ISSN 1818-4952
© IDOSI Publications, 2014
DOI: 10.5829/idosi.wasj.2014.30.icmrp.48
Corresponding Author: Walaa Najm Abood, Department of Biomedical Science, Faculty of Medicine,
Involvement of Inflammatory Mediators in the Gastroprotective Action of Phaleria macrocarpa against Ethanol-Induced Gastric Ulcer
Walaa Najm Abood, Mahmood A. Abdulla and Salmah Ismail
1 1 2
Department of Biomedical Science, Faculty of Medicine,
1
University of Malaya, 50603 Kuala Lumpur, Malaysia
Institute of Biological Science, Faculty of Science, University of Malaya, 50603 Kuala Lumpur, Malaysia
2
Submitted: Jan 5, 2014; Accepted: Feb 24, 2014; Published:Mar 12, 2014
Abstract: This research aimed to determine the potential protective effects ofPhaleria macrocarpafruit extracton rat gastric mucosal injury induced by ethanol andto clarify the roles of prostaglandinE2 (PGE2), transforming growth factor- 1 (TGF- ) and tumor necrosis factor- TNF- ). Main methods: Seven groups of rats were orally pretreated with Tween20 as vehicle control group; Tween20 as ulcer group; 20 mg/kg of omeprazole as reference drug group; and100, 200,500 and 1000 mg/kg of extract as experimental groups. An hour later, ulcer was induced by oral administration of 95% ethanol, except in the vehicle control group.Results showed significant ulcer protective effects through reduction of ulcer area and increase of ulcer inhibition by significant elevation ofgastricpH and increase ofmucus production. In addition, significant increasein levels of inflammatory mediators PGE2 and TGF- 1 and decrease in TNF- were observed in the groups pretreated with P. macrocarpa compared with ulcer control group. In conclusion,our results suggested that P.
macrocarpapretreatment has protective effects against ethanol-induced gastric ulcers in rats by significantly stimulating inflammatory mediators PGE2, TGF- 1 and reducing TNF- which effect in the increase production of mucus and stomach pH to provide a protective environment against the offensive factors.
Key words: Gastroprotective PGE2 TGF- 1 Tinospora crispa TNF-
INTRODUCTION Numerous medications can be used to treat gastric Gastric ulcer is one of the most widespread famotidine function as medications of gastric ulcer by diseases in the world. Gastric ulcersare localized inhibiting the secretion of gastric acid. However, despite breaches of the gastric mucosa, with tissue 80% to 100% rate of healingthrough 4 to 8 weeks when destruction at least to the depth of the muscularis proton pump inhibitors and H2-antagonists are used, the mucosa [1]. Gastric ulcer accounts for the highest ulcer returns at a rate of 40% to 80%when therapy is percentage of affliction among diseases worldwide due stopped [4]. In addition, most of these medications have to rising levels of stress experienced by humans, side effects with long-term use. Therefore, new alcohol consumption, long-term anti-inflammatory therapeutic anti-ulcer agents that are more efficient and drug intake (such as aspirin and indomethacin) safe are necessary. In this framework, studies on the use thatlead to gastric ulcer and nutritional deficiencies [2]. of medicinal plants in preventing and treating diverse The disruptions between endogenous offensive factors pathologies are underway[5]. Natural products are (such as pepsin, hydrochloric acid, refluxed bile, important in pharmaceutical manufacturing; they are also reactive oxygen speciesand leukotrienes) and possible sources of bioactive molecules. Numerous plants endogenous defensive factors (such as bicarbonate and their derivatives, such as flavonoids, alkaloids and mucus barrier, mucosal blood flow,prostaglandins, cell phenolic acids,have large potential for treatingvarious proliferation and enzymatic and non-enzymatic diseases, including gastric ulcer. A large number of antioxidants)are important physio-pathological medicinal plants with gastroprotective potential have characteristics of gastric ulcer [3]. been reported in the literature [6-9].
