Mechanism Of Gastroprotection Research Articles

Pharmacological mechanism of antiulcer activity of chromatographic Fraction B obtained from <i>Acacia nilotica</i> seedpods in experimental rats

Acacia nilotica (Lam) is an important multipurpose tree with many indigenous uses. It is most widely found in Northern Nigeria, tropical and sub-tropical countries. It is used therapeutically to alleviate and manage many illnesses. Acacia nilotica seedpod is used in local traditional medicine to treat gastric-related disorders. The present study was aimed at evaluating the possible mechanism of gastroprotection of chromatographic fraction B derived from Acacia nilotica n-butanol partitioned extract using ethanol for ulcer induction. Chromatographic fractionation of the n-butanol solvent partitioned extract yielded three different fractions (FA, FB, and FC). The possible mechanism of action of FB was assessed by investigating the involvement of endogenous nitric oxide, non-protein sulfhydryl group, and prostaglandin. The ulcer index of ulcerated rats pre-treated with NG-nitro-L-arginine methyl ester (L-NAME) which is a nitric oxide synthase inhibitor and subsequently administered with Fraction B was not significantly higher (p>0.05) from rats in the ulcerated group. Similarly, Pre-treatment with N-ethylmaleimide (NEM), a blocker of endogenous sulfhydryl to ethanol-induced ulcerated rats that were treated with chromatographic FB gave an ulcer index that was not significantly different (p>0.05) from the ulcerated control group. However, prostaglandin synthesis inhibition by pretreatment with indomethacin did not affect the gastroprotective activity of FB. The study concludes that the observed anti-ulcerogenic activity exhibited by chromatographic Fraction B of Acacia nilotica n-butanol partitioned extract is possibly due to the increase in nitric oxide (NO) synthesis and endogenous sulfhydryl group.

Study of the gastroprotective action and healing effects of Kalanchoe pinnata (Lam.) against acidified ethanol- and acetic acid-induced gastric ulcers in rats / Estudo da acção gastroprotectora e dos efeitos curativos de Kalanchoe pinnata (Lam.) contra úlceras gástricas induzidas por etanol acidificado e ácido acético em ratos

Kalanchoe pinnata (Lam.) Pers. (Crassulaceae) is a commonly used species in traditional medicine in Brazil for the treatment of various diseases, including gastric ulcers. This research aims to evaluate the antiulcer aspects of Kalanchoe pinnata leaves. The LD50 value of the hydroethanolic extract (HE) of K. pinnata was 1341.46 mg/kg, after the in vitro cytotoxicity assay. In the phytochemical analysis, several flavonoids were identified in the HE and ethyl acetate fraction (EAF) of K. pinnata. It was verified that the gastroprotective activity of the HE of K. pinnata involved prostaglandins and sulfhydryl compounds. However, the mechanism of gastroprotection of the EAF of K. pinnata is dependent on prostaglandins and nitric oxide. The ulcer healing activity of the HE of K. pinnata was also evaluated. According to the macroscopic results, doses of 200 mg/kg and 400 mg/kg reduced the injury area, with rates of 33% and 39%, respectively, after 7 days of treatment (p <0.05). Histological analysis showed regeneration of the gastric mucosa and re-establishment of the glandular architecture in groups treated with the HE (200 and 400 mg/kg). Antioxidant enzymes (CAT, SOD and GPx) were evaluated in the mechanism of gastric ulcer healing. The results showed that the antiulcerogenic activity was mediated by SOD. The anti-Helicobacter pylori activity was also evaluated; however, the HE did not show anti-H. pylori activity. Analysis of the results suggests that K. pinnata has therapeutic potential against gastric ulcers and that the flavonoids may be linked to the biological effects.

Tu1325 - Sensory Nerves Releasing Calcitonin Gene Related Peptide, Lipid Peroxidation and Expression and Activity of Antioxidative Enzymes in the Mechanism of Gastroprotection Induced by Carbon Monoxide Against Stress Ulcerogenesis

Tu1325 - Sensory Nerves Releasing Calcitonin Gene Related Peptide, Lipid Peroxidation and Expression and Activity of Antioxidative Enzymes in the Mechanism of Gastroprotection Induced by Carbon Monoxide Against Stress Ulcerogenesis

Interaction between endogenous carbon monoxide and hydrogen sulfide in the mechanism of gastroprotection against acute aspirin-induced gastric damage

