Gastric Mucosal Integrity Research Articles

Central, but not peripheral administration of substance P induces opioid-mediated gastroprotection in the rat

Introduction: Although the gastrointestinal effects of the tachykinin substance P (SP) have been studied for a long period, its role in the regulation of gastric mucosal integrity has not been fully clarified. Both aggravation of ethanol-induced damage and lack of effect have been reported after peripheral injection of SP in rats (Evangelista et al., 1987; 1991; Karmeli et al., 1991). In contrast, centrally injected SP reduced cold-restraint stress-induced gastric ulcers (Hernandez et al., 1983). The aim of our study was 1) to analyze the effect of SP in an acid-independent ulcer model in rats, and 2) to clarify, whether the endogenous opioid system is involved in the SP-induced mucosal protection. Methods: The ethanol-ulcer model was used. After 24h starvation, male Wistar rats were given 0.5ml acidified ethanol orally. The mucosal lesions were evaluated 1h later. SP was given either intracerebroventricularly (i.c.v.) or intravenously (i.v.). Results: 1) I.c.v. injected SP (9.3–37pmol/rat) dose-dependently inhibited the formation of ethanol-induced ulcers. 2) In contrast, intravenous SP (0.3–7 nmol/kg i.v.) failed to induce gastroprotective effect. 3) The central gastroprotective effect of SP was inhibited by the NK1-receptor antagonist L-733,060 (1.1 nmol i.c.v.). 4) The non-selective opioid receptor antagonist naloxone (27 nmol i.c.v.) antagonized the effect of SP as well, while the κ opioid receptor antagonist norbinaltorphimine (14 nmol i.c.v.) and the δ opioid receptor antagonist naltrindole (5 nmol i.c.v.) had no effect. 5) Pretreatment with endomorphin-2 antiserum (i.c.v.) also inhibited the SP-induced central gastroprotection. Conclusions: Our results suggest that SP given centrally, but not peripherally induces gastroprotection in rats, and this effect is mediated by NK1-receptors and endogenous opioids (presumably endomorphins) acting on µ-opioid receptors. The work was supported by ETT 341/2009 from the Scientific Health Council and National Office for Research and Technology (NKTH).

Prostacyclin/IP Receptors Involved in Modulating Gastric Mucosal Integrity Under Cold-Restraint Stress Conditions

Prostacyclin/IP Receptors Involved in Modulating Gastric Mucosal Integrity Under Cold-Restraint Stress Conditions

The effect of probiotics on gastric mucosal permeability in humans administered with aspirin

Objective. To examine whether a probiotic strain, Lactobacillus gasseri OLL2716 (LG21), can protect the gastric mucosal integrity from aspirin using urinary sucrose excretion (USE) test. Materials and methods. In the study using high-dose aspirin, the USE tests were carried out in 29 volunteers before and after LG21 treatment for 4 weeks. In the study using patients undergoing low-dose aspirin therapy, USE tests were performed in 37 subjects who took LG21 for 16 weeks. Stool occult blood was examined by the guaiac method. Results. In the former study, the elevation in the USE value after aspirin loading significantly decreased after LG21 treatment (Median ± SD; 0.244 ± 0.237 vs. 0.208 ± 0.112%, p = 0.018). In the latter study, the USE value significantly decreased in the period with LG21 treatment (p = 0.033), while no significant difference was found in the period without LG21 (p = 0.113). The number of positive occult blood tests decreased during LG21 treatment. Conclusions. The regular ingestion of LG21 may protect the integrity of the gastric mucosal permeability against aspirin.

Paracetamol confers resistance to ethanol-induced gastric mucosal damage in rats.

