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Ghrelin Protects Against Ethanol-Induced Gastric Ulcers in Rats: Studies on the Mechanisms of Action

Department of Pharmacology, Chemotherapy, and Medical Toxicology, University of Milan (V.S., F.P., D.R., C.N.), 20129 Milan, Italy; Department of Pathology and Laboratory Medicine, University of Parma (G.R., N.C.), 43100 Parma, Italy; Department of Experimental and Environmental Medicine and Biotechnology, University of Milan-Bicocca (V.L., A.T.), 20052 Monza, Italy; and Europeptides (R.D.), 95108 Argenteuil CEDEX, France

Address all correspondence and requests for reprints to: Prof. Carmela Netti, Department of Pharmacology, Chemotherapy, and Medical Toxicology, University of Milan, Via Vanvitelli 32, 20129 Milan, Italy. E-mail: carmela.netti{at}unimi.it.

Ghrelin, the endogenous ligand for GH secretagogue receptors, has been reported to influence acid gastric secretion and motility, but its potential gastroprotective effect is unknown. The aims of this study were 1) to examine the effects of central and peripheral administration of ghrelin on ethanol-induced gastric ulcers in conscious rats, and 2) to investigate the possible roles of nitric oxide (NO), vagal nerve, and sensory fibers in the gastric effects of ghrelin.

Ghrelin was administered either intracerebroventricularly or sc 30 min before ethanol, and mucosal lesions were examined macroscopically. Additionally, rats were either treated with the inhibitor of NO synthesis N-nitro-L-arginine methyl ester (L-NAME) or underwent bilateral cervical vagotomy or capsaicin-induced sensory denervation. Conventional histology and immunohistochemistry for ghrelin, gastrin, and somatostatin were performed on gastric specimens from representative rats.

Central ghrelin (4–4000 ng/rat) dose-dependently reduced ethanol-induced gastric ulcers by 39–77%. Subcutaneous ghrelin administration (80 µg/kg) reduced ulcer depth only. L-NAME and capsaicin, but not vagotomy, prevented the gastroprotective effect of central ghrelin (4000 ng/rat).

This is the first evidence that ghrelin exerts a potent central gastroprotective activity against ethanol-induced lesions. The gastroprotective effect of ghrelin is mediated by endogenous NO release and requires the integrity of sensory nerve fibers.

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