Antiulcer Activity of Cod Liver Oil in Rats

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Antiulcer activity of cod liver oil in ratsSalaj Khare, Mohammed Asad, Sunil S. Dhamanigi, and V. Satya Prasad1 Krupanidhi College of Pharmacy, Bangalore, India1MNR Medical College, Andhra Pradesh, IndiaCorrespondence to: Dr. Mohammed Asad, E-mail: [email protected] Received March 31, 2008; Revised July 26, 2008; Accepted October 14, 2008.This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use,distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Objective:

Cod liver oil is used widely as a dietary supplement. The present study was carried out to evaluate the

effect of cod liver oil (0.5 g/kg, p.o. and 1 g/kg, p.o.) on gastric and duodenal ulcers.

Materials andMethods:

The study was carried out on different gastric ulcer models such as acetic acid induced chronic gastric

ulcers, pylorus ligation, indomethacin induced ulcers, stress induced ulcers and ethanol induced ulcers.

The duodenal ulcers were induced using cysteamine hydrochloride (HCl). Ranitidine (50 mg/kg p.o.) andmisoprostol (100µg/kg, p.o.) were used as standard drugs.

Results:

Both doses of cod liver oil showed gastric ulcer healing effect in acetic acid induced chronic gastric

ulcers, produced gastric antisecretory effect in pylorus-ligated rats and also showed gastric cytoprotective

effect in ethanol-induced and indomethacin-induced ulcer. Cod liver oil also produced a significant

reduction in the development of stress induced gastric ulcers and cysteamine induced duodenal ulcer.

The high dose of cod liver oil (1 g/kg, p.o.) was more effective compared to the low dose (0.5 g/kg, p.o.).

Conclusion:

Cod liver oil increases healing of gastric ulcers and prevents the development of experimentally induced

gastric and duodenal ulcers in rats.

Keywords: Cod liver oil, duodenal ulcer, gastric cytoprotection, gastric secretion, gastric ulcer

Introduction

Cod liver oil (CLO) is a dietary supplement that consists of polyunsaturated fatty acids (PUFA), which

includes C20 fatty acids (17%), palmitoleic acid (7%) and C22fatty acids (11%), vitamin A not less than 850

USP units/g and vitamin D not less than 85 USP units/g.[1,2] Cod liver oil is widely used in the treatment

of rickets and osteomalacia as a dietary supplement.

The development and progression of gastric ulcer, to some extent, depends on the type of the food

consumed by the patient. Studies have been carried out to specifically evaluate the effect of fish oils on

the development of gastric ulcer. It has been reported that a diet rich in fish oils reduces arachidonic acid

levels in the gastric mucosa and increases stress induced gastric erosions.[3] On the contrary, it is

reported that fish oils rich in polyunsaturated fatty acids (PUFA) reduce the development of

dexamethasone induced gastric damage.[4] Similarly, vitamin E present abundantly in fish oils is reported

to reduce the development of indomethacin induced gastric damage.[5]



Cod liver oil is obtained from the liver of the cod fish and is different from fish oil. The main difference is

that CLO is rich in vitamin A and vitamin D, as compared to fish oil and both these vitamins have

therapeutic effects.[6,7] Earlier studies carried out with CLO indicate that CLO inhibits the development of

indomethacin induced gastric ulcers in rats.[4] However, other studies suggest that CLO may inhibit the

formation of arachidonic acid and may thus decrease the production of cytoprotective prostaglandins

leading to the development of gastric ulcers, especially under conditions of stress.[8] The exact effect of

CLO administration on the healing or development of gastric ulcer is not known. Since CLO is widely

used as a dietary supplement, the present study was undertaken to evaluate its effect on the

development and healing of gastric and duodenal ulcers in rats.

