Teprenone promotes the healing of acetic acid-induced chronic gastric ulcers in rats by inhibiting neutrophil infiltration and lipid peroxidation in ulcerated gastric tissues.

Teprenone, an anti-ulcer drug, has been reported to promote the healing of acetic acid-induced chronic gastric ulcers in rats by stimulating gastric mucus synthesis and secretion. Recently, it has been implicated that neutrophil infiltration and lipid peroxidation in ulcerated gastric tissues have an inhibitory effect on the healing of acetic acid-induced chronic gastric ulcers in rats. Therefore, we attempted to clarify whether teprenone exerts a healing-promoting effect on acetic acid-induced chronic gastric ulcers through its inhibitory effect on neutrophil infiltration and lipid peroxidation in ulcerated gastric tissues. In rats with chronic gastric ulcers made by applying acetic acid to the stomach, gastric ulcer healing started later than 3 days after the acetic acid application. Gastric mucosal myeloperoxidase (MPO) activity, an index of tissue neutrophil infiltration, and lipid peroxide content were higher in the ulcerated region than in the intact region on the 8th, 15th, and 22nd day after the acetic acid application. Gastric mucosal non-protein SH content was lower in the ulcerated region than in the intact region on the 8th, 15th, and 22nd day after the acetic acid application, and gastric mucosal adherent mucus content was lower in the ulcerated region than in the intact region on the 8th and 15th day. Daily oral administration of teprenone (100 mg kg(-1)x 2) for 7 or 14 days, starting on the 8th day after the application of acetic acid to the stomach, enhanced the reduction of the ulcer area with attenuation of all these biochemical changes found in the ulcerated region. The teprenone administration caused a decrease in MPO activity and an increase in adherent mucus content in the gastric mucosa of the intact region. These results suggest that the healing-promoting effect of teprenone on acetic acid-induced chronic gastric ulcers in rats could be due not only to stimulation of gastric mucus secretion but also to inhibition of neutrophil infiltration and enhanced lipid peroxidation in the ulcerated gastric tissue.     

Effect of dopamine on the healing of acetic acid-induced gastric ulcers in rats

Dopamine, as a neurotransmitter in the brain, is also present in the gastroduodenal mucosa and has been implicated in several functions in these tissues. Recent study showed that dopamine acts as a potent antitumor/angiogenic activity through suppression of growth factor expression. Since growth factors are known to play a crucial role in the mechanism of wound healing, it is possible that dopamine has a deleterious influence on the healing of gastric ulcers. In the present study, we examined the effect of dopamine on the healing of acetic acid-induced gastric ulcers in rats. Gastric ulcers were induced in male SD rats by serosal application of acetic acid for 60 sec. Dopamine was subcutaneously given twice daily for 7 days, starting 3 days after ulceration. In some case, the osmotic mini-pump filled with dopamine was implanted into the dorsal subcutaneous space in rats for 7 days. VEGF and Flk-1 mRNA expressions were determined by RT-PCR. Dopamine (3, 10 and 30 mg/kg) given subcutaneously for 7 days did not significantly affect the healing of gastric ulcers. The expression of VEGF and Flk-1 mRNA in the ulcerated mucosa was up-regulated after ulceration, and these expressions were not affected by dopamine. Likewise, dopamine (0.6 mg/kg/hr) infused continuously using the osmotic mini-pump also had no effect on the healing of these ulcers. These results suggest that dopamine, although reportedly shows a potent antitumor/angiogenic activity, does not cause any influence on the healing of the pre-existing gastric ulcers in rats. Received 3 August 2006; accepted 10 November 2006     

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.     

Effects of trimoprostil on healing and recurrence of acetic acid-induced gastric ulcer in rats

Chronic gastric ulcers were produced by injection of 20% acetic acid (0.05 ml) into the submucosal layer of the rat stomach in order to determine the effects of the prostanoid trimoprostil on the healing and recurrence of ulcers. Local injection of acetic acid solution produced large demarcated ulcers in all animals on day 5, which rapidly decreased to reach low levels on days 40-80 and then became exacerbated on day 100. The exacerbation of the ulcer is probably recurrence. Trimoprostil was administered ad libitum in drinking water containing 0.1, 0.3 and 1.0 microgram/ml (average dose 12.4, 37 and 124 micrograms/kg/day) for a period of 14 days (day 1-15) to assess its effect on healing and for a period of 40 days (day 60-100) to assess its ability to prevent recurrence. The higher two doses of trimoprostil accelerated the spontaneous healing of the ulcers. Furthermore, trimoprostil, at both doses, prevented the observed recurrence of this type of ulcer. Trimoprostil dose-dependently (30-300 micrograms/kg, p.o.) inhibited gastric secretion in pylorus-ligated rats. Cimetidine at the antisecretory dose (1 mg/ml, 132 mg/kg/day) failed to affect the healing process of gastric ulcers, but tended to prevent the recurrence of gastric ulcers. Our present study suggests that trimoprostil is a promising antiulcer drug for the treatment of chronic gastric ulcer.     