ulcer. H2-antagonists omeprazole, ranitidine and
Phaleria macrocarpa isa traditional plant used in the Animal Ethics Committee; with an ethic No. (PM 1 treatment of inflammation, cancer, diabetes and November 2011/1111/ MAA (R). Throughout the hypercholesterolemia. P. macrocarpa fruits extract experiments, all criteria of taking care of animals prepared possesses anti-hyperglycemic properties; it stimulates by the National Academy of Sciences and outlined in the insulin release through modulation of B cell[10]. The “guide for the care and use of laboratory animals” are isolated compound from P. macrocarpa isused as an applied[16].The animals were randomly divided into six anticancer medicine[11, 12]. P. macrocarpa ethanol extract groups (six rats/group). The water was removed 1 h before has anti-inflammatory and antioxidant activities[13, 14]. the experiment. For the first group (ulcer control group), However, no data has been reported on the anti-ulcer the rats wereadministered vehicle Tween 20(5% v/v) activities of this plant. Therefore, the current study was (5ml/kg).For the second group (reference drug group), the conducted to assess the gastroprotective effects of rats were pretreated with 20 mg/kg omeprazole solution ethanol extracts of P. macrocarpa against ethanol- (5ml/kg). For others groups, the rats were pretreated with induced gastric ulcers in rats and involvement of 100, 200, 500 and 1000 mg/kg P. macrocarpa fruits inflammatory mediators (PGE2, TGF- 1and TNF- ) in the extracts respectively. After 1 h, all rats received 5ml/kg gastroprotective effect. 95% ethanol orally to induce gastric ulcer. After 1 h, the MATERIALS AND METHODS was removed and opened over the greater curvature[17].
Materials: The ripe dried seedless P. macrocarpa fruits Measurement of Ulcer Index: The ulcers were located in were harvested at the Selangor housing area in the the gastric mucosa and appeared as hemorrhagic Herbarium of University Putra in Malaysia, as voucher extended bands of lesions parallel to the long axis of the specimens (SK1929/11).. Tween 20(Sigma-Aldrich, stomach. The gastric mucosa ulcer was calculated by Germany), omeprazole (TROGE Medical GMBH, measuring the sum of all lesion areas for each stomach, Germany),ethanol (Fisher Scientific, UK), xylazine and which was used in the calculation of the ulcer area (UA) ketamine (Ilium, Australia), Alcian blue (ACROS, USA), equal to the sum of small squares × 4 × 1.8 = UA mm . The D(+) sucrose (Fisher Scientific, UK), sodium acetate and ulcer inhibition percentage (UI %) was calculated by[18]
magnesium chloride (Sigma-Aldrich, Germany), ethyl ether
(Anala R, England) and PBS(DulbeccoA, Oxoid, England) (UI %) = [(UA control-UA treated) ÷ UA control] × 100%.
were also used.
Plant Extraction: Dried fruits ofP. macrocarpa were opened, gastric juice was collected and measured for crushed. The powder (100 g) was soaked in 900 ml of 95% acidity by using a digital pH meter [19].
ethanol in a conical flask for 3 days at room temperature
(30±2°C). The suspension was shaken from time to time to Determining Gastric Wall Mucus Content: The gastric enable the fruits powder to completely dissolve in the mucus contents were determined according to assay ethanol and to changecolor to dark brown. After 3 days, procedures previously described [7]. Adult Sprague- the mixture was filtered using a filter paper (Whitman, Dawleyrats weighing between 200 g to 250g were fasted 185mm) and distilled under reduced pressure in a rotary for 24 h. The animals were randomly divided into three evaporator (Buchi, Switzerland). The productwas kept groups (six rats/group). The water was removed 1 h before at-20°C until use[15]. the experiment. For the first group (vehicle control group), Induction of Gastric Ulcer by Ethanol: Adult healthy SD For the second group (reference drug group), the rats rats weighing 200-250 gare obtained from Animal House were treated with 20 mg/kg omeprazole solution (5ml/kg).
