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Dynamic physiological and molecular changes in gastric ulcer healing achieved by melatonin and its precursor L ‐tryptophan in rats
Author(s) -
Konturek Peter C.,
Konturek Stanislaw J.,
Burnat Grzegorz,
Brzozowski Tomasz,
Brzozowska Iwona,
Reiter Russel J.
Publication year - 2008
Publication title -
journal of pineal research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.881
H-Index - 131
eISSN - 1600-079X
pISSN - 0742-3098
DOI - 10.1111/j.1600-079x.2008.00574.x
Subject(s) - melatonin , endocrinology , proinflammatory cytokine , medicine , wound healing , pineal gland , nitric oxide synthase , calcitonin gene related peptide , receptor , nitric oxide , inflammation , immunology , neuropeptide
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.