Elsevier

Pathophysiology

Volume 17, Issue 1, February 2010, Pages 65-70
Pathophysiology

Gastric healing effect of melatonin against different gastroinvasive agents in cholestatic rats

https://doi.org/10.1016/j.pathophys.2009.08.001Get rights and content

Abstract

Background and objective: The frequency of gastrointestinal ulceration is higher in jaundiced patients than in healthy population. The aim of this study was to assess the effect of pretreatment with melatonin, a potent scavenger of reactive oxygen species, on stress-induced gastric ulcers of cholestatic rats. Materials and methods: Cholestasis was induced by surgical ligation of bile-duct and sham-operated rats served as sham animals. The animals received saline or melatonin (1, 3 or 10 mg/kg) before stress induction. Three different types of gastroinvasive agents including ethanol, indomethacin or water immersion were used as stress agents to induce gastric ulceration. Results: Gastric mucosal damage induced by different gastroinvasive agents was significantly greater in bile-duct-ligated rats than in sham ones. Melatonin was protective against ethanol-, indomethacin- and water immersion-induced gastric damage in bile-duct-ligated and sham rats, dose-dependently, but the protective effect of melatonin was greater in cholestatic rats than sham rats in all three different series of experiments. Conclusions: In conclusion, pretreatment of rats with melatonin protected gastric mucosa of cholestatic rats more effectively than the sham ones possibly by a mechanism involving the scavenging of free radicals.

Introduction

Postoperative gastrointestinal hemorrhage has been reported in 6–14% of patients with obstructive jaundice [1], [2] and gastrointestinal ulcerations is higher in jaundiced patients than in the normal population [3]. Several experimental studies have shown that the gastric mucosa of cholestatic rats is more vulnerable than that of normal animals to water-immersion stress [4] and to gastroinvasive agents such as acetyl salicylic acid (aspirin) and taurocholate [5], [6].

Previous reports have also referred to increased gastric acid output [4], decreased gastric wall blood flow [7] and increased free-radical formation [8] in rats with cholestasis. We also suggested important roles for nitric oxide and endogenous opioids in the pathophysiology of peptic ulcers in cholestatic animals [9], [10], [11].

Melatonin (N-acetyl-5-methoxytryptamine) represents a primary secretory product of the pineal gland and is well known for its effects on seasonal reproduction [12], [13], circadian rhythm [14], and sleep [15]. Melatonin is widely distributed in many extrapineal tissues including retina, Harderian gland, placenta, kidneys, respiratory tract and digestive system [16], [17], [18], [19].

Additionally, melatonin has also been shown to have a variety of other functions, e.g. influence of immune function as well as antiproliferative and antioxidative actions [20], [21], [22], [23]. It also reduces age-related oxidative damage in the central nervous system [24], Alzheimer's disease [25] and Parkinson's disease [26].

Several reports showed that melatonin protects against various types of gastric ulceration through ameliorating the reduction of glutathione levels, stimulating the glutathione reductase activity and reducing polymorphonuclear leukocyte infiltration [27], [28], [29]. Similarly, melatonin protects against stress-induced and ischemia reperfusion-induced gastropathy by scavenging reactive oxygen species [30], [31].

The present study was designed to study the possible healing effect of melatonin in gastric damage of cholestatic rats induced by gastroinvasive agents including ethanol, indomethacin or water-immersion stress.

Section snippets

Animal manipulations

Male albino rats weighing 200–250 g were used in this study. All animals were given free access to food and water. The protocol for this project was approved by the ethics committee of the university and all experiments were performed according to the institutional guidelines for animal care and use. The rats were divided into 24 groups randomly, each group consisted of 6–7 rats. Laparotomy was performed under general anesthesia induced by an intraperitoneal injection of ketamine HCl (50 mg/kg)

Induction of cholestasis

Two days after bile-duct ligation, the animals showed signs of cholestasis (jaundice, dark urine and steatorrhea). These signs were confirmed biochemically by a significant rise in the level of serum total bilirubin (5.2 ± 0.67 μM in sham-operated group versus 90.2 ± 11.35 μM in bile-duct-ligated group) on the seventh day in bile-duct-ligated rats (P < 0.001). None of the rats showed ascites at the time of the experiment.

Ethanol-induced gastric damage

The gastric mucosal damage was significantly more severe in bile-duct-ligated rats

Discussion

This study showed that the development of gastric mucosal lesions induced by different gastroinvasive agents was enhanced in bile-duct-ligated rats compared to sham ones. Administration of melatonin prior to ethanol oral gavage, indomethacin injection or water-immersion stress significantly revealed the gastric mucosal damage in cholestatic and sham rats, but this effect was more greater in bile-duct-ligated rats.

Cholestasis is an impairment of bile secretion, which may result either from a

Conclusion

We conclude that melatonin which applied exogenously protected gastric mucosa of BDL rats more effectively than sham rats possibly by a mechanism involving the scavenging of free radicals. Further experiments are necessary to clarify other possible mechanisms of gastroprotective effect of melatonin.

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