Materials and Methods

Experimental animals

Male albino Wistar rats weighing between 200 and 250 gm were used. The experimental protocol was

approved by the Institutional Animal Ethics Committee. The animals were maintained under standard

conditions in an animal house approved by the Committee for the Purpose of Control and Supervision on

Experiments on Animals (CPCSEA).

Drugs and chemicals

Acetic acid (E-Merck, Mumbai, India), cysteamine hydrochloride (Hi-media, Mumbai, India), ethanol

(Bengal Chemicals, Kolkatta, India), indomethacin (Sigma, St. Louis, MO, USA), ketamine hydrochloride

(Troika Parentrals, Gujarat, India) and CLO (Universal Medicare Pvt. Ltd., Mumbai, India).

Determination of purity of CLO

The monographic analysis of CLO was carried out using procedures mentioned in the British

Pharmacopoeia,[9] the United States Pharmacopoeia[10] and the Indian Pharmacopoeia.[11]

Gastric Ulcers

Acetic acid-induced chronic gastric ulcer

The method described by Okabe et al. (1970)[12] was followed. The animals were fasted for 24 h prior to

the experiment. Under light ether anaesthesia, ulcers were induced by applying glacial acetic acid (0.05

ml) over the anterior serosal surface of the stomach for 60 seconds. The animals were treated with

ranitidine (50 mg/kg, p.o.),[13] low dose of CLO (0.5 g/kg p.o.)[14] or high dose of CLO (1 g/kg p.o.),[14]

once daily, for 10 days after the induction of ulcer, while the control group received only the vehicle. The

rats were sacrificed on the 10th day, the stomachs removed and cut open along the greater curvature.

The ulcer index was determined using the formula:[15]

Where X = Total mucosal area/Total ulcerated area.

Based on their intensity, the ulcers were given scores as follows:



0 = no ulcer, 1 = superficial mucosal erosion, 2 = deep ulcer or transmural necrosis, 3 = perforated or

penetrated ulcer.

Pylorus ligation induced ulcers

The ligation of pyloric end of the stomach was performed on animals fasted for 36 h, under ether

anaesthesia.[16,17] The two doses of CLO or ranitidine was administered intraduodenally, immediately

after pylorus ligation. The animals were sacrificed six hours after pylorus ligation, through an overdose of

ether anaesthesia. The stomachs were isolated and the content collected and centrifuged. The volume of

the gastric juice was measured and this was used for the estimation of free acidity,[18] total acidity[18]

pepsin content[19] and total proteins.[20] The ulcer index and gastric mucous content was

determined.[21]

Healing of indomethacin induced gastric ulcers

The gastric ulcers were induced by administering indomethacin (5 mg/kg. p.o.) for five days.[22] The

animals were then treated either with misoprostol (100 µg/kg, p.o),[23] low dose of CLO (0.5 g/kg p.o.) or

high dose of CLO (1 g/kg p.o.), once daily for another five days, after the induction of ulcer, while thecontrol group received only vehicle. The rats were sacrificed on the fifth day and the ulcer index was

determined. The glandular portion of the stomach was taken and used for estimation of mucin

content,[21] total proteins,[20] antioxidant factor's super oxide dismutase activity[24] and catalase

activity.[25]

Ethanol induced ulcers

All the animals were fasted for 36 h before the administration of ethanol. The standard drug (misoprostol

100 µg/kg, p.o.) or CLO was administered one hour before ethanol administration. Ethanol (90%) was

administered to all the animals at a dose of 1 ml/200gm and after one hour, all the animals were

sacrificed and ulcer index was determined as mentioned above.[26]

Cold restraint stress induced ulcers

The ulcer was induced by subjecting the animals to cold restraint stress. Ranitidine or CLO was

administered 30 min prior to subjecting the animals to stress. The animals were placed in a restraint cage

and the cage was placed at a temperature of 2°C for 3 h. The animals were sacrificed after three hours

and the ulcer index was determined.[27,28]

