|Year : 2014 | Volume
| Issue : 2 | Page : 103-108
Gastroprotective activity of reconstituted red fruit pulp concentrate of Citrullus lanatus in rats
Swapnil Sharma1, Vivek Dave1, Sarvesh Paliwal1, Jaya Dwivedi2, Sonika Jain2
1 Department of Pharmacy, Banasthali University, Banasthali, Tonk, Rajasthan, India
2 Department of Chemistry, Banasthali University, Banasthali, Tonk, Rajasthan, India
|Date of Web Publication||18-Mar-2015|
Department of Pharmacy, Banasthali Vidyapeeth, Banasthali-304022, Rajasthan
Source of Support: None, Conflict of Interest: None
Aim: This study was carried out to evaluate the gastroprotective potential of the aqueous fruit pulp concentrate of Citrullus lanatus citroides (CLC) on pyloric ligation and indomethacin-induced ulcer in Wistar albino rats.
Materials and methods: In indomethacin-induced ulcer model, CLC was administered in the doses of 250 mg/kg, 500 mg/kg and 1000 mg/kg body weight orally, tds for 5 days. The antiulcer activity was determined via observing reduction in ulcer index whereas in the pyloric ligation model, the gastroprotective effect of CLC was assessed from the alteration in volume of gastric juice, pH, free and total acidity, protein concentration in gastric juice. Further lipid peroxide (LPO), and activities of enzymic antioxidants such as superoxide dismutase (SOD) and catalase (CAT) was also determined along with the levels of hexose, hexosamine, sialic acid, fucose in gastric mucosa.
Results: In both models, treatment with CLC caused a significant reduction in lesion index when compared to vehicle treated group, providing evidence for antiulcer capacity. In pyloric ligation model, pretreatment with CLC resulted in significant increase in pH, enzymic antioxidants, that is, SOD, CAT, with a significant decrease in volume of gastric juice, free and total acidity, protein concentration, acid output, and LPO levels respectively. The presence of the flavonoids and polyphenols may be responsible for the gastroprotective effect of CLC.
Conclusions: The aqueous fruit pulp concentrate of CLC showed significant gastroprotective potential against pyloric ligation and indomethacin-induced ulceration in rats.
Keywords: Citrullus lanatus, gastroprotective, indomethacin-induced ulcer, pyloric ligation
|How to cite this article:|
Sharma S, Dave V, Paliwal S, Dwivedi J, Jain S. Gastroprotective activity of reconstituted red fruit pulp concentrate of Citrullus lanatus in rats. Ancient Sci Life 2014;34:103-8
| Introduction|| |
Repeated use of nonsteroidal anti-inflammatory drugs (NSAIDs), consumption of cigarettes and alcohol, trauma, sepsis, shock, infection with Helicobacter pylori and stress contribute to gastric ulcer formation. , Ulcers are associated with the imbalance between the protective factors (mucus and bicarbonate) and aggressive factors (acid and pepsin) in the stomach. , The management of ulcers with synthetic drugs remains a major clinical problem because of adverse reactions. Herbal medicines are rapidly emerging as alternatives to synthetic drugs in the treatment of ulcer possibly due to lower costs, easy availability, fewer adverse effects, and perceived effectiveness. For many years, excess acid, free radicals and low prostaglandin levels were believed to be the major cause of ulcer disease.  Accordingly, treatment of ulcers should emphasize on neutralizing and inhibiting the secretion of stomach acid and cytoprotection.
Citrullus lanatus citroides (CLC), commonly known as watermelon, belonging to the family Cucurbitaceae is native to India. It is found in forest lands, riversides, and wasteland, and also gets cultivated on a large scale. It is an excellent source of the arginine, Vitamin A, B and C, carotenoids, lycopenes, carbohydrates, sodium, magnesium, potassium, and water.  The main constituents present in the fruit are especially from its rind, which is rich in alkaloids, flavonoids, polyphenols, glycosides, steroids and tannins.  In Ayurveda, the plant is considered beneficial as diuretic, vermifuge, demulcent, and said to be helpful in hepatic congestion and intestinal catarrh. Traditionally C. lanatus is in used as energy source and to manage high blood pressure, erectile dysfunction, enlarged liver and jaundice.  Although folklore use suggests that it has antacid activity, exhaustive literature survey revealed that the potential of C. lanatus fruit in gastro-intestinal tract ailments has not been exploited. Moreover, reactive oxygen species (ROS) have been implicated in the etiology of HCl/ethanol- and indomethacin gastric mucosal damage.  An effort is therefore made to evaluate scientifically the gastroprotective, that is, cytoprotective as well as anti-secretory potential of C. lanatus in gastric ulcers induced in rats.
