Dynamic physiological and molecular changes in gastric ulcer healing achieved by melatonin and its precursor L‐tryptophan in rats

Abstract

Following induction of gastric ulcer in rats by serosal application of acetic acid, local mucosal necrosis ensues accompanied by a reduction in mucosal microcirculation and by almost immediate expression of inducible nitric oxide (NO) synthase (iNOS) and proinflammatory cytokines. Daily application of melatonin (20 mg/kg) or l-tryptophan (100 mg/kg) accelerates ulcer healing by affecting the cyclooxygenase-2 (COX-2)-prostaglandin (PG) system with excessive production of protective PG, especially in later period of ulcer healing. Furthermore, expression of hypoxia inducible factor, vascular-endothelial growth factor, an activation of cNOS-NO system and the stimulation of sensory nerves with the expression and release of calcitonin gene related peptide (CGRP) appear to aid the restoration of mucosal repair and microcirculation in the ulcer bed. The enhanced expression of the melatonin MT(2) receptors (MT(2)-R) combined with overexpression of key enzymes involved in biosynthesis of melatonin such as N-acetyltransferase and hydroxyindole-O-methyltransferase contribute to the acceleration of ulcer healing by this indole. Melatonin-induced acceleration of ulcer healing is also mediated by release of gastrin and ghrelin, the most potent stimulants of gastric mucosal cell proliferation and mucosal repair. These sequential steps in ulcer healing accelerated by melatonin can be interfered with by the blockade of MT(2)R, COX-2/PG and cNOS/NO systems, and by reduction in the inflammatory iNOS/NO system. Thus, melatonin and its precursor l-tryptophan, trigger the cascade of molecular events leading to the functional improvement in ulcer healing.

Altered basal and postprandial plasma melatonin, gastrin, ghrelin, leptin and insulin in patients with liver cirrhosis and portal hypertension without and with oral administration of melatonin or tryptophan

“…Our present study compared the plasma levels of melatonin in systemic circulation in humans with intact healthy liver and in patients with liver cirrhosis and portal hypertension with obvious porto‐systemic shunting of portal blood to the systemic circulation. In general, we confirmed previous observations made on pigs and rats [50, 51] that in humans the GIT is the major source of circulating melatonin and that it may originate from ingested Trp.…”

“…We reported recently [51], that the rat gastric mucosa is expressing mRNA for two major enzymes involved in the biosynthesis of melatonin, i.e. arylalkylamine‐ N ‐acetyltransferase (AA‐NAT), that converts serotonin to N ‐acetyl serotonin and hydroxyindole‐ O ‐methyltransferase (HIOMT), which transforms N‐ acetylserotonin to melatonin.…”

Melatonin membrane receptors in peripheral tissues: Distribution and functions

“…An important receptor-independent action of melatonin in the GI tract is its action as a free radical scavenger (Konturek et al, 2006). Importantly, preventive role of melatonin against ulcer formation or its healing is well established (Brzozowska et al, 2009; Celinski et al, 2011; Ganguly et al, 2010; Konturek et al, 2008, 2006). …”

Role of New Appetite Hormones Ghrelin, Orexin-A and Obestatin in the Mechanism of Healing of Chronic Gastric Ulcers

“…Treatment with ghrelin markedly attenuated the expression of IL-1 and TNF- in gastric mucosa around the ulcer suggesting that the acceleration of ulcer healing by ghrelin could be, at least in part, due to the potent anti-inflammatory activity of this hormone. We reported before that the induction of gastric ulcer by serosal application of acetic acid is accompanied by the co-expression of gastroprotective COX-2-PG system with the increased expression and release of vasoactive, proliferative and trophic gastric hormones such as gastrin and ghrelin [Konturek et al, 2008]. Ghrelin was shown to exhibit gastroprotective activity and our present study confirming that this hormone can accelerate ulcer healing, suggests that the upregulation in the ghrelin gene expression could play the central event in the mechanism of gastric ulcer healing.…”

“…Ghrelin was shown to exhibit gastroprotective activity and our present study confirming that this hormone can accelerate ulcer healing, suggests that the upregulation in the ghrelin gene expression could play the central event in the mechanism of gastric ulcer healing. These protective and trophic hormonal responses of gastric mucosa to ulceration, as manifested by increased expression of ghrelin co-expressed www.intechopen.com Role of New Appetite Hormones Ghrelin, Orexin-A and Obestatin in the Mechanism of Healing of Chronic Gastric Ulcers 203 with COX-2 [Konturek et al, 2008] possibly triggered by an overexpression of IL-1 and TNF-, seem to play a crucial role in the restoration cellular and glandular structure of the mucosa and the quality of ulcer healing. Interestingly, obestatin, which is encoded by the same gene as ghrelin has recently been reported to counteract physiological effects of ghrelin [Zhang et al, 2005].…”