Duodenal Ulcers

Cysteamine induced duodenal ulcers

Duodenal ulcer was induced by administering cysteamine hydrochloride (400 mg/kg, p.o.) twice, at aninterval of four hours. Ranitidine or CLO was administered 30 min prior to each dose of cysteamine

hydrochloride. After 24 h, all the animals were sacrificed and the duodena were excised carefully and cut

open along the antimesentric side. The duodenal ulcer area, ulcer score and ulcer index were

determined.[29]

Based on their intensity, the ulcers were given scores as follows:



0 = no ulcer, 1 = superficial mucosal erosion, 2 = deep ulcer or transmural necrosis,

3 = perforated or penetrated ulcer.

The ulcer index was calculated using the following equation:[30]

Statistical analysis

The statistical significance was assessed using one-way analysis of variance ( ANOVA) followed by

Bonferrroni's comparison test. For comparing nonparametric ulcer scores, anova followed by non-

parametric Dunn post test was used. The values are expressed as mean ± SEM and P < 0.05 was

considered significant.

R esults

Determination of purity of CLO

The monographic analysis of CLO revealed the following results:

y Saponification value - 185.13

y Acid value - 1.12

y Refractive index - 1.475

The assay of vitamin A was carried out as per the United States Pharmacopoeia and the vitamin A

content was 2133 IU /ml.

The assay of vitamin D was carried out using the HPLC method mentioned in the Indian Pharmacopoeia

and the CLO sample was found to contain 114 IU/ml of vitamin D.

All the values are within the limits prescribed by the pharmacopoeia.

Acetic acid-induced chronic gastric ulcer

The CLO produced a significant reduction in the ulcer index and the ulcer score. Both the high dose (1

g/kg, p.o.) and the low dose of CLO (0.5 g/kg, p.o.) were effective in reducing the ulcer index and the

ulcer score, when compared to control. The high dose of CLO was significantly more effective than the

low dose in reducing the ulcer index. Ranitidine was most effective in reducing both ulcer score and ulcer

index [Table 1].

Table 1

Effect on acetic acid induced chronic gastric ulcers

Treatment Ulcer score Ulcer index Control 2.8 ± 0.2000 0.508 ± 0.0231



Treatment Ulcer score Ulcer index CLO (0.5 g/kg, p.o.) 1.8 ± 0.2000* 0.334 ± 0.0177*

CLO (1 g/kg, p.o.) 1.2 ± 0.2000* 0.214 ± 0.0050*+

Ranitidine (50 mg/kg, p.o.) 0.0 ± 0.000* 0.028 ± 0.0115*

F-value 26.83 158.37

CLO = Cod liver oil, All values are mean ± SEM, n = 5-6.

Pylorus ligation induced gastric ulcers

Both doses of CLO produced a significant reduction in the ulcer index, free acidity, total acidity and

pepsin content, when compared to control. The effects observed were dose dependent, with high dose of

CLO (1 g/kg, p.o.) showing more effect, as compared to the low dose (0.5 g/kg, p.o.). The mucin content

and total protein were significantly increased by both doses of CLO in a dose dependent manner, when

compared to control. Ranitidine also showed similar effects, but was more effective compared to both

doses of CLO [Table 2].

Table 2

Effect on free acidity, total acidity, ulcer index mucin content, pepsin content and total proteins in pylorusligated rats

Treatment Free acidity

(mEq/litre) Total

acidity

(mEq/litre) Ulcer

index Mucin

content

(µg/g) Pepsin

content

(µmol/6hr) Total

protein

(mg/ml) Control 47.20 ±

2.577

64.80 ±

4.598

0.908 ±

0.010

1.528 ±

0.219

0.774 ±

0.020

9.76 ±

0.654

CLO (0.5

g/kg, p.o.)

35.80 ±

2.010*

41.20 ±

2.746*

0.478 ±

0.020*

2.672 ±

0.234*

0.238 ±

0.009*

16.39 ±

0.913*

CLO (1g/kg, p.o.)

