutase (SOD) activity in the ulcerated region of 8-, 48- and 96-week-old rats was markedly lower than that in the unulcerated region. In contrast, the thiobarbituric acid (TBA)-reactive substance content, an index of lipid peroxidation, in the ulcerated region of rats at three different ages markedly increased, as compared to that in the unulcerated region. The SOD activity tended to decrease with aging, while the TBA-reactive substance content gradually increased. The repeated administration of alpha-tocopherol and probucol accelerated the ulcer healing and inhibited the increase in the TBA-reactive substance content in the ulcerated region. These results suggest that alpha-tocopherol and probucol promote the ulcer healing by their potent antioxidant activities in 48- and 96-week-old rats as well as 8-week-old rats.     

Preventive and curative effects of curcumin on the development of gastric inflammatory diseases in rats

Preventive and curative effects of curcumin on experimental acute and chronic gastric ulcers were investigated to validate its clinical application on a remedy for peptic ulcer. Intraduodenal administration of curcumin, 5–20 mg/kg, inhibited gastric acid secretion in pylorus-ligated rats, and oral administration prevented ethanol-induced acute gastric mucosal lesions. Curcumin (20–80 mg/kg, p.o.) dose-dependently prevented both serotonin-induced gastric mucosal lesions and compound 48/80-induced gastric mucosal lesions in rats. Furthermore, oral administration of curcumin, 10–80 mg/kg, twice daily for 10 days, significantly accelerated the healing of acetic acid-induced chronic gastric ulcer and promoted mucosal regeneration in the ulcerated portion in a dose-related manner. Cimetidine prevented the formation of ethanol-induced gastric mucosal lesions, but not of serotonin-induced and compound 48/80-induced gastric mucosal lesions. Consecutive administration of cimetidine showed a marked acceleration in the healing of acetic acid-induced ulcer. Aminoguanidine, an inducible nitric oxide synthase (iNOS) inhibitor, showed anti-ulcerogenic effects similar to those oberved for curcumin. The present results indicate that curcumin exhibits gastric cytoprotection in the acute lesion models and ulcer healing promotion in the chronic ulcer model. The preventive and curative effects of curcumin might be due to an increase in the mucosal defensive mechanism through its antioxidant property and inhibition of NO or cytokine-mediated inflammation.     

Marked healing-promoting action of cimetidine on acetic acid-induced ulcer in rats with a limited food-intaking-time

The effect of cimetidine on ulcer healing was investigated in rats with acetic acid induced ulcer who were permitted to intake food only between 9:30-10:30 a.m. and 6:00-7:00 p.m. When evaluated on the 15th and 21st days after operation, cimetidine (100 mg/kg X 2/day, p.o.) markedly decreased the ulcer index and the defective area of the ulcerated region. Moreover, this agent pronouncedly increased the decreasing index of exposed ulcer floor and the mucosal regeneration index. On the 21st day, the thickness of the ulcer base was decreased by this agent, the involution of granulation being indicated. Thus, marked healing-promoting action of cimetidine on acetic acid-induced ulcer was observed by limiting the food-intaking-time.     

Effect of zinc sulphate on acetic acid-induced gastric ulceration in rats

The effects of zinc sulphate on gastric ulcer healing rate and mucosal mucus content of acetic acid-induced ulceration in rats have been assessed. Daily treatment with zinc sulphate progressively accelerated ulcer healing in a dose-dependent manner with a significant increase observed on day 15 after ulcer induction in rats treated with 44 and 88 mg kg-1 zinc sulphate. A significant increase in gastric mucosal adherent mucus was also observed in those animals treated with 88 mg kg-1 zinc sulphate. The results suggest that a minimum treatment period of 15 days is needed for the zinc sulphate to be effective, and that zinc ions may promote gastric ulcer healing by enhancing mucus formation to prevent acid back-diffusion into the gastric mucosa.     

Effect of omeprazole on delayed healing of acetic acid-induced gastric ulcers in rats

Omeprazole, a gastric mucosal proton pump inhibitor, significantly and dose-dependently prevented the delayed healing of acetic acid-induced gastric ulcers in response to repeatedly administered indomethacin to rats. Both basal and histamine-stimulated gastric acid secretions in rats with acetic acid-induced ulcers that were given indomethacin were markedly and persistently (greater than 24 hr) inhibited after 4 weeks treatment with omeprazole. The prevention of delayed ulcer healing by omeprazole appears to be due to its long-lasting antisecretory activity.     