Acetylsalicylic acid (ASA) is mainly recognized as painkiller or anti-inflammatory drug. However, ASA causes serious side effects towards gastrointestinal (GI) tract which limits its usefulness. Carbon monoxide (CO) and hydrogen sulfide (H2S) have been described to act as important endogenous messengers and mediators of gastroprotection but whether they can interact in gastroprotection against acute ASA-induced gastric damage remains unknown.In this study male Wistar rats were pretreated with 1) vehicle (saline, i.g.), 2) tricarbonyldichlororuthenium (II) dimer (CORM-2, 5mg/kg i.g.), 3) sodium hydrosulfide (NaHS, 5mg/kg i.g.), 4) zinc protoporphyrin (ZnPP, 10mg/kg i.p.), 5) D,L-propargylglycine (PAG, 30mg/kg i.g.), 6) ZnPP combined with NaHS, 7) PAG combined with CORM-2 or 8) 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ, 10mg/kg i.p.) combined with CORM-2 or NaHS and 30min later ASA was administered i.g. in a single dose of 125mg/kg. After 1h, gastric blood flow (GBF) was determined by H2 gas clearance technique and gastric lesions were assessed by planimetry and histology. CO content in gastric mucosa and COHb concentration in blood were determined by gas chromatography and H2S production was assessed in gastric mucosa using methylene blue method. Protein and/or mRNA expression for cystathionine-γ-lyase (CSE), cystathionine-β-synthase (CBS), 3-mercaptopyruvate sulfurtransferase (3-MST), heme oxygenase (HO)-1, HO-2, hypoxia inducible factor-alpha (HIF)-1α, nuclear factor (erythroid-derived 2)-like 2 (Nrf-2), cyclooxygenase (COX)-1 and COX-2, inducible nitric oxide synthase (iNOS) and interleukin (IL)-1β were determined by Western blot or real-time PCR, respectively.ASA caused hemorrhagic gastric mucosal damage and significantly decreased GBF, H2S production, CO content, mRNA or protein expression for CSE, 3-MST, HO-2 and increased mRNA and/or protein expression for CBS, HO-1, Nrf-2, HIF-1α, iNOS, IL-1β, COX-2 in gastric mucosa and COHb concentration in blood. Pretreatment with CORM-2 or NaHS but not with PAG decreased ASA-damage and increased GBF. ZnPP reversed protective and hyperemic effect of NaHS but PAG failed to affect CORM-2-induced gastroprotection. CORM-2 elevated CO content, mRNA or protein expression for HO-1, Nrf-2, and decreased expression of CBS, HIF-1α, COX-2, IL-1β, iNOS, the H2S production in gastric mucosa and COHb concentration in blood. NaHS raised mRNA or protein expression for CSE, COX-1 and decreased mRNA expression for IL-1β and COHb level in blood.We conclude that CO is involved in gastroprotection induced by H2S while beneficial protective action of CO released from CORM-2 in gastric mucosa seems to be H2S-independent. In contrast to H2S, CO ameliorates hypoxia, regulates Nrf-2 expression but similarly to H2S acts on sGC-dependent manner to restore gastric microcirculation and exhibit anti-inflammatory activity in gastric mucosa compromised by ASA.

Gastroprotective activity of the rhizome ethanol extract of Zingiber simaoense Y. Y. Qian in rats

Ethnopharmacological relevanceZingiber simaoense Y. Y. Qian belongs to the Zingiberaceae family. Its rhizome has been used in Thai folk medicine to relieve gastric disorders; however, scientific evidence of its pharmacological activities has not yet been revealed. Aim of the studyThis study was designed to validate the gastroprotective activity and to identify possible mechanisms of gastroprotection of Z. simaoense rhizome ethanol extract (ZSE) in rats. Materials and methodsThe gastroprotective effect of ZSE was tested using models of gastric ulcers induced by acidified ethanol, indomethacin, and restraint water immersion stress. Models for determination of gastric wall mucus secretion and plasma malondialdehyde levels as well as pylorus ligation were used to explore the mechanisms of action. ResultsAfter oral administration by intragastric gavage, ZSE 7.5, 15, and 30mg/kg or cimetidine 100mg/kg significantly inhibited the formation of gastric ulcer in all gastric ulcer models. The gastric wall mucus amount was significantly higher than that of the ulcer control group, plasma malondialdehyde levels were normalized, and gastric secretion was partly inhibited by pretreatment with ZSE. ConclusionsThis study demonstrates the gastroprotective activity of ZSE in rats. The mechanisms of action of ZSE may depend on its ability to maintain the integrity of gastric wall mucus through the protection of gastric mucus, and/or by increasing the gastric mucus synthesis and secretion through prostaglandin synthesis. Moreover, the antioxidant activity of ZSE may also contribute to its mechanism of gastroprotection.