| Materials and Methods|| |
Fresh CLC (watermelon) was purchased from the local market of Jaipur (Rajasthan, India). Botanical authentification was carried out at the Department of Botany, University of Rajasthan (voucher specimen number RUBL20685). Fresh fruit pulp was homogenized and dried under shade. 0.5% of sodium benzoate was added to avoid decay during complete drying. A dark brownish red powder mass obtained after drying, was powdered using grinder (yield - 24%). The dried C. lanatus fruit pulp was reconstituted in water termed as CLC and this concentrate so obtained was subjected to qualitative phytochemical analysis and assessment of pharmacological activity.
Healthy Wistar rats of either sex weighing between 180 and 250 g were used in this study. Animals were maintained at 25 ± 2°C and kept in well ventilated animal house under natural photoperiodic condition in polypropylene cages with paddy husk as bedding with free access to food and water ad libitum. The experimental protocol described in the present study was approved by Institutional Animal Ethical Committee of Pinnacle Biomedical Research Institute, Bhopal (Register Number 1283/C/09/CPCSEA).
C. lanatus citroides was administered in the doses of 250, 500, and 1000 mg/kg body weight orally for 5 days thrice daily before ulcer induction. Ranitidine (50 mg/kg) was used as the standard drug, in both the ulcer models. The doses were administered orally to different experimental groups thrice daily at 8 h and 14 h, 22 h respectively, for 5 days for gastric cytoprotective studies. Vehicle treated group received suspension of 1% CMC in distilled water.
Indomethacin-induced ulcer model
The albino rats of either sex weighing between 180 and 200 g were divided into six groups of six animals each and fasted for 24 h with water ad libitum prior to experiment. The animals of group I were treated with vehicle (1% CMC in distill water) thrice a day, for 5 days and the animals of groups II, III, IV, V and VI were treated with indomethacin sodium (30 mg/kg p. o.) once, on day 1. Animals of group III were treated with ranitidine 50 mg/kg thrice a day in water, for 5 days before the induction of ulcer. Similarly the animals of groups IV, V and VI were treated with CLC at the doses of 250, 500, and 1000 mg/kg for 5 days respectively before the induction of ulcer. Indomethacin (30 mg/kg p.o.) was administered to the animals of groups II-VI on day 6. On 6 th day, the animals were sacrificed by cervical dislocation after 12 h of the last dose. The stomach was taken out and cut open along the greater curvature of the stomach. The number of ulcers per stomach was noted, and severity of the ulcers was observed microscopically and scoring was done as described by Hollander et al. 
Pylorus ligation-induced ulcers
Drugs were administered for a period of 5 days as described above. On day 6 after the last dose, the rats were kept for 12 h fasting, and care was taken to avoid caprophagy. Pylorus ligation was done according the method described by Sanyal et al.  The animals were deprived of water during the postoperative period. After 4 h, stomachs were dissected out, and contents were collected in tubes for estimation of physical and biochemical parameters.
Physical parameters-cytoprotection studies
In both models ulcer, healing was observed via measurement of the severity of the lesion. The following arbitrary scoring
system was used to grade the incidence and severity of
lesion: 0 = Normal, 1 = Red coloration, 2 = Spot ulcers, 3 = Hemorrhagic streaks, 4 = Ulcers >3 but <5 and
5 = Ulcers >5
The mean ulcer index (UI) was calculated using following formula:
UI = UN + US + UP × 10−1
Where, UN = Average of number of ulcer per animal, US = Average of severity score, UP = Percentage of animals with ulcers. The UI was scored for both the models following the method of Hollander et al. 
Biochemical parameters in pyloric ligation-induced ulcer model
Collection of gastric juice
After postoperative period, animals were sacrificed by cervical dislocation and the stomach was dissected out as a whole by passing a ligature at the esophageal end. Gastric content was evacuated into a graduated tube by cutting along the greater curvature of the stomach, and it was centrifuged at 3000 rev/min for 10 min. The volume of the centrifuged sample was expressed as ml/100 g body weight. The pH of gastric juice was measured with the help of pH meter.