Paracetamol given orally or subcutaneously did not produce any observable gastric mucosal damage, nor did it change the acidity of the residual secretion in rat stomachs. However, it delayed the gastric emptying rate and increased the residual volume of gastric secretion. Pretreatment with paracetamol 250 mg kg-1 significantly prevented ethanol-induced gastric ulceration. Although it did not influence ethanol-stimulated acid secretion, it increased the mucosal mucus content in the ethanol-treated animals. The findings suggest that the protective mechanism of paracetamol against ethanol-induced damage is likely to be due to improved gastric mucosal integrity, through an increase in the adherent mucosal mucus which protects the underlying delicate cellular structures.

In vitro effect of carprofen and meloxicam on the conductance and permeability to mannitol and the histologic appearance of the gastric mucosa of dogs

To evaluate the effects of carprofen and meloxicam on conductance and permeability to mannitol and on the histologic appearance of sections of canine gastric mucosa. Gastric mucosa from 6 mature mixed-breed dogs. Sections of gastric mucosa were mounted in Ussing chambers, and carprofen (40 or 400μg/mL [CAR40 and CAR400, respectively]), meloxicam (8 or 80μg/mL [MEL8 and MEL80, respectively]), or no drug (controls) was added to the bathing solution. For all sections, conductance was calculated every 15 minutes for 240 minutes and flux of mannitol was calculated for 3 consecutive 1-hour periods; histologic examination was performed after the experiment. The area under the conductance-time curve for each chamber was calculated. Values of conductance × time, flux of mannitol, and the frequency distribution of histologic findings were analyzed for treatment effects. For CAR400- and MEL80-treated sections, conductance X time was significantly higher than that for control and MEL8-treated sections. The effect of CAR40 treatment was not different from that of any other treatment. Over the three 1-hour periods, mannitol flux increased significantly in MEL80-, CAR40-, and CAR400-treated sections but not in MEL8- treated or control sections. Major histologic changes including epithelial cell sloughing were limited to the CAR400-treated sections. In the gastric mucosa of dogs, carprofen and meloxicam increased in vitro conductance and permeability to mannitol. At a concentration of 400 μg/mL, carprofen caused sloughing of epithelial cells. Carprofen and meloxicam appear to compromise gastric mucosal integrity and barrier function in dogs.

Effect of Intravenous Polyunsaturated Fatty Acids Administration on Gastric Mucosal Integrity in Pig-tailed Macaques with Obstructive Jaundice

Background: Acute gastric mucosal injury commonly occurs in patients with obstructive jaundice. We studied the effect of intravenous polyunsaturated fatty acids (PUFA) administration on gastric mucosal integrity in pig-tailed macaques (Macaca nemestrina) with obstructive jaundice by ligating common bile duct (CBD). Method: The study was conducted between February 2009 and May 2010 at the Primate Research Center, Bogor Agricultural Institute. Eight selected male pig-tailed macaques with 6.625 ± 0.83 kg of body weight were used and divided into two groups. In both groups, laboratory examination, including liver function tests and upper gastrointestinal endoscopy were performed before CBD ligation and every two weeks after ligation. In the first group, intravenous PUFA with the dose of 2 g/day was administered every day since four weeks post-ligation up to four weeks later, and in the second group, intravenous PUFA was administered since before ligation up to eight weeks later. Results: In both groups, increased total bilirubin, direct bilirubin, indirect bilirubin, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase and gamma glutamyl transpeptidase were obviously found, meanwhile decreased albumin level was detected and the cholinesterase level of both groups remained unchanged. Ulcer formation occurred among the first group during 4 weeks after CBD ligation, and these ulcers showed obvious healing within four weeks after intravenous PUFA administration. In the second group, there was no significant ulcer formation within eight weeks after CBD ligation. Conclusion: The potential appearance of acute gastric mucosal injury which reflected by ulcer formation in pig-tailed macaques with obstructive jaundice was significantly decreased by intravenous PUFA administration. We also have successfully developed animal model of obstructive jaundice by CBD ligation, based on the result of liver function tests. Keywords : acute gastric mucosal injury, intravenous PUFA administration, obstructive jaundice, pig- tailed macaques

Rebamipide, a mucoprotective drug, inhibits NSAIDs-induced gastric mucosal injury: possible involvement of the downregulation of 15-hydroxyprostaglandin dehydrogenase

