Role of prostaglandins, nitric oxide, sensory nerves and gastrin in acceleration of ulcer healing by melatonin and its precursor, L‐tryptophan

Abstract

Melatonin, a major hormone of pineal gland, was recently shown to attenuate acute gastric lesions induced by strong irritants because of the scavenging of free radicals but its role in ulcer healing has been little investigated. In this study we compared the effects of intragastric (i.g.) administration of melatonin and its precursor, L-tryptophan, with or without concurrent treatment with luzindole, a selective antagonist of melatonin MT2 receptors, on healing of chronic gastric ulcers induced by serosal application of acetic acid (ulcer area 28 mm2). The involvement of endogenous prostaglandins (PG), nitric oxide (NO) and sensory nerves in ulcer healing action of melatonin and L-tryptophan was studied in rats treated with indomethacin and NG-nitro-L-arginine (L-NNA) to suppress, respectively, cyclo-oxygenases (COX) and NO synthases or in those with functionally deactivated sensory nerves with capsaicin. The influence of melatonin on gastric secretion during ulcer healing was tested in separate group of rats with gastric ulcer equipped with gastric fistulas (GF). At day 8 and 15 upon the ulcer induction, the area of gastric ulcers was measured by planimetry, the mucosal blood flow (GBF) was determined by H2-gas clearance technique and gastric luminal NO2-/NO3- levels was assessed by Griess reaction. Plasma melatonin and gastrin levels were measured by specific radioimmunoassay (RIA). Biopsy mucosal samples were taken for expression of constitutive NO-synthase (cNOS) and inducible NOS (iNOS) by reverse transcriptase-polymerase chain reaction (RT-PCR). Melatonin (2.5-20 mg/kg-d i.g.) and L-tryptophan (25-100 mg/kg-d i.g.) dose-dependently accelerated ulcer healing, the dose inhibiting by 50% (ED50) of ulcer area being 10 and 115 mg/kg, respectively. This inhibitory effect of melatonin (10 mg/kg-d i.g.) and L-tryptophan (100 mg/kg-d i.g.) on ulcer healing was accompanied by a significant rise in the GBF at ulcer margin and an increase of plasma melatonin. luminal NO2-/NO3- and plasma gastrin levels. Gastric acid and pepsin outputs were significantly inhibited during the ulcer healing in melatonin-treated gastric mucosa as compared with those in vehicle-treated animals. Luzindole abolished completely the healing effects of melatonin and L-tryptophan and attenuated significantly the rise in plasma gastrin evoked by the hormone and its precursor. Indomethacin (5 mg/kg-d i.p). that blocked PG biosynthesis by 90% or L-NAME (20 mg/kg i.v), inhibitor of NOS. that suppressed luminal NO release, attenuated significantly melatonin and L-tryptophan-induced acceleration of ulcer healing and accompanying rise in GBF at ulcer margin and luminal NO release. The melatonin-induced acceleration of ulcer healing, hyperemia at ulcer margin and increase in the release of NO were enhanced when L-arginine but not D-arginine was added to L-NAME. The ulcer healing and the GBF effects of melatonin and L-tryptophan were significantly impaired in rats with capsaicin-induced denervation of sensory nerves and both, ulcer healing and the hyperem...

An Overview of Acetic Acid Ulcer Models<br>&mdash;The History and State of the Art of Peptic Ulcer Research&mdash;

“…Brzozowski concluded that the ulcer healing effects of L-arginine are possibly related to NO, gastrin, and polyamines. As expected, repeated administration of NO synthase (NOS) inhibitor 156) resulted in significantly delayed healing of Type 1 acetic acid ulcers in rats. Furthermore, Larginin clearly reversed the effects of NOS inhibitor on ulcer healing.…”

“…Watanabe suggested that the drug exerted its effect by modulating cell kinetics (apoptotic and proliferating cells) and inhibiting neutrophil infiltration (MPO activity). Brzozowski et al 132) found that exogenous melatonin and L-tryptophan significantly accelerated acetic acid ulcer healing in rats, probably via interaction with MT2 receptors. The underlying mechanism appears to involve increases in gastric mucosal blood flow via COX-derived PGs, iNOS-derived NO, and CGRP released from sensory nerves.…”

“…Based on such data, it was generally suggested that such stimulated epithelial proliferation in response to increased gastrin levels is directly related to the enhanced ulcer healing that was observed. Brzozowski et al 178) found that melatonin and its precursor L-tryptophan significantly enhanced acetic acid ulcer healing in rats. Gastrin levels were significantly increased upon exposure to the two compounds.…”

Amelioration of methotrexate‐induced enteritis by melatonin in rats

“…In experimental studies, melatonin has been shown to be effective in reducing mucosal breakdown in experimental colitis 37 or gastric ulcer. 38 Apart from its radical scavenging activity, melatonin is believed to exert a direct defence on the epithelium and to enhance submucosal blood flow. 11 It was reported that melatonin enhances microcirculation by cyclo-oxygenasederived prostaglandins and nitric oxide.…”

“…11 It was reported that melatonin enhances microcirculation by cyclo-oxygenasederived prostaglandins and nitric oxide. 38 Moreover, the hormone is reported to stimulate the synthesis of gastroprotective hormones. It was suggested that gastrin, which exhibits trophic activity and calcitonin gene-related peptide (CGRP), released from sensory nerves, may also contribute to the mucosal protective effects of melatonin.…”