Determination of total acidity
Gastric juice (1 ml) was pipetted into a 100 ml conical flask and diluted with 9 ml distilled water. Two to three drops of Toepfer's reagent were added and titrated with 0.01N sodium hydroxide until the color of the solution was yellowish-orange. The volume of alkali added was noted. This volume corresponds to free acidity. Two or three drops of phenolphthalein were then added, and the titration was continued until a definite red tinge appeared; the volume of alkali added was noted. The volume corresponded to total acidity. Acidity was expressed in terms of mEq/L. 
Estimation of total proteins
The dissolved protein in gastric juice was estimated in the alcoholic precipitate obtained by adding 90% alcohol with gastric juice in the ratio 9:1. 0.1 ml of alcoholic precipitate of gastric juice was then dissolved in 1 ml of 0.1N NaOH and from this, 0.05 ml was taken in another test tube. To this 4 ml of alkaline mixture was added and kept for 10 min. Then 0.4 ml of phenol reagent was added and again allowed for 10 min for color development. Absorbance was measured against a blank prepared with distilled water at 610 nm using a spectrophotometer. The protein content was calculated in terms of μg/ml of gastric juice. 
Estimation of total carbohydrates
The dissolved mucosubstances in gastric juice were estimated in the alcoholic precipitate obtained by adding 1 ml of gastric juice to 9 ml of 90% alcohol, the mixture was kept for 10 min, and the supernatant was discarded. The precipitate separated was dissolved in 0.5 ml of 0.1N sodium hydroxide. To this 1.8 ml of 6N, HCl was added. This mixture was hydrolyzed in a boiling water bath for 2 h. The hydrolysate was neutralized using 5N sodium hydroxide with phenolphthalin as indicator and the volume was made up to 4.5 ml with distilled water and used for the estimation of total hexoses, hexosamine and fucose as described below. 
Estimation of total hexoses
To 0.4 ml of hydrolysate, 3.4 ml of orcinol reagent was added. The mixture was then heated in a boiling water bath for 15 min and intensity of the color was read in a spectrophotometer at 540 nm against the blank. Total hexoses content was determined from the standard curve of D (+)-galactose-mannose and has been expressed in μg/ml of gastric juice. 
Estimation of hexosamine
A volume of 0.5 ml of the hydrolysate fraction was taken. To this 0.5 ml of acetylacetone, reagent was added. The mixture was heated in boiling water bath for 20 min and 1.5 ml of 90% alcohol was then added, followed by an addition of 0.5 ml of Ehrlich's reagent. The reaction was allowed for 30 min. The color intensity was measured in spectrophotometers at 530 nm against the blank prepared by using distilled water instead of hydrolysate. Hexosamine content of the sample was determined from the standard curve of D (+)-galactose-mannose and concentration has been expressed in μg/ml of gastric juice. 
Estimation of fucose
In this method, three test tubes were taken. In one tube, 0.4 ml of distilled water was taken to serve as a control and in each of the other two tubes 0.4 ml of hydrolysate was taken. To all three tubes 1.8 ml of sulfuric acid and water in the ratio of 6:1 was added by keeping the tubes in ice cold water bath to prevent breakage due to strong exothermic reaction. This mixture was then heated in boiling water bath for exactly 30 min. The tubes were then taken out and cooled. In the blank and one of the hydrolysate containing tubes (unknown) 0.1 ml of cysteine reagent was added, while cysteine reagent was added to the last test tube containing the hydrolysate (unknown), it was kept aside for 90 min. The absorbance was measured at 396 and 430 nm using a spectrophotometer. The optical density for the fucose in the hydrolysate was calculated from the differences in the reading obtained at 396 and 430 nm and subtracting the values without cysteine. This was read against the standard curve prepared with D (+)-fucose. The fucose content was expressed as μg/ml of gastric juice. 