Prostaglandin E2 plays an important role in the maintenance of gastric mucosal integrity. The level of biologically active prostaglandin E2 in the tissue is regulated by the balanced expression of its synthetic enzymes, such as cyclooxygenase, and its catabolic enzyme, 15-hydroxyprostaglandin dehydrogenase. We examined the effect of rebamipide, a mucoprotective drug, on prostaglandin E2 production and metabolism in the gastric tissue and its effect on indomethacin-induced gastric mucosal injury in mice. Rebamipide suppressed indomethacin-induced gastric mucosal injury. Suppressive effect of rebamipide on indomethacin-induced gastric mucosal injury was also observed in cyclooxygenase-2-knockout mice. The mice that were treated with rebamipide showed a 2-fold increase in cyclooxygenase-2 mRNA expression in the gastric tissue, whereas 15-hydroxyprostaglandin dehydrogenase mRNA expression markedly decreased as compared to vehicle-treated control mice. Rebamipide did not affect the expression of cyclooxygenase-1 in the gastric tissue. Rebamipide did not increase prostaglandin E2 production in the gastric tissue; however, it induced a 1.4-fold increase in the concentration of prostaglandin E2 in the gastric tissue as compared to vehicle-treated control mice. These results suggest that the suppressive effect of rebamipide on non-steroidal anti-inflammatory drugs-induced gastric mucosal injury can be attributed to reduced 15-hydroxyprostaglandin dehydrogenase expression, which increases the prostaglandin E2 concentration in the gastric tissue.

Asymmetric dimethylarginine: A novel biomarker of gastric mucosal injury?

Nitric oxide (NO), a multifunctional endogenous gas molecule, is metabolized from L-arginine by enzymatic reaction in the presence of nitric oxide synthase. NO, an important gas signaling molecule, is a gastric mucosa protective factor that contributes significantly to maintain normal gastric mucosa integrity. NO increases gastric mucosa blood flow, regulates the secretion of mucus and bicarbonate, and inhibits the secretion of gastric juice. Asymmetric dimethylarginine (ADMA) has been identified as the major endogenous inhibitor of nitric oxide synthase. The function of ADMA is to decrease NO production via inhibiting nitric oxide synthase activity. Besides inhibiting NO synthesis, ADMA also directly induces oxidative stress and cell apoptosis, and participates in inflammation reaction. Its systemic accumulation was observed in conjunction with several cardiovascular and metabolic diseases. ADMA also mediates gastric ulcer injury induced by ethanol, stress, helicobacter pylori and indomethacin. The mechanism of ADMA directly producing adverse effect in gastric mucosa is incompletely understood. It is widely accepted that NO bioavailability decrease is the majority reason. Promotion of apoptosis and aggravation of inflammation may be other important mechanisms of ADMA-induced gastric injury. ADMA might be a novel clinical and experimental biomarker related to gastric mucosa disorder. Although therapeutic tool targeting to ADMA is available in multiple cardiovascular diseases, it is unknown in gastrointestinal disease. The strategy to inhibit ADMA is beneficial to gastric ulcer induced by ethanol in rats. Thus, ADMA might be a candidate of therapeutic target in gastric mucosa damage.

TLQP-21, a VGF-Derived Peptide, Prevents Ethanol-Induced Gastric Lesions: Insights into Its Mode of Action