PP99 - Interaction of hydrogen sulfide and carbon monoxide in the mechanism of gastroprotection: Involvement of afferent sensory neurons

PP99 - Interaction of hydrogen sulfide and carbon monoxide in the mechanism of gastroprotection: Involvement of afferent sensory neurons

527 Carbon Monoxide and Hydrogen Sulfide: the Crosstalk in the Mechanism of Gastroprotection Against Aspirin-Induced Gastric Lesions

viability (n=3; p<0.05). Oxidative stress and autophagy were also documented in a murine EoE model, in which autophagy inhibition in vivo resulted in enhanced disease activity and morphological changes consistent with esophageal epithelial degeneration. Conclusions: Autophagy is activated in the epithelium of EoE patients and may serve a cytoprotective function. Our findings suggest that the inflammatory EoE microenvironment induces oxidative stress in epithelial cells, which subsequently activates autophagy to restore redox balance and maintain epithelial integrity.

Endogenous prostaglandins and afferent sensory nerves in gastroprotective effect of hydrogen sulfide against stress-induced gastric lesions.

Hydrogen sulfide (H2S) plays an important role in human physiology, exerting vasodilatory, neuromodulatory and anti-inflammatory effects. H2S has been implicated in the mechanism of gastrointestinal integrity but whether this gaseous mediator can affect hemorrhagic lesions induced by stress has been little elucidated. We studied the effect of the H2S precursor L-cysteine, H2S-donor NaHS, the H2S synthesizing enzyme (CSE) activity inhibitor- D,L-propargylglycine (PAG) and the gastric H2S production by CSE/CBS/3-MST activity in water immersion and restraint stress (WRS) ulcerogenesis and the accompanying changes in gastric blood flow (GBF). The role of endogenous prostaglandins (PGs) and sensory afferent nerves releasing calcitonin gene-related peptide (CGRP) in the mechanism of gastroprotection induced by H2S was examined in capsaicin-denervated rats and those pretreated with capsazepine to inhibit activity of vanilloid receptors (VR-1). Rats were pretreated with vehicle, NaHS, the donor of H2S and or L-cysteine, the H2S precursor, with or without the concurrent treatment with 1) nonselective (indomethacin) and selective cyclooxygenase (COX)-1 (SC-560) or COX-2 (rofecoxib) inhibitors. The expression of mRNA and protein for COX-1 and COX-2 were analyzed in gastric mucosa pretreated with NaHS with or without PAG. Both NaHS and L-cysteine dose-dependently attenuated severity of WRS-induced gastric lesions and significantly increased GBF. These effects were significantly reduced by pretreatment with PAG and capsaicin denervation. NaHS increased gastric H2S production via CSE/CBS but not 3-MST activity. Inhibition of COX-1 and COX-2 activity significantly diminished NaHS- and L-cysteine-induced protection and hyperemia. NaHS increased expression of COX-1, COX-2 mRNAs and proteins and raised CGRP mRNA expression. These effects of NaHS on COX-1 and COX-2 protein contents were reversed by PAG and capsaicin denervation. We conclude that H2S exerts gastroprotection against WRS-induced gastric lesions by the mechanism involving enhancement in gastric microcirculation mediated by endogenous PGs, sensory afferent nerves releasing CGRP and the activation of VR-1 receptors.

Gastroprotective effects of L-lysine salification of ketoprofen in ethanol-injured gastric mucosa.

Ketoprofen L-lysine salt (KLS), a NSAID, is widely used for its analgesic efficacy and tolerability. L-lysine salification was reported to increase the solubility and the gastric absorption and tolerance of ketoprofen. Since the management of NSAIDs gastrotoxicity still represents a major limitation in prolonged therapies, mainly when gastric lesions are present, this study investigated the gastro-protective activity of L-lysine by using a well-established model of gastric mucosa injury, the ethanol-gastric injury model. Several evidences show that the damaging action of ethanol could be attributed to the increase of ROS, which plays a key role in the increase of lipid peroxidation products, including malonyldialdehyde and 4-hydroxy-2-nonenal. With the aim to unravel the mechanism of L-lysine gastroprotection, cellular MDA levels and 4-HNE protein adducts as markers of lipid peroxidation and a panel of key endogenous gastro-protective proteins were assayed. The data obtained indicate a gastroprotective effect of L-lysine on gastric mucosa integrity.