24.40 ±1.030*+

28.80 ±0.969*+

0.236±0.013*+

4.798 ±0.023*+

0.184 ±0.009*

23.58 ±0.997*+

Ranitidine(50 mg/kg,

p.o.)

16.60 ±1.435*

22.40 ±0.927*

0.064 ±0.005*

4.242 ±0.012*

0.108 ±0.012*

30.40 ±1.841*

F-value 56.88 53.64 818.94 104.53 528.7 49.98

CLO = Cod liver oil. All values are mean ± SEM, n = 5-6.*P <0.05 vs control

+P <0.05 Vs low dose.

Healing of indomethacin induced gastric ulcers

The healing of indomethacin induced gastric ulcers was significantly increased by both doses of CLO, as

indicated by a reduction in the ulcer index. Both the doses of CLO also produced a significant increase in



mucin content, superoxide dismutase and catalase activity, with the high dose showing more activity, as

compared to the low dose. The standard drug misoprostol reduced the ulcer index and increased gastric

mucus secretion, but did not affect the protein content or enzyme activity [Table 3].

Table 3

Effect on mucin content, ulcer index, total proteins, anti oxidant factors in indomethacin induced ulcers

Treatment Mucin

content µg/g Ulcer

index Total

protein

(mg/ml) SOD Units

of proteins Catalase

Units/mg of

proteins Control 0.556 ± 0.111 0.730 ±

0.015

17.84 ±

0.936

41.30 ±

3.597

38.76 ± 3.452

CLO (0.5 g/kg,

p.o.)

1.671 ± 0.193* 0.424 ±

0.011*

40.94 ±

3.577*

96.10 ±

6.254*

84.72 ± 3.176*

CLO (1 g/kg,

p.o.)

2.686 ±

0.227*+

0.174 ±

0.008*+

57.90 ±

3.794*+

126.20 ±

5.687*+

109.70 ±

6.414*+

Misoprostol(100 µg/kg, p.o.)

2.303 ± 0.191* 0.080 ±0.008*

26.04 ±0.106

46.46 ±4.816

43.16 ± 3.456

F-value 23.05 761.23 44.58 62.68 58.28

CLO = Cod liver oil. All values are mean ± SEM, n = 5-6.*P <0.05 Vs control

+P <0.05 Vs low dose.

Ethanol induced and cold restraint stress induced ulcers

Both the doses of CLO showed a significant reduction in the ulcer index, when compared to control.

Misoprostol and ranitidine showed more reduction in the ulcer index than CLO, in ethanol induced and

cold restraint stress induced ulcer models respectively [Tables 4 and 5]

Table 4

Effect on ulcer index in ethanol induced gastric ulcers

Treatment Ulcer index Control 1.175 ± 0.1116

CLO (0.5 g/kg, p.o.) 0.275 ± 0.0154*

CLO (1 g/kg, p.o.) 0.178 ± 0.0175*

Misoprostol (100 µg/kg, p.o.) 0.161 ± 0.0127*

F-value 87.41

All values are mean ± SEM, n = 5-6*P <0.05 vs control.



Table 5

Effect on ulcer index in cold restraint stress induced gastric ulcers

Treatment Ulcer index Control 0.732 ± 0.055CLO (0.5 g/kg, p.o.) 0.210 ±0.013*

CLO (1 g/kg, p.o.) 0.098 ± 0.005*

Ranitidine(50 mg/kg, p.o.) 0.068 ± 0.003*

F-value 139.14

CLO = Cod liver oil, All values are mean ± SEM, n = 5-6,*P <0.05 vs control

Cysteamine induced duodenal ulcers

Both the doses of CLO produced significant reduction in the ulcer index, the ulcer area and the ulcer

score, when compared to control. The high dose (P < 0.001) of CLO showed more significant effect in

ulcer area and ulcer score than the low dose. Ranitidine completely prevented the development of

duodenal ulcers. The ulcer was developed in the anti-mesenteric side of the duodenum [Table 6].