Background and Aim: TLQP-21, a peptide derived from the vgf gene, has been reported to play a role in the regulation of rat gastric motility, but its influence on gastric mucosal integrity is unknown. Experimental Approach: We investigated the effects of central (0.8–8 nmol/rat) or peripheral (48–240 nmol/kg) TLQP-21 administration on ethanol- (EtOH, 50%, 1 ml/rat) induced gastric lesions in the rat. The mechanisms involved in such activity were also examined. Results: Central TLQP-21 injection dose-dependently reduced EtOH-induced gastric lesions (ED₅₀ = 3.16 nmol), while peripheral TLQP-21 administration had no effect. The TLQP-21 gastroprotective effect against EtOH injury was accompanied by a significant increase in gastric prostaglandin E₂ (PGE₂) production linked to an increase in constitutive cyclooxygenase (COX) expression. The nitric oxide (NO) synthase inhibitor L-NAME (70 mg/kg, s.c.), the nonselective COX inhibitor indomethacin (10 mg/kg, orally) and capsaicin denervation removed TLQP-21 gastroprotection. Conclusions: This study shows for the first time that central TLQP-21 exerts a protective action on the gastric mucosa exposed to the noxious agent EtOH. TLQP-21 gastroprotection is mediated by constitutive-derived NO and PGE₂, and requires the integrity of sensory nerve fibers.

Impact of diets' physical form (particle size; meal/pelleted) on the stomach content (dry matter content, pH, chloride concentration) of pigs

Pars nonglandularis (PN) is the main affected area of gastric ulcers in pigs. Several factors are discussed to affect integrity of porcine gastric mucosa, but special emphasis is given to physical form of the feed. A total of 26 pigs (bw: 36.4 ± 10.5 kg) were housed individually and test diets were fed ad libitum for 3 days. The four diets used in this study were identical in botanical and chemical composition, but differed in grinding intensity (fine/coarse) and physical form (pelleted/meal). On day 3, animals were sacrificed 6 hours after free access to feed (after an overnight fast). The stomach was withdrawn in toto and frozen immediately at − 80 °C. A sagittal cut was made and samples of the frozen gastric content were taken from 15 standardized localisations to determine dry matter content, pH and chloride (Cl) concentration using standard methods. Physical form of diets noticeably affected quality and composition of stomach content. Marked effects were found in the PN. The finely ground and pelleted diet (FP) resulted in a more liquid chyme and a significantly higher Cl-concentration at PN in comparison to the results observed after feeding the unpelleted diets (CM/FM). There was no distinct pH gradient between the regions after feeding FP. However, the coarsely ground meal (CM) caused highest pH values at PN and low pH values at fundus region. Cl-concentrations at PN were markedly lower when pigs were fed the unpelleted diets (CM/FM). In pigs fed FP a significantly higher Cl-secretion rate of the upper gastrointestinal tract was found. Therefore this study shows clearly effects of grinding intensity and physical form of the diet on composition and quality of gastric chyme within the different regions of porcine stomach. The relatively high pH at PN after feeding the FP indicates that pH presumably is not the key factor for development of gastric ulcers in pigs at PN.

Effect of grinding intensity and crude fibre content of the feed on growth performance and gastric mucosa integrity of growing –finishing pigs

The influence of the interaction between crude fibre content and grinding intensity of the diet on performance results and gastric mucosa integrity was studied in a 2 × 2 factorial trial. Therefore, the 4 treatments were: low fibre-finely ground, low fibre-coarsely ground, high fibre-finely ground and high fibre-coarsely ground. Ninety-six pigs were allotted to 16 pens, with 3 barrows and 3 gilts per pen. Each pen was randomly assigned to 1 out of 4 treatments, leading to 4 pens per treatment. The low fibre diet contained 4% crude fibre, and the high fibre diet 9%. The higher fibre content was achieved by including beet pulp and alfalfa in the diet and using soybean meal with a lower protein content. The finely ground feed was produced using a hammermill with a screen of 1.5 mm for grinding the ingredients, the coarsely ground was produced with a screen of 6 mm. Three-phase feeding was applied and within each phase, diets were formulated to be identical in net energy, crude protein, digestible lysine, methionine + cystine, threonine and tryptophan content. No significant interaction between grinding intensity and crude fibre content on performance was observed, although, during the second feeding phase (40-70 kg), a small effect on feed intake was noticed. Performance results were not significantly affected by grinding intensity. While crude fibre content did not affect the growth performance during the first or second feeding phase, an adverse effect on feed conversion ratio was noticed during the third feeding phase. Possibly, the net energy content of the high fibre diet was overestimated in the third phase. Macroscopic lesion scores of the pars oesophagea of the stomach were not affected by grinding intensity or crude fibre content exclusively. However, animals on the coarsely ground high fibre diet showed lower macroscopic lesion scores, indicating a synergistic effect of grinding intensity and crude fibre content on preventing lesions in the gastric mucosa.