Role of hydrogen sulfide in the physiology of gastrointestinal tract and in the mechanism of gastroprotection

Hydrogen sulfide (H2S) is commonly known as a toxic gas with an unpleasant odor. However, in the human body it plays a role as a gaseous transmitter involved in the control of physiological processes. Studies published so far have shown that H2S increased synaptic long-term potentiation in the central nervous system and exerted the inflammatory and anti-inflammatory effects on vascular endothelium. These effects clearly depend on the concentration of this gaseous molecule. H2S exerts vasodilatory effect in the cardiovascular system similar to those exhibited by carbon monoxide or nitric oxide. It is believed that H2S may play a potential role in the physiology of the gastrointestinal tract including the mechanism of gastroprotection of gastric mucosa and possibly exerts a protective effect in other parts of the digestive system. The administration of L-cysteine, the precursor of H2S or NaHS, the exogenous donor of this gaseous molecule, significantly reduced gastric damage induced by ethanol, an agent that is known to induce acute gastric damage and hemorrhagic necrosis to the gastric mucosa. The administration of H2S results in increased secretion of protective bicarbonate and mucus secretions and these effects could, in part, explain the H2S-induced protection of duodenal mucosa against the damage induced by gastric acid. Despite these promising results, little is known about the therapeutic efficacy of H2S in relation to two other important gases, nitric oxide and carbon monoxide, and future studies are definitely needed to assess its usefulness in the treatment of upper and lower gastrointestinal tract disorders.

Su1735 Effects of Melatonin and Tryptophan on Healing of Gastric and Duodenal Ulcers With Helicobacter pylori Infection in Humans

Melatonin (MT) and its precursor L-tryptophan (TRP) are implicated in the protection of gastric mucosa against aspirininduced lesions and in the acceleration of healing of idiopathic gastro-duodenal ulcers, but no information is available whether these agents are also effective in healing of gastroduodenal ulcers accompanied by Helicobacter pylori (H. pylori) infection. In this study three groups A, B and C, each including 7 H. pylori-positive patients with gastric ulcers and 7 H. pylori-positive patients with duodenal ulcers, aging 28-50 years, were randomly assigned for the treatment with omeprazole 20 mg twice daily combined with placebo (group A), MT administered in a dose of 5 mg twice daily (group B) or TRP applied in a dose of 250 mg twice daily (group C). All patients underwent routine endoscopy at day 0 during which the gastric mucosa was evaluated and gastric biopsies were taken for the presence of H. pylori and histopathological evaluation. The rate of ulcer healing was determined by gastroduodenoscopy at day 0, 7, 14 and 21 after the initiation of the therapy. Plasma MT, gastrin, ghrelin and leptin were measured by specific RIA. At day 21, all ulcers were healed in patients of groups B and C but only 3 out of 7 in group A of gastric ulcers and 3 out of 7 in duodenal ulcers. Initial plasma MT showed similar low levels in all three groups but it increased several folds above initial values in ulcer patients at day 7, 14 and 21. Plasma gastrin and leptin levels showed a significant rise over initial values in patients treated with omeprazole and placebo, MT or TRP while plasma ghrelin levels were not significantly affected by these treatments. We conclude that MT or TRP added to omeprazole treatment, significantly accelerates healing rate of H. pylori infected chronic gastroduodenal ulcers over that obtained with omeprazole alone and this likely depends upon the significant rise in plasma MT and possibly also in leptin levels, both hormones involved in the mechanism of gastroprotection and ulcer healing.

