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Cochinchina momordica seed extract (SKMS10), which is composed of the major compounds momordica saponins, has been evaluated for its gastroprotective effects in rat models of acute gastric mucosal damage. Ethanol and water immersion restraint stress (WRS) induced gastric damage, including hemorrhages and edema, was significantly attenuated by pretreatment with SK-MS10. In addition, SK-MS10 reduced increases of mucosal myeloperoxidase (MPO), IL-1β, and TNFα levels and the expression of cPLA(2), and 5-LOX induced by ethanol or WRS. SK-MS10 also increased hexosamine, adherent mucus, and the expression of MUC5AC. Furthermore, SK-MS10 enhanced the mucosal expression of the CGRP gene and its serum levels.N(G)-methyl L-arginine (L-NMMA) or capsaicin desensitization reversed the SK-MS10-induced gastroprotection effect. These results suggest that SK-MS10 is a gastroprotective agent against acute gastric mucosal damage by suppressing proinflammatory cytokines, downregulating cPLA(2), 5-LOX, and increasing the synthesis of mucus. Furthermore, CGRP-NO pathway was found to play an important role in these gastroprotective effects of SK-MS10., (© Springer Science+Business Media, LLC 2009)

Even though there are many drugs for the treatment of gastric ulcers, these drugs sometimes cannot succeed. Since the 1950s, antidepressant drugs have been used for several non-psychiatric indications. A lot of antidepressant drugs have been shown experimentally to produce antiulcer activity in various ulcer models. This study aimed to investigate the antiulcer effects of mirtazapine and to determine its relationship with antioxidant mechanisms. The antiulcer activities of 15, 30, and 60 mg/kg mirtazapine have been investigated on indomethacin-induced ulcers in rats, and the results have been compared with that of the control group. Mirtazapine decreased the indomethacin-induced ulcers significantly at all doses used. Mirtazapine significantly increased the glutathione (GSH) level, which decreased in the control group given only indomethacin. All doses of mirtazapine significantly decreased the catalase (CAT) level in stomach tissue compared to the control. Additionally, all doses of mirtazapine reversed the decrease in the superoxide dismutase (SOD) level in the stomach tissue of control rats. And finally, all doses of mirtazapine decreased malondialdehyde (MDA) and myeloperoxidase (MPO) levels significantly compared to the control. In conclusion, the activation of enzymatic and non-enzymatic antioxidant mechanisms and the inhibition of some toxic oxidant mechanisms play a role in the antiulcer effect mechanism of mirtazapine. This new indication of mirtazapine will make it the first-choice drug in depressive patients with gastric ulcers.

Helicobacter pylori can colonize the stomachs of Mongolian gerbils and subsequently induce penetrating ulcers five months later. Using this gerbil model, the effects of both combined treatment with omeprazole and clarithromycin, as well as treatment with each drug separately, on the healing of H. pylori-induced gastric ulcers, and the effects of the cessation of the drug treatment on healed ulcers were examined. Beginning five months after H. pylori (NCTC11637) inoculation, omeprazole (four weeks), clarithromycin (two weeks), their combination, or the vehicle was orally administered once daily. These drugs, in combination or separately, markedly enhanced ulcer healing and lowered the increased myeloperoxidase (MPO) activity. While omeprazole had no effect on viable H. pylori, clarithromycin and the drug combination significantly reduced viable H. pylori. The degree of bacterial eradication was much higher in the case of the drug combination compared to clarithromycin alone. Four months after cessation of the treatment, visible ulcers, hypertrophic gastritis and increased MPO activity were found in the control animals (all H. pylori-positive). Nonetheless, only one of the eight gerbils subjected to the drug combination developed a small ulcer, although no hypertrophic gastritis was exhibited. It is concluded that: (1) the gerbil model of H. pylori infection is useful for the study of ulcer healing; (2) combined treatment with omeprazole and clarithromycin enhances the ulcer healing in infected gerbils; and (3) healed ulcers do not relapse, despite cessation of the drug treatment.

Growth factors and their receptors are known to play important roles in normal cell proliferation, tissue repair, and ulcer healing. Epidermal growth factor (EGF) inhibits acid secretion, protects gastric mucosa against injury, mediates mucosal adaptation, and accelerates gastroduodenal ulcer healing. EGF exerts its actions by binding to its receptor (EGF-R), which is a transmembrane protein tyrosine kinase. Binding of EGF to its receptor triggers receptor dimerization and autophosphorylation, recruitment of kinase substrates (signaling enzyme adapter proteins with an SH2 domain, Grb2 adapter protein, and Grb2-SOS complex). These events lead to Ras (GTP-binding protein) phosphorylation and activation of the Ras/Raf/MAP kinase pathway, in turn leading to phosphorylation of regulatory proteins and transcription factors and culminating in cell proliferation. Other pathways potentially activated by EGF include the phosphatidylinositol pathway (leading to activation of protein kinase C and an increase in cytosolic calcium) and the JAK/STAT signaling pathway. While EGF-induced signaling events have been extensively studied in various cell systems, predominantly neoplastic and/or transformed cells, the relevance of those findings to gastric mucosal injury repair or ulcer healing is as yet not fully elucidated. This paper is intended to provide an overview of signaling pathways triggered by EGF-R activation and on this background to summarize current knowledge pertaining to involvement of EGF-R signaling pathways in gastric mucosal repair and ulcer healing.