The protective effects of ghrelin and leptin against stress-induced gastric ulcer in rats

Background and study aims Ghrelin and leptin hormones have been well recognised as key factors in regulating appetite and energy homeostasis. Recently, it has been reported that both are produced in the stomach, but little is known about their influence on gastric mucosal integrity. Therefore, this study aims to compare the effects of subcutaneous (sc) administration of ghrelin and leptin on acute gastric ulcer induced by immobilisation stress. Materials and methods The study was carried out on 36 adult male albino rats. The animals were divided into four main groups: group I (control group); group II (ghrelin-treated group, 40 μg kg –1 body weight (BW) sc), which was divided into two equal subgroups: group IIa (ghrelin alone) and group IIb (pretreated with nitro-l-arginine methyl ester ‘L-NAME’) (70 mg kg −1 BW sc); group III (leptin-treated group, 10 μg kg −1 BW sc), which was divided into two equal subgroups: group IIIa (leptin alone) and group IIIb (pretreated with L-NAME) (70 mg kg −1 BW sc); and finally group IV (treated with both ghrelin and leptin). In all the groups studied, ulcer score, ulcer index and preventive index were evaluated. Results sc administration of ghrelin or leptin produced a significant decrease in the ulcer score ( p < 0.001) and ulcer index, with an increase in the preventive index. Moreover, the combined treatment with both ghrelin and leptin induced a more protective effect than each one alone. In L-NAME-pretreated animals, the ulcer prevention ability of both ghrelin and leptin was significantly reduced ( p < 0.05). However, there was still a significant reduction in the ulcer score and ulcer index when compared with that of the control rats ( p < 0.05). Conclusion Both ghrelin and leptin play a protective role against stress-induced gastric ulcer and their combination effect is additive in nature. Furthermore, their effects proved to be mostly, but not completely, through nitric oxide pathway.

The protective effects of calcitonin gene-related peptide on gastric mucosa injury of gastric ischemia reperfusion in rats

Gastric mucosa is one of the most vulnerable tissues in human and animal. However, little is known about the effects of calcitonin gene-related peptide (CGRP) on gastric mucosa injuries induced by gastric ischemia reperfusion. The purpose of the present study was to investigate the protective effects and mechanism of CGRP on gastric mucosa injury after gastric ischemia reperfusion in rats. Thirty-six healthy Wistar rats were randomly divided into CGRP-treated, sham-operated, and control groups. Twelve rats were involved in each group. These groups were further divided into 24-h and 48-h subgroups. Gastric ischemia reperfusion injury (GI-RI) rat model was established by a 30-min celiac artery occlusion by an artery clamp, followed by 24 h or 48 h of reperfusion. CGRP (1 μg/ml) at the dose of 3 μg/kg was given intraperiloneally (IP) at the beginning of reperfusion for rats in CGRP-treated group. Saline as vehicle (3 ml/kg body weight), IP, was administered at the beginning of reperfusion for rats in control group. Sham-operated animals were subjected to an operation without GI-RI. Twenty-four hours or 48 h after operation, the samples were taken out and processed for calculating stomach mucous membrane damage index according to Guth method, detecting pathological changes of gastric mucosa tissue by light microscopy and observing the expression of gastrin (Gas) and somatostatin (SST) by immunohistochemical staining. The results showed the following: (i) gastric mucosa with diffuse edema, splinter hemorrhage and erosion, numerous endothelial cells necrosis, mucosa dissociation, and infiltration of inflammatory cells were observed in both control and CGRP-treated animals, especially in the earlier period (24 h) and then gradually healing. CGRP administration could reduce the damage of gastric mucosa. The injury index of gastric mucosa was lower in CGRP-treated group as compared with that in control group (P < 0.01). (ii) Gas expression in gastric antrum mucosa was lower in CGRP-treated group than that in control group (P < 0.01). SST expression in gastric antrum mucosa was higher in CGRP-treated group than that in control group (P < 0.01). It is concluded that CGRP regulated the secretion of Gas and SST and thus alleviated the damage of gastric mucosa induced by ischemia and reperfusion. CGRP might be a potential candidate for clinical therapy on modulating gastric mucosal protection and maintaining gastric mucosal integrity after ischemia and reperfusion of the stomach.