Unit, Faculty of Medicine, University of Malaya, For the third group, the rats were treated with 250 mg/kg Malaysia. They are kept in wire bottomed cages at 25 ± P. macrocarpa fruits extract. After 1 h treatment, all the 3°C temperature, 50-60 % humidity and a 12 h light-dark rats received 5ml/kg of 95% ethanol orally to induce cycle for at least a week before the experiment. They were gastric ulcer. After 1 h, all the rats were sacrificed by maintained at standard housing conditions and free euthanasia and their stomachs were removed. Each access to standard diet and water ad libitum during the glandular part was weighed and submerged into 1%
experiment. The experimental protocol is approved by Alcian blue solution (0.16 M sucrose/0.05 M sodium rats were sacrificed, blood was collected and the stomach
2
Measurement of Gastric Juice pH: After the stomach was
the rats were given vehicle Tween 20(5% v/v) (5ml/kg).
acetate, pH 5.8). After 2 h of immersion, the excess stain was rinsed with 10 ml sucrose at 0.25 M for twoconsecutive washes: the first time for 15 min and the second for 45 min. Then, the stomachs were transmitted to the tubes containing10ml magnesium chloride at 0.5 M for 30 min. After 30 min, 4 ml of the mixture was mixed with 4 ml of ethyl ether and then shaken for 2 min. The final emulsion was centrifuged for 10 min at 3000 rpm and then the supernatant was discarded. The absorbance was read at 598 nm. The quantity of Alcian blue extracted per gram of glandular tissue was calculated.
Tissue Homogenate Sample Preparations for Assessment of PGE2: To assess PGE2 (Cayman PGE2 assay ELISA kit; Cat# 400141) in gastric tissue homogenate, the gastric tissue was weighed, minced and homogenized on ice in 5 ml cold PBS buffer using a Teflon homogenizer (Polytron, Heidolph RZR 1, Germany).After each tissue stomach piece was fully homogenized, the mixture was centrifuged at 10.000xg for 15min at 4°C.Then, the supernatant was collected in a sterile tube and kept at- 80 °C until use.The assay was performed as per the detailed instructions of the manufacturer.The sensitivity limit of these assays was =15.6 pg for PGE2.
Preparations of Blood Sample for Assessment of Serum TGF- 1 and TNF- : After the rat blood samples were collected in tubes, they were allowed to clot for 30 min at 25 °C. Then, they were centrifuged at 2000xg for15min at 4 °C using a refrigerated centrifuge Rotofix 32 (Hettich Zentrifugen, Germany). The serum was collected and preserved at (-80 °C) until use. TGF- 1 was measured by ELISA kit (Abnova, Cat#. KA0279, version 4) and rat TNF- by ELISA kit (Thermo Scientific, Cat#.ER3TNFA).
The assays were performed as per the detailed instructions of the manufacturer. The sensitivity limit of these assays was 7.8 pg/ml for TGF- 1 and <15pg/ml for TNF- .
Statistical Analysis: The values were presented as mean
±standard division. Statistical examination of data was through one-way analysis of variance (ANOVA)and post hoc LSD test (comparing the treated groups with the control). P 0.05was considered statistically significant compared with the control.
RESULT
Gastric Lesions: The gastroprotective effect and the enhancement of the mechanism defense of gastric ulcer byP. macrocarpa were investigated through the
Table 1: Ulcer area, ulcer inhibition percentage and stomach pH in the pretreated groups withP. macrocarpa (P.m) and omeprazole compared with ulcer control group
Group Ulcer area (mm2) Inhibition% Stomach pH
Ulcer control 532.8±119.2 0 2.6±0.7
Omeprazole 25.2±61.7 95.3 7.5±0.5
P.m 100mg/kg 67±37.8 87.4 6.1±2.1
P.m 200mg/kg 58.3±32.9 89.1 6.4±1.1
P.m 500mg/kg 40.8±59.3 92.3 6.7±0.6
P.m1000mg/kg 23±46.1 95.7 7.0±1.1
Data was expressed as mean ± SD, *significant at P=0.000.
induction of gastric ulcer in rats by using ethanol as necrotizing agent. This scheme resulted in mucosal injury characterized by submucosal edema, increased secretory products of the cell and disturbances in microcirculation.
Pretreatment with ethanol extract of P. macrocarpa fruits at doses of 100, 200, 500 and 1000 mg/kg or omeprazole at 20mg/kg inhibited the formation of gastric ulcer lesions in the rats. The intensity of ulcer was detected by the statistically significant ulcer area in the pretreated groups (P. macrocarpa or omeprazole) (P=0.000), which was lower than that of the ulcer control group. The ulcer inhibition percentage result reflected that results of pretreatment with all doses of theP. macrocarpa fruits were statistically and significantly (P=0.000) higher than those of the ulcer control group (Table1).