Estimation of sialic acid
To 0.5 ml of the hydrolysate in 0.1N sulfuric acid, 0.2 ml of sodium periodate was added and mixed thoroughly by shaking. A time of 20 min was allowed to elapse before addition of 1 ml of sodium arsinate solution mixture. The brown color which developed disappeared after shaking. Then 3 ml of thiobarbituric acid (TBA) was added and while shaking 4.5 ml of cyclohexanone was added, till the entire color was taken up by the cyclohexanone supernatant. The resulting mixture was centrifuged to get a clear pink layer of cyclohexanone. The supernatant was pipetted out and intensity of color was measured using a spectrophotometer at 550 nm. The sialic content of the sample was determined from the standard curve of sialic acid and was expressed in μg/ml of gastric juice. 
Estimation of free radical generation
The fundic part of the stomach was homogenized (5%) in ice cold 0.9% saline with a glass homogenizer for 30 s. The homogenate was then centrifuged at 800 g for 10 min followed by centrifugation of the supernatant at 12,000 rpm for 15 min and the obtained fraction was used for the following estimations. 
Lipid peroxide (LPO) product malondialdehyde was estimated using 1, 1, 3, 3-tetraethoxypropane as the standard and is expressed as nmol/mg protein. The glandular portion of the gastric mucosa was homogenized with cold 0.15 M Tris-HCl (pH 7.4) to give a 10% (w/v) homogenate. After 10 min, 0.2 ml of tissue homogenate, 0.2 ml of 8.1% sodium dodecyl sulfate, 1.5 ml of 20% acetic acid and 1.5 ml of 8% TBA were added. The volume of the mixture was made up to 4 ml with distilled water and then heated at 95°C on a water bath for 60 min using glass balls as condenser. After incubation, the tubes were cooled to room temperature, and final volume was made to 5 ml in each tube. 5.0 ml of butanol and pyridine (15:1) mixture was added and the contents were vortexed thoroughly for 2 min. After centrifugation at 3000 rpm for 10 min, the upper organic layer was taken and its OD read at 532 nm against the blank. 
Superoxide dismutase activity
Superoxide dismutase (SOD) was estimated by following the method of  the inhibition of reduction of nitrobluetetrazolium to blue colored Formosan in the presence of phenazine methylsulfate and NADH was measured at 560 nm using n-butanol as blank. One unit of enzyme activity was defined as the amount of enzyme that inhibits rate of reaction by 50% in 1 min under the defined assay conditions and the results were expressed as units (U) of SOD activity/mg protein.
A volume of 100 μl of supernatant was added to cuvette containing 1.9 ml of 50 mM phosphate buffer (pH 7.0). Reaction was started by the addition of 1.0 ml of freshly prepared 30 mM H 2 O 2 . Decrease in absorbance was read at 240 nm for 3 min at intervals of 30 s. The activity was calculated using extinction coefficient of H 2 O 2 0.041 μmol/cm 2 . Results were expressed as micromole of H 2 O 2 utilized/min/g tissue. The rate of decomposition of H 2 O 2 was measured spectrophotometrically from changes in absorbance at 240 nm. 
Results were expressed as the mean ± standard error of mean. Statistical significance was determined by one-way analysis of variance, followed by Dunnett's test, with the level of significance set at P < 0.05.
Phytochemical analysis of the CLC was done following standard methods of Trease and Evans and Kokate et al. ,
| Results and Discussion|| |
The CLC revealed the presence of alkaloids, flavonoids, polyphenols, glycosides, steroids and tannins.
C. lanatus 250-1000 mg/kg, given orally, thrice daily for 5 days showed dose-dependent cytoprotective effect against gastric ulcers induced by indomethacin and pyloric ligation [Table 1] and [Table 2]. In indomethacin-induced ulcer model, it was observed that the treatment with CLC (250, 500 and 1000 mg/kg) and ranitidine (50 mg/kg) significantly reduced the lesion index, and provided cytoprotection as compared to the indomethacin treated group (P < 0.05). The percentages of protection against ulcer were 23.03, 40.07 and 74.72 for the treated groups with 250, 500 and 1000 mg/kg of CLC and positive control (ranitidine) whereas in pyloric ligation 21.26, 44.82 and 79.56, respectively. CLC 250 mg/kg, tds, administered orally showed a weak protection against ulcer in both models [Table 1] and [Table 2].
|Table 1: Effect of dried fruit pulp of CLC on indomethacin-induced gastric ulcers in rats |
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|Table 2: Effect of dried fruit pulp CLC on pyloric ligation-induced gastric ulcers in rats |
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In pyloric ligated rats, there was an increase in gastric volume, free and total acidity in comparison to the positive control group. CLC showed reduction in all the three parameters along with the rise in pH in the same group as well. However only the highest dose 1000 mg/kg caused a significant reduction in above parameter, which was comparable to standard drug ranitidine [Table 2] and [Table 3].