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.     

Nicotine withdrawal alleviates acetic acid-induced gastric injury in rats

Epidemiological and experimental studies have demonstrated that cigarette smoking intensifies gastric ulceration. Although nicotine can act as an anxiolytic and antidepressant, its withdrawal may also lead to increased anxiety and depression. In order to associate the toxic actions of nicotine on gastric mucosa with alterations of anxiety level and to evaluate the impact of nicotine withdrawal on the anxiety level and the severity of ulcer, an acetic acid-induced ulcer model was used. Male Sprague-Dawley rats were given either tap water or nicotine bitartarate (50μg/ml in drinking water) for 15 days, while another group of rats had 5 days of withdrawal following 10 days of nicotine treatment. Ulcer was induced by acetic acid on the 15th day of the treatments, and the rats were followed for 3 days until they were decapitated and the gastric tissues were obtained. Using the hole-board test, basal anxiety levels measured on the first day of the treatments were compared with the measurements made at the early and late phases of ulcer induction. Chronic administration of nicotine did not have a potentiating effect on acetic acid-induced gastric ulcer, since the gastric injury, as assessed by both macroscopic and microscopic evaluation and increased gastric myeloperoxidase activity indicating neutrophil recruitment, was not exaggerated or attenuated by nicotine intake. On the other hand, nicotine withdrawal attenuated gastric mucosal injury, despite an increased level of anxiety. Smoking cessation, which triggers the onset of depressive symptoms with nicotine withdrawal, still has a worthwhile positive effect on the gastric mucosa.     

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.     

虾青素对大鼠乙酸性胃溃疡的治疗作用

This study is to investigate therapeutic effect of astaxanthin on acetic acid-induced gastric ulcer in rats.  Rats were divided into control group, ulcer control group, and astaxanthin (5, 10, and 25 mg·kg^-1) groups at random, 8 rats in each group.  After administered for 10 days consecutively, all the rats were sacrificed.  The area of ulcer and the levels of MDA, SOD, CAT and GSH-Px in gastric mucosa were measured.  Compared with ulcer control group, in astaxanthin (5, 10, and 25 mg·kg^-1) groups, the area of ulcer was decreased significantly.  Level of MDA decreased while activities of SOD, CAT and GSH-Px increased (P < 0.05).  Astaxanthin has good therapeutic effect on acetic acid-induced gastric ulcer in rats.  Eliminating free radical and improving local blood circulation of the ulcer may be the mechanism of action.     

Effects of orally administered human epidermal growth factor on natural and delayed healing of acetic acid-induced gastric ulcers in rats

We examined the effects of orally administered human epidermal growth factor (hEGF) on healing of acetic acid-induced gastric ulcers in rats. hEGF, given twice daily at 30 and 100 micrograms/kg for 2 weeks or at 100 micrograms/kg for 4 weeks to rats with ulcers, had no effect on natural healing or the gastric secretion, delayed one caused by indomethacin. Oral hEGF had no effect on basal histamine-stimulated gastric secretion, and stomach weight. These results indicate that oral hEGF has no biological activity on the pathophysiology of the stomach.     

Prostaglandin content in the rat gastric mucosa during healing of chronic ulcers induced by acetic acid

Non-steroidal anti-inflammatory compounds delayed the regeneration of chronic gastric ulcers induced by acetic acid in the rat. The delayed regeneration was connected with a decreased PGE2 content in the proliferating tissue. Glucocorticoid influenced neither the regeneration of mucosal damages nor the gastric PGE2 content. The carboanhydrase inhibitor, acetazolamide, also did not alter the restoration of gastric mucosa after being damaged. From the clinical point of view, the safe use of NOSAC will be emphasized in patients with ulcer anamnese. The findings with prednisolone did not confirm a similar safe use of this drug in patients.     