Gastric pH: The gastric pH in the experimental groups pretreated with P. macrocarpa fruits or omeprazole increased more significantly compared with that in the ulcer control group (P 0.05;Table1).
Mucus Barrier of the Protective Stomach: The results of the mucus barrier contents presented in Figure 1 show statistically significant (P=0.000) higher mucus contents in the groups pretreated with P. macrocarpa extracts compared with those in the ulcer control group.
Evaluation of PGE2: In the groups pretreated with P. macrocarpa and omeprazole, the result showedsignificant (P<0.05) increase in the level of PGE2 in the groups pretreated with P. macrocarpaor omeprazole compared with the ulcer control group (Figure 2).
Estimation of TGF- 1 and TNF- : The results showed that the level of TGF- 1 significantly increased (P<0.03) in the groups pretreated with P. macrocarpa extractsat 200, 500 and 1000 mg/kg doses, as well asin
Fig. 1: Mucus content in the pretreated groups with Fig. 3: TGF- 1level in the pretreated groups withP.
P. macrocarpa(P.m) and omeprazole (reference macrocarpa (P.m) and omeprazole (reference drug) compared with ulcer control group. drug) compared with ulcer control group. Data Data was expressed as mean ± SD, +significant at was expressed as mean ± SD, +significant at P
P=0.000. <0.03.
Fig. 2: PGE2 level in the pretreated groups with Fig. 4: TNF- level in the pretreated groups P. macrocarpa (P.m) and omeprazole (reference withP.macrocarpa (P.m) and omeprazole drug) compared with ulcer control group. (reference drug) compared with ulcer control Data was expressed as mean ± SD, +significant at group. Data was expressed as mean ± SD,
P<0.05. +significant at P <0.01.
the omeprazolegroup (Figure 3). By contrast, the level of combined with vigorous and rapid arteriolar dilation TNF- significantly decrease(P 0.01) in all doses in the induces damage in mucosal capillaries [20, 21]. A previous groups pretreated with P. macrocarpa or omeprazole study reported that ethanol stimulatesthe formation of group compared with the ulcer control group (Figure 4). leukotriene C4(LTC4)[22], mast cell secretory products DISCUSSION gastric mucosa[23]. The necrotic lesion of the gastric This study showed that the ethanol extract ofP. factors. It causes disruption of the mucus-bicarbonate macrocarpa has gastroprotective activity as manifested barrier upon reaching the mucosa, as well as cell rupture by its significant inhibition of the formation of ulcers in the wall of blood vessels. These effects are possibly induced by ethanol. The injury of ethanol-induced ulcers caused by biological actions, namely, formation of free is dominant in the glandular part of the stomach. radicals, lipid peroxidation, intracellular oxidative stress Administration of absolute ethanol orally in rats has and permeability and depolarization of the mitochondrial deleterious effects on the stomach, affecting the gastric membrane before cell death [24].
mucosa topically by disabling its barrier and Gastric ulcer defined as the damage resulting from the causing microvascular changes a few minutes after its disturbance in the gastric mucosal defense, which means application. A strong and rapid vasoconstriction that ulcer is caused by the imbalance between offensive and reactive oxygen species, resulting in damage of rat mucosa caused by ethanol occurs through multiple
and protective factors of the gastric mucosa. Pepsin and PGE2 concentration in ulcerative regions compared with gastric acid are aggressive factors whose proteolytic other parts of the gastric mucosa because PGE2causes effect is buffered by mucosal glycoprotein,mucin vasodilatation. The supply of blood reveals the active re- secretion, prostaglandins and cell proliferation [25].P. epithelization, which requires an abundant supplyof macrocarpa fruits extracts decrease ulcer area and oxygen and glucose[29].Therefore, increasing the increase ulcer inhibition percentage by increasing the production of PGE2 gained in the treatment withP.
production of mucin from mucous cells to form the first macrocarpa fruits extract clearlyindicated the excitement line of defense in protecting the mucosal epithelial layer of cytoprotective factors that accelerate healing of gastric from the ulcerogenic action of ethanol. Mucus is an ulcer.
