Gastric healing effect of melatonin against different gastroinvasive agents in cholestatic rats
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.
References (57)
- et al.
N(G) nitro-l-arginine methylester is protective against ethanol-induced gastric damage in cholestatic rats
Eur. J. Pharmacol.
(1999) - et al.
Pineal, retinal and harderian gland melatonin in a diurnal species, the richardson's ground squirrel (Spermophilus richardsonii)
Neurosci. Lett.
(1981) - et al.
Antioxidant properties of melatonin—an emerging mystery
Biochem. Pharmacol.
(1998) - et al.
Melatonin affords protection against gastric lesions induced by ischemia-reperfusion possibly due to its antioxidant and mucosal microcirculatory effects
Eur. J. Pharmacol.
(1997) - et al.
Gastric hyperacidity and mucosal damage caused by hypothermia correlate with increase in GABA concentrations of the rat brain
Eur. J. Pharmacol.
(1991) - et al.
Endogenous opiates and stress ulceration
Life Sci.
(1982) - et al.
Role of glutathione, lipid peroxidation and antioxidants on acute bile-duct obstruction in the rat
Biochim. Biophys. Acta
(1999) - et al.
Acute cholestasis-induced renal failure: effects of antioxidants and ligands for the thromboxane A2 receptor
Kidney Int.
(1999) - et al.
Antioxidant enzyme status in biliary obstructed rats: effects of N-acetylcysteine
J. Hepatol.
(1997) - et al.
Bile duct ligation and oxidative stress in the rat: effects in liver and kidney
Comp. Biochem. Physiol. C: Toxicol. Pharmacol.
(2000)