SMALL INTESTINE

Antidiarrhoeal properties of a novel sigma ligand (JO 2871) on toxigenic diarrhoea in mice: mechanisms of action

V Theodorou¹, M Chovet², H Eutamene¹, H Fargeau², M Dassaud², M Toulouse¹, C Bihoreau², F J Roman², L Bueno³

¹ Ecole Superieure d'Agriculture de Purpan, 75 voie du Toec, 31076 Toulouse, France
² Pfizer Global R&D Fresnes Laboratories, 3–9 rue de la Loge, BP100, 94265 Fresnes, France
³ Department of Neurogastroenterology and Nutrition, INRA, 180 chemin de Tournefeuille, BP3, 31931 Toulouse, France

Correspondence to:
Correspondence to:
Dr V Theodorou, Neurogastroenterology and Nutrition Unit, INRA, 180 chemin de Tournefeuille, BP 3, 31931 Toulouse cedex, France;
vtheodor{at}toulouse.inra.fr

Background and aims: Sigma ligands display antisecretory activity against various secretagogues, suggesting antidiarrhoeal properties. In this study, we evaluated: (i) the antidiarrhoeal effect of JO 2871, a high affinity sigma ligand, in three models of toxigenic diarrhoea in mice; and (ii) the site and mechanism of action of this compound.

Methods: Faeces were collected after toxin or vehicle administration in male DBA2 or NMRI mice. Diarrhoea was determined by cumulative stool weight (mg) over a 120 minute period. Diarrhoea was induced by intravenous administration of Salmonella enteriditis lipopolysaccharide (LPS), or oral administration of Escherichia coli heat stable (E coli-sta) or Clostridium difficile toxins. Two sigma ligands, igmesine and JO 2871, were administered either orally or intravenously, 60 and 30 minutes before the toxins, respectively. JO 2871 was also given orally 30 minutes after E coli-sta. In addition, JO 2871 was administered intracerebroventricularly five minutes before LPS and E coli-sta. BMY 14802 (1000 µg/kg orally), a sigma receptor antagonist, or cyclosomatostatin (CSS 1 µg/kg intravenously), a somatostatin antagonist, were given five minutes prior to JO 2871 in LPS, E coli-sta, and C difficile toxin treated mice. Gastric emptying and intestinal transit were evaluated after oral JO 2871 and BMY 14802 and intravenous CSS.

Results: Stool weight measured 120 minutes after administration of the toxins was significantly increased. Oral JO 2871 and igmesine dose dependently inhibited toxigenic diarrhoea in all models. ED₅₀ values obtained using JO 2871 (1–20 µg/kg) were more than 40 times lower than those obtained with igmesine. Oral JO 2871 given after E coli-sta also inhibited diarrhoea in a dose dependent manner (ED₅₀ 50 µg/kg). Both sigma ligands were active by the intravenous route on LPS and E coli-sta induced stool weight increases. JO 2871 administered intracerebroventricularly failed to block this effect at any dose tested. Both BMY 14802 and CSS reversed the antidiarrhoeal effect of oral JO 2871. JO 2871, BMY 14802, and CSS did not affect transit parameters.

Conclusions: JO 2871 exerts a potent oral antidiarrhoeal effect, acting peripherally through sigma sites and somatostatin release.

Keywords: sigma ligands; diarrhoea; Escherichia coli heat stable toxin; Clostridium difficile toxins; Salmonella enteriditis lipopolysaccharides; somatostatin

Abbreviations: E coli-sta; Escherichia coli heat stable toxin; CSS, cyclosomatostatin; LPS, lipopolysaccharide; ED₅₀, efficacy dose 50; IC₅₀, inhibitor concentration 50; TTX, tetrodotoxin; GE, gastric emptying; GC, geometric centre; VIP, vasoactive intestinal polypeptide

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