|Table 3: Effect of pretreatment of dried fruit pulp of CLC on pH, gastric volume, free acidity and total acidity in pyloric ligated rat |
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Anti-secretory potential of CLC is clearly observed in pyloric ligation model. The volume of gastric fluid was reduced remarkably with CLC at the doses of 500 mg/kg and 1000 mg/kg when compared to vehicle treated group [Table 3]. Pyloric ligation results in increased lipid peroxidation in the gastric mucosa with decrease in catalase (CAT) and SOD level. The CLC in both doses of 500 and 1000 mg/kg significantly protected the animals against pyloric ligation free radical damage as seen from the decrease in LPO and reversal of changes induced by stress on SOD and CAT [Table 4]. Further, CLC in both doses of 500 and 1000 mg/kg led to significant increase in individual carbohydrates like total hexoses, fucose and sialic acid leading to increase in total carbohydrates in the gastric juice as well [Table 5].
|Table 4: Effect of pretreatment of dried fruit pulp of CLC on LPO, SOD and CAT level in pyloric ligated rat |
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|Table 5: Effect of pretreatment of dried fruit pulp of CLC on protein and carbohydrate level in pyloric ligated rat |
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The anti-ulcer activity of the aqueous of C. lanatus against pyloric ligation and indomethacin-induced ulcers was established in this study. The concentrate protected the stomach against indomethacin necrotic damage. Pyloric ligation induces gastric injury due to production of oxygen free radicals leading to increased lipid peroxidation, which causes damage to cell and cell membrane presenting as red streaks of sores.  The protection by the concentrate of this type may suggest a possible cytoprotective mechanism of action. However, an anti-secretory effect might be indicated as the concentrate protected the stomach mucosa from indomethacin (NSAID) and pyloric ligation-induced damage. This damage is the result of inhibition of prostaglandin synthesis, which is essential for mucosal integrity and regeneration.  This results in a sustained reduction in mucosal blood flow and a subsequent generation of ulcer. Ranitidine was employed in this study for its cytoprotective and anti-secretory effect and its effectiveness against indomethacin-induced ulcers. Ranitidine exhibits an anti-secretory effect against ulcers and other agents providing ulcer healing against NSAID induced ulcers may have a similar effect. Oxidative damage is considered to be a common factor in the pathogenesis of ulcers by different experimental and clinical models. Stress induced ulcers are due to increase in free radical generation apart from acid pepsin factors.  Stress significantly induced lipid peroxidation as seen from an increase in LPO levels. This is due to increase in the generation of ROS during stress leading to oxidative damage. Normally the increase in damage due to O2− is contained by dismutation with SOD.  The SOD converts the reactive O 2 to H 2 O 2 , which if not scavenged by the CAT can by itself cause lipid peroxidation by increase in the generation of hydroxyl radicals. Hence, decrease in CAT levels has led to increase in accumulation of these reactive products. Treatment with CLC reversed these oxidative changes induced by stress. The antioxidant activity of the plant has been observed earlier.  As the drug treatment significantly reduced the protein concentration and increased the total carbohydrate content, it may be suggested that the CLC drug concentrate may act by strengthening the mucosal barrier of the gastric mucosa. The concentrate effectively inhibited gastric hemorrhagic lesions induced by pyloric ligation and indomethacin, and with effective doses of 500 and 1000 mg/kg.
Ulcer protection may be attributed to any of the phytochemical constituents of C. lanatus viz., flavonoids, tannins cucurbitacin, triterpenes, sterols and alkaloids, vitamins, minerals and saponins, which have been shown to produce anti-ulcerogenic and anti-gastric activity. , However, until specific constituents are isolated and characterized, exact mechanism of action cannot be ascertained.
| Conclusion|| |
The aqueous fruit pulp concentrate of C. lanatus has a gastroprotective property against experimentally induced ulcers in rats and hence can be used to treat ulcers.
| Acknowledgments|| |
The authors are thankful to the Director, PBRI, Bhopal (Madhya Pradesh, India) for providing facilities to carry out this research work.
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[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]