Involvement of Orexigenic Peptides in the Mechanism of Gastric Mucosal Integrity and Healing of Chronic Gastric Ulcers

Orexigenic peptides are group of endocrine hormones exerting a pleiotropic influence on many physiological functions including regulation of the feeding behaviour and energy expenditure, release of growth hormone (GH) and inotropic effects on the heart. Some of these peptides such as ghrelin, originally identified in the gastric mucosa, has been involved not only in control of food intake and growth hormone release but also exerts the immunomodulatory and anti-inflammatory properties. This review summarizes the recent attempts to prove the concept that orexigenic peptides such as ghrelin, orexin-A and obestatin besides playing an important role in the mechanism of food intake, exhibit a potent gastroprotective action against the formation of acute gastric mucosal injury induced by various ulcerogens. This protective effect depends upon vagal activity and hyperemia mediated by NOS/NO and COX/PG systems and CGRP released from sensory afferent nerves. In addition, the appetite peptides such as ghrelin and orexin-A are implicated in the mechanism of the healing of preexisting gastric ulcers due to an activation of specific GHS-R1a and OX-R1 receptors and PG/COX system.

Methods to Measure Gastric Mucosal Lesions in the Rat

The maintenance of gastric mucosal integrity is ensured by a dynamic balance between protective and noxious factors. The gastric mucosa has multiple protective mechanisms that allow the mucosa to withstand frequent exposure to potentially damaging agents such as acid and peptic secretions, bacterial products, ingested food, alcoholic beverages, and certain drugs. The imbalance between defensive and aggressive factors is at the basis of the formation of erosions/lesions or ulcerations of the gastric mucosa. The difference between an erosion/lesion and ulceration is that the former is confined to the mucosa, while an ulceration penetrates to the muscularis mucosae. This unit presents two models of acute mucosal lesions induced in the rat by gastrotoxic agents acting through different mechanisms of action. The protocols explain how to measure gastric mucosal lesions by microscopic examination of the stomach by light microscopy and by scanning electron microscopy.

Cytosolic phospholipase A2 S-nitrosylation in ghrelin protection against detrimental effect of ethanol cytotoxicity on gastric mucin synthesis ——Ghrelin in gastric mucosal protection

Ghrelin, a peptide hormone produced mainly in the stomach, has emerged recently as an important regulator of nitric oxide synthase (NOS) and cyclooxygenase (COX) enzyme systems, the products of which play direct cytoprotective function in the maintenance of gastric mucosal integrity. In this study, using gastric mucosal cells, we report on the role of ghrelin in countering the cytotoxic effect of ethanol on mucin synthesis. We show that the countering effect of ghrelin on mucin synthesis was associated with the increase in NO and PGE2 production, and characterized by a marked up-regulation in cytosolic phospholipase A2 (cPLA2) activity. The ghrelin-induced up-regulation in mucin synthesis, like that of cPLA2 activity, was subject to suppression by Src inhibitor, PP2 and ERK inhibitor, PD98059, as well as ascorbate. Moreover, the loss in countering effect of ghrelin on the ethanol cytotoxicity and mucin synthesis was attained with cNOS inhibitor, L-NAME as well as COX-1 inhibitor SC-560. The effect of L-NAME was reflected in the inhibition of ghrelin-induced mucosal cell capacity for NO production, cPLA2 S-nitrosylation and PGE2 generation, whereas COX-1 inhibitor caused only the inhibition in PGE2 generation. Our findings suggest that the activation of gastric mucosal cPLA2 through cNOS-induced S-nitrosylation plays an essential role in the countering effect of ghrelin on the disturbances in gastric mucin synthesis caused by ethanol cytotoxicity.