Novel Concept in the Mechanism of Injury and Protection of Gastric Mucosa: Role of Renin-Angiotensin System and Active Metabolites of Angiotensin

The term cytoprotection pioneered by Robert and colleagues has been introduced to describe the remarkable ability of endogenous and exogenous prostaglandins (PGs) to prevent acute gastric hemorrhagic lesions induced by noxious stimuli such as ethanol, bile acids, hiperosmolar solutions and nonsteroidal anti-inflammatory agents such as aspirin. Since that time many factors were implicated to possess gastroprotective properties such as growth factors including epidermal growth factor (EGF) and transforming factor alpha (TGFα), vasodilatory mediators such as nitric oxide (NO) and calcitonin gene related peptide (CGRP) as well as appetite gut hormones including gastrin and cholecystokinin (CCK), leptin and recently ghrelin. This protective action of gut peptides has been attributed to the release of PG but question remains whether another peptide angiotensin, the classic component of the systemic and local renin-angiotensin system (RAS) could be involved in the mechanism of gastric integrity and gastroprotection. After renin stimulation, the circulating angiotensin I is converted to angiotensin II (ANG II) by the activity of the Angiotensin Converting Enzyme (ACE). The ANG II acting via its binding to two major receptor subtypes the ANG type 1 (AT1) and type 2 (AT2) has been shown be activated during stress and to contribute to the pathogenesis of cold stress- and ischemia-reperfusion-induced gastric lesions. All bioactive angiotensin peptides can be generated not only in systemic circulation, but also locally in several tissues and organs. Recently the new functional components of RAS, such as Ang-(1-7), Ang IV, Ang-(1-12) and novel pathways ACE2 have been described suggesting the gastroprotective role for the novel ANG II metabolite, Ang-(1-7). The fact that Ang-(1-7) is produced in excessive amounts in the gastric mucosa of rodents and that pretreatment by Ang-(1-7) exhibits a potent gastroprotective activity against the gastric lesions induced by cold-restraint stress suggests that this and possibly other vasoactive metabolites of ANG II pathway could be involved in the mechanism of gastric integrity and gastroprotection. This review summarizes the novel gastroprotective factors and mechanisms associated with metabolic fate of systemic and local RAS activation with major focus to recent advancement in the angiotensin pathways in the gut integrity.

Editorial [Hot Topic: Emerging Drugs in Gastrointestinal Tract (Executive Guest Editor: Predrag Sikiric)

There is little doubt that the pathogenesis of gastrointestinal disorders, diagnosis as well as the therapy is a pertinent scientific focus and one of the largest and most intriguing areas in medicine. Likewise, it has been generally accepted that most of the therapy and understanding of pathophysiology in the gastrointestinal tract is well and should be validated in clinical practice. Therefore, there is still an open door for one or more new ways. Hopefully, the most recent findings may provide a new insight into future developments. In this, I hope, in scope of Emerging Drugs in Gastrointestinal Tract, these papers may contribute a new view that may likely improve the future understanding of pathogenesis and therapy in gastrointestinal tract. In this issue, Yanaka (Faculty of Pharmaceutical Sciences, Tokyo University of Science, Japan) reviewed cellular mechanisms by which the nrf2-keap1 system contributes to induction of a variety of antioxidant enzymes during exposure to oxidative stress and introduced the beneficial effects of sulforaphane, an isothiocyanate family, rich in broccoli sprouts, on the gastric mucosa through such mechanisms [1]. Brzozowski and collaborators (Jagiellonian University Medical College, Cracow, Poland and Thuringia-Clinic, Saalfeld, Germany) reviewed COX-2 derived products, “lipoxins” in the mechanism of gastric mucosal defense. Aspirin-triggered lipoxin synthesis via COX-2 plays also an important role in gastric adaptation during chronic aspirin administration, in addition to the mechanism of injury, gastroprotection and healing of acute and chronic gastric ulcers in the gut [2]. Chen and Zhao (Norwegian University of Science and Technology, Trondheim, Norway)reviewed gut-bone axis, based on the various factors affecting bone mass, an issue that may be particularly important. They examined critically the influence of ; acid, serotonin, lowdensity lipoprotein receptor-related protein5, etc, affecting bone mass. They concluded that evidence still could not completely prove a close relationship between these factors and bone mass [3]. Historically, the phenomenon of “cytoprotection” caused a big impact to many GI investigators, like “an epoch-making finding”, and although caused major impacts on GI research & development, the current clinic did not gain adequate advantage. In this, Mozsik (University of Pecs, Hungary) extensively reviewed gastrointestinal cytoprotection (at the level of isolated cells, animal experiments, healthy human beings and patients with different gastrointestinal disorders), including the historic lookback, reviewing the huge range of agents supposed to be involved in cytoprotection [4]. Wood (The Ohio State University College of Medicine Columbus, Ohio, USA)focused on chronic functional abdominal and pelvic pain syndromes. Within the scope of Visceral Pain: Spinal Afferents, Enteric Mast Cells, Enteric Nervous System and Stress, Wood reviews and expands the understanding of visceral hypersensitivity and functional abdominal pain of intestinal origin in relation to the enteric nervous system, spinal sensory neurons and enteric mast cells [5]. Until recently, fat was considered a relatively inactive tissue serving only as a depot for the storage of excess lipid around the body. Over the last decade, however, several studies have established fat as a metabolically active endocrine organ able to affect human pathophysiology at multiple levels. Karagainides and collaborators (David Geffen School of Medicine at the University of California Los Angeles, USA) reviewed the potential pathways by which changes in fat physiology may affect the development and progress of intestinal pathological conditions such as inflammatory bowel disease, and especially discussed the central role of neuropeptides in the pathogenesis and course of inflammatory bowel disease, via adipose tissue associated responses as well as the potential crosstalk between obesity-associated fat tissue and neuropeptides [6]. The role of constitutive and inducible antibacterial peptides has been investigated thoroughly over the recent years ; especially in the gastrointestinal tract, where the balance between luminal bacteria and antibacterial peptides is crucial. Wong and collaborators (The Chinese University of Hong Kong, Shatin, Hong Kong, China) focused on and emphasized the role of defensins and cathelicidins, two of the most popular mammalian antibacterial peptides (produced by neutrophils and epithelial cells and are highly expressed during infection), in gastrointestinal inflammation and cancers as well as other physiological processes such as cell proliferation, wound healing and so on. In addition, they also proposed that the dysregulation of their expressions could be used as a biomarker for early diagnosis, especially for H. pylori-related diseases as well as cancers in the gastrointestinal tract [7]

