Protective effect of centrally-injected glucagon-like peptide-1 on reserpine-induced gastric mucosal lesions in rat: Possible mechanisms

Abstract

Background/aims: Intracerebroventricular glucagon-like peptide-1 (GLP-1) has been shown to prevent the gastric mucosal lesions induced by reserpine. In the present study, we aimed to investigate the contribution of 1- the cholinergic pathway, 2- the sympathetic pathway, 3- somatostatin and 4- endogenous nitric oxide to this gastroprotective effect. Methods: Rats were equipped with intravenous and intracerebroventricular cannulas under ether anesthesia for drug delivery. Rats were pretreated with mecamylamine (5 mg / kg; i.p.) and atropine sulfate (1 mg / kg; i.p.), yohimbine (1 mg/kg; i.p.), cysteamine (280 mg / kg; s.c.), and NG-nitro-L-arginine methyl ester (3 mg/kg; i.v.) to investigate the role of the cholinergic pathway, sympathetic pathway, somatostatin and endogenous nitric oxide, respectively, in the gastroprotective effect of GLP-1. To produce gastric mucosal lesions, reserpine was administered intraperitoneally at a dose of 25 mg / kg in 10 ml / kg of 0.5% acetic acid solution. Four hours later, the animals were decapitated, and their stomachs were removed and scored for mucosal damage. Results: Glucagon-like peptide-1 (100 ng / 10 μl; i.c.v.) inhibited the reserpine-induced gastric mucosal damage by 90% (p<0.01). Neither the nicotinic receptor antagonist mecamylamine (5 mg / kg; i.p.) nor the muscarinic receptor antagonist atropine sulfate (1 mg / kg; i.p) affected the gastroprotective activity of GLP-1. On the other hand, pretreatment with yohimbine, an α2-adrenergic receptor antagonist (1 mg / kg; i.p.), cysteamine, a somatostatin depletor (280 mg / kg; s.c), and NG-nitro-L-arginine methyl ester, a nitric oxide synthase inhibitor (3 mg / kg; i.v.), significantly abolished the protective effect of GLP-1 on reserpine-induced gastric mucosal lesions (p<0.001, p<0.01 and p<0.01, respectively). Conclusions: We conclude that the sympathetic pathway, somatostatin and nitric oxide, but not the cholinergic pathway, contribute to the gastroprotective effect of intra-cerebroventricular GLP-1 on reserpine-induced gastric mucosal lesions.