Anti-ulcer effects of chitin and chitosan, healthy foods, in rats

In this study, we compared the effects of low molecular weight (LMW) chitosan (MW: 25,000-50,000), high molecular weight (HMW) chitosan (MW: 500,000-1000,000) and chitin on ethanol-induced gastric mucosal injury and on the healing of acetic acid-induced gastric ulcers in rats. Oral administration of LMW chitosan (250, 500 and 1000 mg/kg) dose-dependently prevented ethanol-induced gastric mucosal injury. Repeated oral administration of LMW chitosan (100, 200 and 400 mg/kg twice daily) also dose-dependently accelerated the gastric ulcer healing. However, the effects of HMW chitosan and chitin on the gastric mucosal injury formation and the gastric ulcer healing were less potent than those of LMW chitosan. LMW chitosan (250 and 500 mg/kg, orally) was ineffective in inhibiting gastric acid secretion in pylorus-ligated rats, although it had a weak acid-neutralizing action. LMW-chitosan (250, 500 and 1000 mg/kg orally) dose-dependently prevented the decrease in gastric mucus content induced by ethanol. These results indicate that of the three compounds, LMW chitosan has the most potent gastric cytoprotective and ulcer healing-promoting actions. In addition, gastric mucus-increasing action of LMW-chitosan may be, at least in part, related to the anti-ulcer effect of this compound.     

Healing-promoting action of rhinax with dual action on chronic gastric and duodenal ulcers induced by acetic acid in rats

Healing promoting actions of Rhinax, a multiconstituent herbal preparation, was investigated in chronic gastric and duodenal ulcer models induced by acetic acid in rats and the effects were compared with those of famotidine by gross of histological evaluation. Rhinax markedly promoted the well balanced healing of gastric ulcer at oral does of 25-100 mg/kg x 2 /day, as evidenced by the reduction of ulcer, regeneration of mucosa and proliferation of connecitve tissue. Rhinax caused an increase in gastric mucosa secretion in all the regenerated mucosa around the gastric ulcers. Famotidine failed to promote the healing of gastric ulcers at 100 mg/kg x 2/ day p.o. Rhinax also significantly accelerated the healing of acetic acid -induced duodenal ulcers as well famotidine. These results indicate that Rhinax is characterised by a potent promoting action on the healing of chronic ulcers, suggesting that the increase in gastric mucus secretion might be associated with the antiulcer action of Rhinax in rats.     

Effects of 15(R)-15-methyl prostaglandin E2 (arbaprostil) on gastric secretion and various gastric lesions induced in rats

We studied the effects of 15(R)-15-methyl prostaglandin E2 (arbaprostil) on gastric secretion and various acute and chronic gastric lesions produced in rats. Arbaprostil significantly inhibited gastric secretion in 4 hr-pylorus-ligated preparations when given intraduodenally in a dose of 30 or 100 micrograms/kg. The agent, however, significantly stimulated gastric secretion of rats with either a ligated or intact pylorus when given orally in doses of 3-100 micrograms/kg. Orally administered arbaprostil dose-dependently prevented the development of HCI-ethanol-, histamine-, water-immersion stress-, or indomethacin-induced gastric erosions. Intraduodenally administered arbaprostil also dose-dependently prevented the development of aspirin-induced gastric erosions in pylorus-ligated rats. Arbaprostil, given orally in doses of 1-100 micrograms/kg twice daily for 2 weeks, had little or no effect on the healing of acetic acid-induced gastric ulcers. However, oral administration of the agent in a dose of 3 or 10 micrograms/kg twice daily for 4 weeks significantly accelerated the healing of acetic acid-induced gastric ulcers. The increase in doses up to 100 micrograms/kg twice daily for 4 weeks had no effect on ulcer healing. These results indicate that arbaprostil, at either antisecretory or even acid stimulating doses, is effective in preventing the development of acute gastric erosions and in accelerating the healing of chronic gastric ulcers.     