Lipoxins, The Novel Mediators of Gastroprotection and Gastric Adaptation to Ulcerogenic action of Aspirin

Previous studies revealed that prostaglandins contribute to the mechanism of maintenance of gastrointestinal integrity and mediate various physiological aspects of mucosal defense. The suppression of prostaglandin synthesis in the stomach is a critical event in terms of the development of mucosal injury after administration of various NSAID including aspirin (ASA). A worldwide use of ASA is now accepted due to its remarkable analgesic, antipyretic and anti-thrombotic prophylactics against myocardial infarct and coronary disorders despite the fact that the use of NSAIDs is associated with the risk of gastrointestinal bleedings, haemorrhagic lesions and ulcerations. It has become clear that other mediators besides prostaglandins can similarly act to protect the gastrointestinal mucosa of experimental animals and humans from injury induced by ASA. For instance, nitric oxide (NO) released from vascular epithelium, epithelial cells of gastrointestinal tract and sensory nerves can influence many of the same components of mucosal defense as do prostaglandins. This review was designed to provide an updated overview based on the experimental and clinical evidence on the involvement COX-2 derived products, lipoxins in the mechanism of gastric defense, gastroprotection and gastric adaptation to ASA. Lipoxins were recently considered as another group of lipid mediators that can protect the stomach similarly as NO-donors known to exert protective influence on the stomach from the injury under condition where the mucosal prostaglandin levels are suppressed. The new class of NO-releasing NSAIDs, including NO-aspirin or NO-naproxen, represent a very promising approach to reducing the toxicity of their parent NSAIDs. Aspirin-triggered lipoxin (ATL) synthesis, via COX-2, acts to reduce the severity of damage induced by this NSAID. Lipoxin analogues may prove to be useful for preventing mucosal injury and for modulating mucosal inflammation. Evidence presented in this review documents that ATL also play in important role in gastric adaptation during chronic ASA administration. Suppression of COX-2 activity by selective COX-2 inhibitors such as rofecoxib or celecoxib was shown to abolish the production of ATL and to diminish the gastric tolerability of ASA and gastric adaptation developed in response to repetitive administration of this NSAID. Synthetic analogues of lipoxins as well as newer class of NSAIDs releasing NO may be used in the future as the therapeutic approach to counteract adverse effects in the stomach associated with NSAIDs ingestion.