Healing process of acetic acid-induced gastric ulcer and gastric mucosal prostaglandin E generation level in rats

The prostaglandin E (PGE) generation level (PGE level) in the gastric mucosa was investigated in relation to the healing and relapse of acetic acid-induced gastric ulcers in the rat. The PGE level around ulcers showed higher levels after ulcer induction and decreased during the ulcer diminishing period. Thereafter, the PGE levels showed an inclination to increase during the ulcer exacerbation period. In reulcerated rats, PGE levels were significantly higher. In conclusion, a high level of PGE may indicate an ulcer exacerbation state.     

Ethanolic extract of roots from Arctium lappa L. accelerates the healing of acetic acid-induced gastric ulcer in rats: Involvement of the antioxidant system

We evaluate the curative efficacy of the ethanolic extract (EET) of roots from Arctium lappa (bardana) in healing of chronic gastric ulcers induced by 80% acetic acid in rats and additionally studies the possible mechanisms underlying this action.Oral administration of EET (1, 3, 10 and 30 mg/kg) reduced the gastric lesion area in 29.2%, 41.4%, 59.3% and 38.5%, respectively, and at 10 mg/kg promoted significant regeneration of the gastric mucosa, which was confirmed by proliferating cell nuclear antigen immunohistochemistry. EET (10 mg/kg) treatment did not increase the gastric mucus content but restored the superoxide dismutase activity, prevented the reduction of glutathione levels, reduced lipid hydroperoxides levels, inhibited the myeloperoxidase activity and reduced the microvascular permeability. In addition, EET reduced the free radical generation and increased scavenging of 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radicals in vitro. Furthermore, intraduodenal EET (10 and 30 mg/kg) decreased volume and acidity of gastric secretion. Total phenolic compounds were high in EET (Folin–Ciocalteau assay) and the analysis by liquid chromatography-mass spectrometry revealed that the main compounds present in EET were a serie of hydroxycinnamoylquinic acid isomers. In conclusion, these data reveal that EET promotes regeneration of damaged gastric mucosa, probably through its antisecretory and antioxidative mechanisms.     

Changes in the biosynthetic activity of gastric glycoproteins during the healing process of acetic acid ulcer in rats

Changes in the incorporation of 3H-glucosamine into the macromolecular glycoprotein during the healing process of acetic acid induced gastric ulcer in rats were sequentially examined in the ulcer region and the intact region at 2, 10, 40, 80 and 365 days after the operation. 1) The total radioactivity (Tissue + Medium) and the radioactivity which remained in the tissue after incubation of the ulcer region were increased significantly as compared with those of the control at 2 days after the operation (275, 175% of the control, respectively), and then total radioactivity returned to the control level. On the other hand, the radioactivity in the tissue was gradually decreased, and then it became 50% of the control at 365 days. In contrast, the incorporating activity into the macromolecular glycoproteins was decreased to 50% of the control at 2 days, and was once recovered to the control level at 10 days. After 40 days, it was again decreased to 50% of the control and became 30% at 365 days. 2) Changes in the incorporation of 3H-glucosamine into the macromolecular glycoproteins of the intact region of rats with ulcers were the same as that of the ulcer region. 3) Elution profiles of gel filtration of the macromolecular glycoproteins isolated from the relapse and recurrence region of rats with ulcers at 365 days were the same as that of the healing region, and their radioactivities were decreased to 30% of the control. The results suggested that such a decrease in the biosynthetic activity of the macromolecular glycoproteins extending over the whole gastric tissue is one of the reasons for the increased relapse and recurrence.     

Anti-inflammatory activity of phycocyanin extract in acetic acid-induced colitis in rats.

The anti-inflammatory effect of c-phycocyanin extract was studied in acetic acid-induced colitis in rats. Phycocyanin (150, 200 and 300 mg kg(-1) p.o.) was administered 30 min gbefore induction of colitis with enema of 1 ml of 4% acetic acid per rat. Twenty-four hours later myeloperoxidase (MPO) activity was determined as well as histopathological and ultrastructural studies were carried out in colonic tissue. Phycocyanin substantially reduced MPO activity which was increase din the control colitis group. Also, histopathological and ultrastructural studies were carried out in colonic tissue. Phycocyanin substantially reduced MPO activity which was increased in the control colitis group. Also, histopathological and ultrastructural studies showed inhibition in inflammatory cell infiltration and reduction to some extent in colonic damage in rats treated with phycocyanin. The probable role of antioxidative and the scavenging properties of phycocyanin against reactive oxygen species in the anti-colitic effect is discussed in this paper. To our knowledge this is the first report on the anti-inflammatory effect of phycocyanin in an experimental model of colitis.     