Table 6

Effect on ulcer area, ulcer score and ulcer index in cysteamine induced duodenal ulcers

Treatment

Ulcer index

Ulcer area

Ulcer score

Control 4.0 38.0 ± 1.449 2.0 ± 0.000

CLO (0.5g/kg, p.o.) 2.6 25.4 ±3.234* 1.2 ± 0.200*

CLO (1g/kg, p.o.) 1.2 14.6 ± 2.040*+ 0.4 ± 0.244*+

Ranitidine

(50mg/kg, p.o.) 0 0.0 ± 0.000* 0.0 ± 0.000*

F-value 68.36 29.63

CLO = Cod liver oil, All values are mean ± SEM, n = 5-6,*P <0.05 vs control,

+

P <0.05 vs low dose.

Discussion

The present study investigated the effect of CLO on the gastric and duodenal ulcers. Cod liver oil showed

effect on the healing of gastric ulcers induced by acetic acid and prevented the development of gastric

ulcers induced by different methods and cysteamine induced duodenal ulcer.



Application of glacial acetic acid (0.05ml) on the serosal surface of the stomach produced deep

penetrating gastric ulcer that resembles human peptic ulcer disease. Since the healing process of this

ulcer closely resembles that of human peptic ulcers, this model is quite useful for studying the effect of

drugs on the healing of peptic ulcers.[31] CLO was effective in augmenting the gastric ulcer healing in this

model. To evaluate the mechanism by which CLO increased gastric ulcer healing, further studies were

carried out using other models of gastric ulcers.

Pylorus ligation induced ulcer is one of the most widely used methods for studying the effect of drugs on

gastric secretion. Agents that decrease gastric acid secretion and/or increase mucus secretion are

effective in preventing the ulcers induced by this method. The ligation of the pyloric end of the stomach

causes accumulation of gastric acid in the stomach, leading to the development of ulcers in the stomach.

The original Shay rat model involves fasting of rats for 72 h, followed by ligation of the pyloric end of the

stomach for 19 h.[16] In the present study, the modification of Shay rat model described by Kulkarni[17]

was followed, which involves fasting of the animals for 36 h and pyloric ligation only for six hours.

Ranitidine and CLO significantly decreased the secretion of gastric aggressive factors, free acidity, total

acidity and pepsin content, and increased the mucus secretion, which is cytoprotective.

Ethanol induced gastric ulcer and indomethacin induced gastric ulcers were employed to study the

cytoprotective effect of CLO. Ethanol induces gastric lesion, due to its corrosive effect. It rapidly

penetrates the gastric mucosa, causing cell and plasma membrane damage, leading to increased

membrane permeability to sodium and water. It also produces massive intracellular accumulation of

calcium, which represents a major step in the pathogenesis of gastric mucosal injury. This leads to cell

death and exfoliation in the surface epithelium.[32,33] Both the doses of CLO were effective in preventing

development of ethanol induced gastric ulcers, indicating that CLO possesses gastric cytoprotective

effect.

Indomethacin produces erosions and ulcers in the stomach due to the inhibition of prostaglandinsynthesis.[34] The gastric cytoprotective agents are effective in preventing ulcers induced by

indomethacin. Like ethanol induced gastric ulcers, CLO was effective in reducing ulcer index and in

increasing the mucus content. Further, CLO produced an increased activity of antioxidant enzymes,

suggesting that its effect on ulcer may partly be due to its antioxidant action.

The pathophysiology of stress-induced ulcers is complex; the ulcers are produced due to the release of

histamine, leading to an increase in acid secretion and a reduction in mucus production.[35,36] Stress

also causes an increase in gastrointestinal motility, which causes folds in the gastrointestinal tract The

folds in the stomach are more susceptible to damage, when they come in contact with acid. The stress

also brings the central nervous system into play. Agents that decrease G.I. motility, gastric secretion or

those having central actions are helpful in reducing ulcers due to stress. Ranitidine and CLO were

effective in reducing ulcers induced by stress. The reduction in stress induced gastric ulcers may

probably be due to the reduction in gastric secretion, as there are no reports to indicate the effect of CLO

on gastric motility or the central nervous system.