Gastroprotective mechanism of Vanillosmopsis arborea bark essential oil

This study was aimed to clarify the mechanism of gastroprotection by Vanillosmopsis arborea Baker essential oil (EOVA) using ethanol-induced gastric mucosal damage in mice. Gastric lesions were significantly reduced by EOVA (200 and 400 mg/kg). Chemical analysis showed that the major compound of EOVA was alpha-bisabolol. Pretreatment of mice with yohimbine, the alpha2-antagonist, greatly suppressed the gastroprotective effect of OEVA. Furthermore, OEVA gastroprotection was not attenuated in mice pretreated with indomethacin, L-NAME or glibenclamide, the respective inhibitors of cyclooxygenase, nitric oxide synthase and K(+)(ATP) channel activation. These data suggest that OEVA affords gastroprotection most possibly by alpha2-receptor activation.

Gastroprotective and anti-inflammatory effects of resin from Protium heptaphyllum in mice and rats

The natural resin collected from the trunk wood of Protium heptaphyllum is used in folk medicine to treat inflammatory conditions and to hasten wound repair. In the search of new potential anti-inflammatory agents with gastroprotective property, the present study evaluated its effects in experimental models of gastric ulcer and inflammation. In mice, the resin (200 and 400 mg/kg) significantly attenuated the gastric damage induced by ethanol or acidified ethanol (HCl/ethanol), in a manner similar to N-acetyl- l-cysteine (NAC), a replenisher of sulfhydryls. Unlike NAC the resin failed to restore the ethanol-induced depletion of non-protein sulfhydryl content, indicating a different mechanism of gastroprotection. However, in 4-h pylorus-ligated rats, the resin significantly reduced the total acidity without much change in gastric secretory volume. In rats, at similar doses the resin did not modify the hind-paw edema induced by carrageenan, but effectively reduced the formation of cotton pellet-induced granuloma, suggesting its inhibitory effect on collagen formation but not on acute edema. Furthermore, the vascular permeability increase induced by acetic acid was significantly reduced in mice that received 400 mg/kg resin. The resin demonstrated no overt toxicity in mice up to an oral dose of 5 g/kg. Phytochemical analysis revealed the presence of α- and β-amyrins as principal triterpenoid constituents of resin, which were previously described to have anti-ulcer property. These findings indicate the potential gastroprotective and anti-inflammatory property of P. heptaphyllum resin and further support its popular use in gastrointestinal disorders.

Mechanism of prevention by capsaicin of ethanol-induced gastric mucosal injury--a study in the rat using intravital microscopy.

Capsaicin acts specifically on primary afferent neurones to release neuropeptides, including calcitonin gene-related peptide (CGRP), and prevents ethanol-induced mucosal injury. To investigate the microvascular changes in the gastric mucosa in response to ethanol using intravital microscopy to elucidate the mechanism of capsaicin-induced gastroprotection. The posterior gastric wall in the rat was secured in an observation chamber and perfused with Tyrode's solution. The microcirculation was observed through a window made by removing a limited area of smooth muscle. Ethanol (50%) applied to the mucosa constricted the collecting venules and venules but dilated arterioles. The constriction of the collecting venules resulted in mucosal congestion, which caused mucosal injury. Application of capsaicin to the mucosa dilated the arterioles but not the collecting venules or venules. Arteriolar dilation was inhibited by a CGRP antagonist, CGRP-(8-37). Prior application of capsaicin prevented ethanol-induced constriction of the collecting venules, and the action of capsaicin was inhibited by prior application of CGRP-(8-37). The results suggest that the inhibition of ethanol-induced gastric injury by capsaicin is attributable to the suppression of collecting venule constriction, via CGRP release.

Mechanism of gastroprotection by bismuth subsalicylate against chemically induced oxidative stress in cultured human gastric mucosal cells.