Suprofen, a potent antagonist of acetic acid-induced writhing in rats.

A new standardized acetic acid-induced writhing test in rats is described in detail and its methodology is discussed briefly. The described method has proved to be useful for evaluating the anti-writhing activity of narcotic analgesics, non-narcotic anti-inflammatory compounds and narcotic-antagonists with analgesic activity. A direct quantitative comparison of anti-writhing activity was made between orally administered acetyl-salicylic acid, phenylbutazone, indometacin, tolmetin, ketoprofen and alpha-methyl-4-(2-thienylcarbonyl)benzeneacetic acid (suprofen) in a specially designed experiment. Among the known non-narcotic, non-steroidal anti-inflammatory compounds suprofen appeared to be the most potent antagonist of acetic acid-induced writhing in rats, about 200 to 300 times as potent as acetyl-salicylic acid and phenylbutazone, 15 to 30 times as potent as indometacin and tolmetin, and about 6 times as potent as ketoprofen.     

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.     

Ameliorative effect of pyrrolidinedithiocarbamate on acetic acid-induced colitis in rats

Ulcerative colitis is a chronically recurrent inflammatory bowel disease of unknown origin. The present study examined the effect of NF-kappaB inhibitor and antioxidant, pyrrolidinedithiocarbamate (PDTC) on experimental ulcerative colitis in rats. Animals were randomly divided into 4 groups, each consisting of 6 animals; normal control group, acetic acid group, PDTC-treated group and sulfasalazine-treated group as a positive control group. Induction of colitis by intracolonic administration of 3% acetic acid produced severe macroscopic inflammation in the colon 24 h after acetic acid administration as assessed by the colonic damage score. Microscopically, colonic tissues showed ulceration, oedema and inflammatory cells infiltration. Biochemical studies revealed increased serum levels of lactate dehydrogenase (LDH), and nitrite/nitrate and colonic concentrations of tumor necrosis factor-alpha (TNF-alpha) and the neutrophil infiltration index, myeloperoxidase (MPO). Oxidative stress was indicated by elevated lipid peroxides formation and depleted reduced glutathione concentrations (GSH) in colonic tissues. Immunohistochemical studies of colonic sections revealed upregulation of inducible nitric oxide synthase (iNOS). Pretreatment with PDTC at a dose of (200 mg/kg/day, i.p.), three days before induction of colitis decreased serum LDH, nitrite/nitrate and TNF-alpha levels, colonic concentrations of MPO and lipid peroxides while increased colonic GSH concentration. Moreover, PDTC pretreatment attenuated colonic iNOS expression. Finally, histopathological changes were nearly restored by PDTC pretreatment. The findings of the present study provide evidence that PDTC may be beneficial in patients with inflammatory bowel disease.     

胃力康颗粒对实验性胃溃疡模型大鼠的影响

目的:观察胃力康颗粒对实验性胃溃疡大鼠的影响,探讨胃力康颗粒对实验性胃溃疡大鼠溃疡愈合的作用。方法:制备大鼠胃溃疡模型,大鼠随机分成正常组、模型组、法莫替丁对照组和胃力康治疗组,术后连续给药7d,测定大鼠血清中一氧化氮(NO)、超氧化物歧化酶(SOD)活性和丙二醛(MDA)含量。结果:与模型组比较,胃力康组能显著提高大鼠血清中NO和SOD含量,降低MDA的含量,差异均有统计学意义(P<0.05)。结论:胃力康对大鼠胃溃疡的保护性治疗作用,其机制可能与提高血清NO和SOD含量,降低MDA含量有关。     

Collagen and collagenase in ulcer tissue--1. The healing process of acetic acid ulcers in rats

We have reported that collagenase activity of the gastric mucosa increased significantly in acetic acid ulcers of dogs. The present study revealed that acetic acid ulcers in showed that the active collagenase level in the ulcer tissue increased rapidly with a peak (412.5%) on the 3rd day after induction of the acetic acid ulcer. Thereafter, the collagenase activity levels decreased gradually by the 7th day and returned practically to the control levels by the 14th day. On the other hand, collagen (hydroxyproline content) decreased by the 7th day (-16.5%) and recovered by the 14th day after induction of the acetic acid ulcer. The peak of active collagenase on the 3rd day coincident with the maximum ulcer index, suggesting involvement of collagenase activity in ulceration. In addition, destruction and production of collagen are considered to take place not only at the base of the ulcer and its margin, but also along its circumference.