Ghrelin Protection against Lipopolysaccharide-Induced Gastric Mucosal Cell Apoptosis Involves Constitutive Nitric Oxide Synthase-Mediated Caspase-3 S-Nitrosylation

Ghrelin, a peptide hormone produced mainly in the stomach, has emerged as an important modulator of the inflammatory responses that are of significance to the maintenance of gastric mucosal integrity. Here, we report on the role of ghrelin in controlling the apoptotic processes induced in gastric mucosal cells by H. pylori lipopolysaccharide (LPS). The countering effect of ghrelin on the LPS-induced mucosal cell apoptosis was associated with the increase in constitutive nitric oxide synthase (cNOS) activity, and the reduction in caspase-3 and inducible nitric oxide synthase (NOS-2). The loss in countering effect of ghrelin on the LPS-induced changes in apoptosis and caspase-3 activity was attained with Src kinase inhibitor, PP2, as well as Akt inhibitor, SH-5, and cNOS inhibitor, L-NAME. Moreover, the effect of ghrelin on the LPS-induced changes in cNOS activity was reflected in the increased cNOS phosphorylation that was sensitive to SH-5. Furthermore, the ghrelin-induced up-regulation in cNOS activity was associated with the increase in caspase-3 S-nitrosylation that was susceptible to the blockage by L-NAME. Therefore, ghrelin protection of gastric mucosal cells against H. pylori LPS-induced apoptosis involves Src/Akt-mediated up-regulation in cNOS activation that leads to the apoptotic signal inhibition through the NO-induced caspase-3 S-nitrosylation.

The protective effects of calcitonin gene-related peptide on gastric mucosa injury after cerebral ischemia reperfusion in rats

High is the incidence of gastrointestinal dysfunction induced by cerebrovascular disease. However, little is known about the effects of CGRP on gastrointestinal injuries induced by cerebrovascular disease. The purpose of the present study was to investigate the protective effects of calcitonin gene-related peptide (CGRP) on gastric mucosa injury after focal cerebral ischemia reperfusion in rats. Thirty healthy adult male Wistar rats were selected for this experiment and were randomly divided into CGRP-treated, sham-operated, and control groups, respectively. Ten rats were involved in each group. Focal cerebral ischemia reperfusion rat model was established by a 2-hour left middle cerebral artery occlusion (MCAO) using an intraluminal filament, followed by 46 h of reperfusion. CGRP (1 μg/ml) at the dose of 3 μg/kg was injected intraperitoneally (i.p.) at the beginning of reperfusion for rats in CGRP-treated group. Saline as vehicle (3 ml/kg body weight), i.p., was administered at the beginning of reperfusion for rats in control group. Sham-operated animals were subjected to an operation without MCAO. Forty-eight hours after operation, the samples were taken out and processed for calculating stomach mucous membrane damage index according to Guth method, detecting pathological changes of gastric mucosa tissue by light microscopy, determining mast cell distribution by toluidine blue staining, and observing the expression of gastrin (Gas), somatostatin (SST), aquaporin-4 (AQP4), and basic fibroblast growth factor (bFGF) by immunohistochemical staining. The results showed that: (1) Gastric mucosa with diffuse edema, splinter hemorrhage and erosion, numerous endothelial cells necrosis, mucosa dissociation, infiltration of inflammatory cells were observed in both control and CGRP-treated animals. CGRP administration could reduce the damage of gastric mucosa. The injury index of gastric mucosa was lower in CGRP-treated group as compared with that in control group ( P < 0.05). (2) Gas expression in gastric antrum mucosa was lower in CGRP-treated group than that in control group ( P < 0.01). SST expression in gastric antrum mucosa was higher in CGRP-treated group than that in control group ( P < 0.01). AQP4 expression in gastric mucosa was lower in CGRP-treated group than that in control group ( P < 0.05). bFGF expression in gastric mucosa was higher in CGRP-treated group than that in control group ( P < 0.01). (3) The mast cell degranulation ratio in control group in gastric mucosa was significantly higher than that in CGRP-treated group ( P < 0.01). It is concluded that CGRP can regulate the secretion of Gas, SST, AQP 4, and bFGF, inhibit mast cell degaranulation and thus alleviate the damage of gastric mucosa induced by cerebral ischemia and reperfusion. CGRP may be one of the good candidates of potential clinical therapy drugs for regulating gastric mucosal protection and maintaining gastric mucosal integrity after cerebral ischemia and reperfusion.