Cysteamine induced duodenal ulcer in rat resembles that of duodenal ulcer in humans,

histopathologically and pathophysiologically. Cysteamine hydrochloride inhibits the alkaline mucus



secretion from the Brunner's glands in the proximal duodenum and stimulates the rate of gastric acid

secretion. Gastric emptying is also delayed and serum gastrin concentration is increased.[27]

Cod liver oil was effective in reducing the ulcer area and the ulcer score. The effect of fish oil on the

development of gastric and duodenal ulcers has been studied extensively. Fish oil is reported to reduce

gastric secretion and also prevent the development of indomethacin induced gastric ulcers.[37,38] Fish oilis also used as dietary supplements for ulcerative colitis.[39]

As mentioned earlier, CLO inhibits the development of indomethacin induced gastric ulcers in rats.[40]

However, other studies suggest that CLO may inhibit the formation of arachidonic acid and may thus

decrease the production of cytoprotective prostaglandnins, leading to the development of gastric ulcers,

especially under conditions of stress.[3]

Although earlier reports on the effect of CLO on gastric ulcers are confusing, studies carried out using

different constituents of fish oils such as omega-3-fatty acid and polyunsaturated fatty acids reveal that

they possess antiulcer and antioxidant effect. Omega 3 triglycerides are also known to inhibit ulcer

formation in pylorus ligated rats[41] and increase healing of gastric ulcers in rats.[42] Omega-3-fatty acidalso possesses antioxidant effect.[43] Fish oil, rich in omega-3-fatty acid, is reported to inhibit offensive

mucosal factors and oxidative stress and to augment defensive mucosal factors.[44] Further, fish oil

reduced development of cold plus restraint ulcers in rats.[45]

Polyunsaturated fatty acids (PUFA) are reported to reduce the development of dexamethasone induced

and indomethacin induced gastric ulcers healing.[4,46] Moreover, decrease in intake of polyunsaturated

fatty acid was shown to be associated with increased incidence of duodenal ulcers in humans.[47]

The exact constituents and the mechanism by which CLO reduced gastric and duodenal ulcer formation

and increased gastric ulcer cannot be explained by the present data. However, it is speculated that the

polyunsaturated fatty acid and the omega-3-fatty acids present abundantly in the CLO may be

responsible for this effect. Furthermore, the antioxidant effect of CLO may also be responsible for its anti-

ulcer action.[48]

The results of the present investigation suggest that consumption of CLO is beneficial for patients

suffering from peptic ulcer disease. Cod liver oil may produce both gastric antisecretory and gastric

cytoprotective effect, resulting in increased healing of gastric and duodenal ulcers. However, the effect of

CLO on the growth of H elicobacter pylori , one of the main causes for the development of gastric and

duodenal ulcer, is not known. Studies on the effect of CLO on the H elicobacter pylori infection have to be

carried out to further support the beneficial effect of CLO in peptic ulcer patients.

Conclusion

Cod liver oil has an antiulcer effect. It increased healing of acetic acid induced chronic gastric ulcers and

prevented the development of gastric ulcers induced by pylorus ligation, ethanol, stress or indomethacin.

Cod liver oil was also effective in preventing the development of cysteamine induced duodenal ulcers.

Acknowledgments



The authors are thankful to Prof. Suresh Nagpal, Chairman, Krupanidhi Educational Trust (Bangalore,

India), for funding the research work and Dr. Amit Kumar Das, Professor and Principal, Krupanidhi

College of Pharmacy for his suggestions.

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Antiulcer Activity of Cod Liver Oil in Rats

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