脑室注射催产素对大鼠胃和十二指肠溃疡的作用

INTRODUCTION Central neurons that synthesize oxytocin are locatedin the supraoptic(SON) and paraventricular nuclei(PVN) of the hypothalamus. Magnocellular neurons inboth nuclei project to the posterior pituitary gland,     

Healing promoting effect of proamipide, a novel drug that increases gastric defense mechanisms, on acetic acid-induced gastric ulcers in the rat

The healing process of acetic acid-induced gastric ulcers was studied for over 180 days after ulcerogen injection, and the effect of a new antiulcer agent, proamipide, was also assessed by histological measurements. In the control group, rapid reduction in the macroscopic ulcer index and increment in histological indices such as healing, regeneration of defective mucosa and proliferation of granulation tissue were observed from the 5th day to the 60th day after the ulcer induction followed by significant aggravation on the 120th and 140th day, suggesting the recurrence or relapse of gastric ulcers may occur at about 120 to 140 days after acetic acid administration. Proamipide (20 mg/kg/day, p.o.) decreased all of these indices significantly from those in the control group. This indicates that proamipide remarkably promotes the healing process in acetic acid-induced gastric ulcers, the regeneration of the injured mucosa and also the formation of granulation tissue. The glandular index in the surrounding areas of the regenerated mucosa was lower than that in the central part in the control animals and this difference was decreased by proamipide intake, suggesting an imbalance in the regenerated mucosa of the scar may have significant roles in the induction of the recurrence or relapse of gastric ulcers.     

Effect of N-(3-aminopropionyl)-L-histidinato zinc (Z-103) on healing and hydrocortisone-induced relapse of acetic acid ulcers in rats with limited food-intake-time

In the healing test of acetic acid ulcers in rats with limited food-intake-time, Z-103 given, p.o., at doses of 3 and 10 mg/kg, twice a day, for 14 consecutive days from the day after acetic acid injection not only reduced the size and depth of the ulcers, but also promoted the regeneration of the defective mucosa. In the hydrocortisone-induced relapse test of acetic acid ulcers in rats with limited food-intake-time, Z-103 given, p.o., twice a day, at doses of 3 and 10 mg/kg for 20 consecutive days from the 40th day after the acid injection strongly prevented the exfoliation of the regenerated mucosa. Cimetidine (100 mg/kg x 2/day, p.o.), like Z-103, showed a marked relapse-preventive action in addition to the healing-promoting action. However, it was more effective on the healing. Gefarnate (300 mg/kg x 2/day, p.o.) markedly reduced the size and depth of the ulcers and strongly prevented the steroid-induced relapse, but showed no apparent effect on the regeneration of the defective mucosa. These results suggest that Z-103 may be a new therapeutic agent sharing both healing-promoting and relapse-preventive actions on gastric ulcers.     

Increasing action of teprenone, a new antiulcer agent, on high-molecular-weight glycoprotein in gastric mucus during the healing process of acetic acid-induced ulcer in rats

The effects of teprenone on quantitative changes in gastric mucus glycoprotein during the healing process of acetic acid-induced ulcer in rats were investigated in comparison to those of cimetidine and proglumide. When estimated on the 15th day after operation, teprenone (50 and 100 mg/kg X 2/day, p.o.) significantly decreased the ulcer index by approx. 30%. On the other hand, cimetidine (100 mg/kg X 2/day, p.o.) and proglumide (500 mg/kg X 2/day, p.o.) did not significantly affect it. The high-molecular-weight glycoprotein (HMG, molecular weight of 2 X 10(6) or more) concentration in the gastric mucus of the control group (non-medicated ulcer rats) was 48.7% lower than that of the normal group (non-medicated rats without ulcer). On the contrary, the lower-molecular-weight glycoprotein (LMG, molecular weight between 5 X 10(5) and 2 X 10(6)) concentration of the control group was 95.3% higher than that of the normal group. Teprenone (at both doses) remarkably increased the concentration and secretion of the HMG. In contrast, those of the LMG were decreased by this drug. Cimetidine significantly decreased both the concentration and secretion of the total glycoprotein (HMG + LMG). Proglumide showed only slight increases in the concentration and secretion of the HMG, although it pronouncedly increased the total glycoprotein secretion. These results indicate that teprenone may strengthen the defensive force of gastric mucosa by increasing the HMG with a polymeric structure. In contrast, cimetidine may weaken the mucosal defense.