important factor that protects the gastric mucosa. Mucus One of the important findings in this study was that is a transparent gel composed of water and glycoproteins the level of pro-inflammatory factor TNF- significantly that coats the gastrointestinal mucosa and preserves the decreased in the groups pretreated with P. macrocarpa gastric mucosa against agents such as ethanol and fruits extract, which increased the level of anti- Hcl [26]. Moreover, the anti-secretory activity of the inflammatory cytokine TGF- 1 . These results indicated P. macrocarpa fruits extract may be important in gastric that the immunomodulatory effect of P. macrocarpa mucosa protection. The gastroprotective effect has been might be effectedthrough the inflammatory mediator.
proven by histological examination. This protection Gastrointestinal mucosa integrity depends on the balance results from the inhibition of gastric acid secretion and between defensive and offensive factors. Many of the increased stomach pH by the extracts. The obtained data components of mucosal defense have proven to be revealed that the stomach pH increasedin the treatment influenced by inflammatory mediators, such as groups compared with the ulcer control group. Thus,the prostaglandins, leukotrienes and thromboxanes [30].
mechanism of mucosa protection is due to the anti- Prostaglandins can also have anti-inflammatory effects secretory activity of P. macrocarpa fruits and the through inhibition of leukocyte recruitment, which can enhanced production of mucin. contribute to their beneficial effects during situations The findings in this study also showed that such as inflamed gastrointestinal mucosa[31]. TNF- is a pretreatment with P. macrocarpa fruits extract induced a key mediator of intestinal injury caused by endotoxins.
remarkable decrease in the level of serums gastrinand One of the mechanisms through which TNF- can pepsin and causedan increase in PGE2 level compared develop inflammatory responses and tissue injury is via with the ulcer control group, indicating the mechanism of its regulation of the expression of receptors for other P. macrocarpa fruits in more than one anti-ulcer inflammatory mediators, including leukotriene B4 and mechanism. Gastric secretion decreased after P. platelet-activating factor [32].
macrocarpa fruits extract pretreatment. The foregoing Prostaglandins are powerful inhibitors of TNF- may be a negative feedback mechanism that is, increase in released from both the macrophage [33] and the mast cell mucus and PGE2 caused a reduction in gastrin and pepsin [30], which may cause elevation of PGE2 level during release in rats treated with P. macrocarpa fruits extract. pretreatment with P. macrocarpa .In turn, they are The protective mechanism depends on mucus and caused by the inhibition of the production of TNF- . bicarbonate secretion and to a large degree, PGE2 Another immunomodulatory effect of P. macrocarpa is secretion; the activity of the cyclooxygenase enzyme also incitingthe production of TGF- 1, an important cytokine has an important role in this function [27]. Our results that accelerates gastric ulcer healing.The healing of proved that pretreatment of rats withP. macrocarpa gastric ulcer is a complex process controlled by numerous fruits extract inducedincreased PGE2 levels compared factors, hormones and cytokines. TGF- 1 is one of the with rats in the ulcer control group. These results give a multifunctional peptide growth factors thatexhibit clear indication of the involvement of PGE2 in the positive, regulatory healing of gastric ulcer by inducing gastroprotective mechanism of P. macrocarpa fruits cell migration and angiogenesis and improving extract. In the stomach, prostaglandins cause elevation extracellular matrix production. TGF- 1 exerts its action by the mucus and bicarbonate secretions, keeping the normal binding to its transmembrane serine/threonine kinase response of the gastric environment to intrinsic factors receptor, which in turn triggers activation of various and inhibiting inflammatory mediator release from mast intracellular signaling pathways [34]. A previous study cells and free radical production. A previous study has reported that the immunoreactive effect of TGF- 1 [28]examined the increase in blood flow in the ulcer region protein is focuses on epithelial cells and thus, the and suggested thatit may be caused by higher increase in proliferation of gastric glands [35].
In conclusion, our results indicate that 11. Rahmawati, E., H.R. Dewoto and P. Wuyung, P. macrocarpa pretreatment has protective effects in
ethanol-induced gastric ulcers in rats. Moreover, these results provide evidence that these protective effects of P. macrocarpa are carried out by stimulation of some inflammatory mediators,such as PGE2, TGF- 1and TNF- . Moreover, important increase in the mucus production and elevated stomach pH can prevent gastric injury.
ACKNOWLEDGMENT
This research was supported by the University of Malaya Grant (PV046/2012A).
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