Reactive oxygen species (ROS) are implicated in the pathogenesis of chemically induced gastric mucosal injury. We have investigated the effects of ethanol, hydrochloric acid (HCl), and sodium hydroxide (NaOH) on: (1) enhanced production of ROS including superoxide anion and hydroxyl radicals, (2) modulation of intracellular oxidized states by laser scanning confocal microscopy, and (3) DNA fragmentation, indices of oxidative tissue, and DNA damage in a primary culture of normal human gastric mucosal cells (GC), which were isolated and cultured from Helicobacter pylori-negative endoscopic biopsies from human subjects. The induction of ROS and DNA damage in these cells following exposure to ethanol (15%), HCl (150 mM) and NaOH (150 mM) were assessed by cytochrome c reduction (superoxide anion production), HPLC detection for enhanced production of hydroxyl radicals, changes in intracellular oxidized states by laser scanning confocal microscopy, and DNA damage by quantitating DNA fragmentation. Furthermore, the protective ability of bismuth subsalicylate (BSS) was assessed at concentrations of 25, 50, and 100 mg/liter. Incubation of GC with ethanol, HCI, and NaOH increased superoxide anion production by approximately 8.0-, 6.1-and 7.1-fold and increased hydroxyl radical production by 13.3-, 9.6-, and 8.9-fold, respectively, compared to the untreated gastric cells. Incubation of GC with ethanol, HCl, and NaOH increased DNA fragmentation by approximately 6.7-, 4.3-, and 4.8-fold, respectively. Approximately 20.3-, 17.5-, and 13.1-fold increases in fluorescence intensities were observed following incubation of gastric cells with ethanol, HCl, and NaOH, respectively, demonstrating dramatic changes in the intracellular oxidized states of GC following exposure to these necrotizing agents. Preincubation of GC with 25, 50, and 100 mg/liter of BSS decreased ethanol-induced increases in intracellular oxidized states in these cells by 36%, 56%, and 66%, respectively, demonstrating a concentration-dependent protective ability by BSS. Similar results were observed with respect to BSS in terms of superoxide anion and hydroxyl radical production, and DNA damage. The present study demonstrates that ethanol, HCl, and NaOH induce oxidative stress and DNA damage in GC and that BSS can significantly attenuate gastric injury by scavenging these ROS.

Mechanism of gastroprotection by bismuth subsalicylate against chemically-induced oxidative injury in human gastric mucosal cells

Mechanism of gastroprotection by bismuth subsalicylate against chemically-induced oxidative injury in human gastric mucosal cells

Involvement of endogenous cholecystokinin and somatostatin in gastroprotection induced by intraduodenal fat.

Duodenal fat such as oleate is known to influence gut functions by release of cholecystokinin (CCK), but the contribution of CCK endogenously released by duodenal fat or by diversion of pancreatic juice from the duodenum in the mechanism of mucosal integrity and gastroprotection has been little studied. This study was designed to compare the effect of CCK-8 and intraduodenal (i.d.) instillation of sodium oleate, or diversion of the pancreatic biliary secretions that are known to release CCK, on the gastric mucosal lesions induced by topical application of 100% ethanol or acidified aspirin (ASA) in rats with or without the pretreatment with a CCK-A receptor antagonist, loxiglumide, or with L-365,260 to block CCK-B receptors. In addition, the effect of suppression of prostaglandin (PG) biosynthesis by indomethacin (5 mg/kg i.p.), inhibition of nitric oxide (NO)-synthase by L-NAME (5 mg/kg i.v.), or blockade of sensory nerves by capsaicin (125 mg/kg s.c.) on the protective activity of sodium oleate was determined. Sodium oleate (50-200 mM i.d.), or diversion of pancreatic juice from the duodenum for 3 h that produced significant rise in plasma CCK levels, significantly reduced gastric lesions induced by 100% ethanol to an extent similar to that induced by exogenous CCK-8 (5 nmol/kg s.c.). The protective effect of oleate or diversion of pancreatic juice was accompanied by an increase in gastric blood flow (GBF). Both protection and accompanying hyperemia were completely abolished by blockade of CCK-A receptors with loxiglumide, whereas L-365,260, an antagonist of CCK-B receptors, had no effect. Oleate given i.d. significantly attenuated acidified ASA-induced gastric lesions and gastric secretion while increasing the luminal concentration of somatostatin. These effects were significantly reduced by loxiglumide but not by L-365,260. In contrast, CCK-8, which stimulated gastric acid secretion, failed to affect the lesions induced by acidified ASA and the decrease in the GBF produced by this ulcerogen. Indomethacin, which suppressed PG generation by approximately 90%, failed to influence the protective activity of oleate or CCK-8 against ethanol-induced lesions, whereas L-NAME, vagotomy, or sensory denervation significantly attenuated this protection and accompanying hyperemia. Addition to L-NAME of L-arginine, but not D-arginine, restored the protective and hyperemic effects of CCK-8 and duodenal oleate against gastric lesions induced by ethanol or acidified ASA. We conclude that endogenous CCK released by oleate or diversion of pancreatic secretion exerts a potent gastroprotective action on the stomach involving predominantly CCK-A receptors and depending on vagal activity, and hyperemia mediated by NO and sensory nerves but unrelated to acid secretory effects and endogenous PG.