Adenosine deaminase (ADA), 5'-Nucleotidase (5NT), Xanthine oxidase (XO), Cu-Zn Superoxide dismutase (SOD) and Catalase (CAT) activities were determined in gastric juices from patients with gastric cancer, ulcer, gastritis and from healthy subjects. Enzyme activities were given as units per ml gastric juice and units per mg protein in gastric juice. ADA, 5NT and XO activities were found lower and protein concentrations were found higher in the cancer group than controls. There was however no significant difference between Cu-Zn SOD activities of the cancer and control groups. In all groups including control one, we could not find catalase activities in most of the samples. On the other hand, ADA, 5NT activities and protein concentrations in the gastric juice were lower in the gastritis group than control group. In the ulcer group, we found higher Cu-Zn SOD and XO activities and lower 5NT activity and protein concentrations compared with control values. In an attempt to establish statistical correlations between mean enzyme activities, pH and protein concentrations in the gastric juices of the groups, we found noticeable intra and inter-correlations, which indicated possible relations between DNA and free radical metabolizing enzymes.

A modification of Berstad's spectrophotometric method was tested and proved capable of detecting pepsin concentrations in mucosal perendoscopic biopsy homogenates. The relationship between this parameter and pepsin in gastric juice and pepsinogen group I in serum and in biopsy homogenates was analyzed. From the biochemical point of view, the assay was found sufficiently accurate. Mucosal pepsinogen group I, but not mucosal pepsin, concentration was found higher in gastric and duodenal ulcer patients than in controls. Patients with corpus-fundic gastric ulcer showed significantly lower mucosal pepsin and mucosal pepsinogen group (PG) I. Aging and smoking did not influence either parameter but male duodenal ulcer subjects presented higher mucosal pepsinogen group I concentration. The lack of any relationship between serum and mucosal PG I and between pepsin in gastric juice and in mucosa raises a question, at least in methodological terms, about the validity of using serum pepsinogen group I and pepsin as indicators of peptic output.

It is widely accepted that the absence of acid-peptic activity excludes the presence of a benign upper gastrointestinal ulcer. We assessed the frequency of a history of benign upper gastrointestinal ulcer disease in patients with and without serological evidence of achlorhydria with reference to the use of nonsteroidal antiinflammatory drugs (NSAIDs). In total 857 patients were interviewed, using a standard questionnaire with emphasis on demographic data, chronic use of NSAID, and history of upper gastrointestinal ulcers. The frequency of achlorhydria was determined by extremely low serum levels of pepsinogen A (PgA < 17 micrograms/liter). Of the total group of patients, 36 patients (4.2%; 95% CI 2.9-5.5) had a PgA lower than 17 micrograms/liter. A history of benign upper gastrointestinal ulcer was found in 57/827 (6.9%) of patients with serum PgA higher than 17 micrograms/liter and in 3/36 (8.3%) of patients with serum PgA lower than 17 micrograms/liter (NS). The three patients with upper gastrointestinal ulcer and PgA lower than 17 micrograms/liter were known to have pernicious anemia (PA) before (two patients) or simultaneously (one patient) with the diagnosis of the upper gastrointestinal ulcer and were using NSAIDs at that time. The presence of gastric acid is not obligatory for the development of ulcers during NSAID use.

Ornithine decarboxylase (ODC) activity has been associated with mucosal growth and injury, yet, little information is available on ODC activity during gastric ulcer healing. We measured ODC activity in the ulcer base submucosa and the surrounding mucosa at 1 cm and 2 cm and assessed ulcer surface healing and a histologic score in experimentally induced ulcers (Quinton ulcer-maker) at 0 and 5 hr and at one, two, three, four, and seven days. A total of 26 dogs were studied, eight of which received 2% difluoromethylornithine (DFMO, a specific inhibitor of ODC) in drinking water. Ulcer healing was assessed by digitizing initial (plug size), and final ulcer surface area and was expressed as percent ulcer surface reduction. A histologic score was assessed by two independent pathologists unaware of the treatment. ODC induction was observed in the submucosa of the ulcer base but not in the surrounding mucosa. The baseline submucosal ODC activity was measured at 0.2 +/- 0.1 pmol (14CO2)/mg protein/hr, and at one day the ODC activity increased to 4.0 +/- 0.7, at three days to 15.2 +/- 5.5, and at seven days to 2.6 +/- 1.0 (P less than 0.001). DFMO treatment delayed GU healing significantly up to three days, but no difference was noted at seven days. The assessed histologic parameters did not correlate with ODC activity, and DFMO treatment did not alter the histologic score. These data suggest that polyamine biosynthesis occurs in the ulcer base submucosa during the first seven days of experimentally placed gastric ulcers.(ABSTRACT TRUNCATED AT 250 WORDS)

The presence of unbuffered acid appears to be an essential contributory factor in the pathogenesis of peptic ulcer disease. Treatment has concentrated therefore on the reduction of acidity, and the last decade has seen the widespread and effective use of H2 antagonists. They are, at low doses, more successful in improving the natural history of duodenal ulcer disease than of gastric or esophageal ulceration. The H2 receptor plays a central role in activation of parietal cell acid secretion, and antagonists at this receptor block most (but not all) of the acid secretion due to even gastrinergic or muscarinic (vagal) stimulation. In hypergastrinemic states such as Zollinger-Ellison syndrome, or where acid secretion has to be inhibited by more than 20% over a 24-hr period, such as for treatment of esophagitis, NSAID damage, or gastric ulcers, the dose and frequency of administration of the currently available antagonists must be increased to achieve reliable therapy. This has led to a search for an alternative target for acid inhibitory drugs, such as the gastric acid pump, the H+,K(+)-ATPase. This article focuses on the function of this ATPase and suggests that inhibition of this pump will provide a more efficacious means of reduction of acid secretion by the stomach, hence improving and simplifying therapy of acid related diseases.