Influence of Cyclooxygenase Inhibitors on the Function of the Prostaglandin Transporter Organic Anion-Transporting Polypeptide 2A1 Expressed in Human Gastroduodenal Mucosa

The human organic anion-transporting polypeptide 2A1 (OATP2A1) is a prostaglandin transporter expressed in several tissues and plays an important role for local distribution of prostaglandins, which contribute to the integrity of gastric mucosa. Blockade of prostaglandin pathways by cyclooxygenase (COX) inhibitors has been associated with serious side effects such as gastrointestinal ulceration and bleeding. However, little is known regarding OATP2A1 expression in the upper gastrointestinal tract and the potential impact of cyclooxygenase inhibitors on OATP2A1 function. We first investigated the expression of OATP2A1 mRNA and protein in human gastroduodenal mucosa using human biopsy specimens obtained from antrum, corpus, and duodenum. The results indicate that OATP2A1 is expressed in the neck region and deep pyloric glands of antrum and in parietal cells of gastric corpus. Second, we examined various COX inhibitors for their effects on OATP2A1 transporter activity. Using HEK293 cells expressing OATP2A1, we found that diclofenac and lumiracoxib are potent inhibitors of OATP2A1-mediated transport of prostaglandin (PG) E(2) with IC(50) values of 6.2 +/- 1.2 and 3.1 +/- 1.2 microM. In contrast, indomethacin, ketoprofen, and naproxen led to significant stimulation of OATP2A1-mediated PGE(2) transport by 162.7 +/- 13.9, 77.2 +/- 3.6, and 32.3 +/- 4.9%, respectively. Taken together, our results suggest that various clinically used COX inhibitors have differential impact on the function of the prostaglandin transporter OATP2A1 in human stomach and that these effects may contribute to differences in the gastrointestinal side effects of COX inhibitors.

Sesame lignan sesamol protects against aspirin-induced gastric mucosal damage in rats

Non-steroidal anti-inflammatory drugs are commonly used to control pain, fever, and various inflammatory diseases; however, they have been identified as gastro-toxic. The aim of the present study was to evaluate the effect of aspirin plus sesamol on gastric mucosa in rats. Rats were given oral aspirin (30 mg/kg/d) and oral sesamol (ranging from 0 to 30 mg/kg/day) for 5 weeks, after which their gastric mucosal integrity, oxidative stress, inflammation, and neutrophil infiltration were assessed 6 h after gastric surgery. Sesamol dose-dependently decreased aspirin-induced gastric haemorrhage and mucosal ulceration, and significantly reduced (a) gastric mucosal lipid peroxidation, (b) nitric oxide production, (c) gastric mucosal proinflammatory cytokines (tumor necrosis factor-α and interleukin 1-β levels), and (d) the activity of gastric mucosal myeloperoxidase compared with aspirin-alone groups. We hypothesize that aspirin plus sesamol decreases aspirin-induced gastro-toxicity by inhibiting neutrophil infiltration and subsequent gastric mucosal inflammation and oxidative stress in rats.