Prophylactic Effect of Irsogladine Maleate Against Indomethacin-Induced Small Intestinal Lesions in Rats

Abstract

The effect of irsogladine maleate, a widely used antiulcer drug in Japan, on indomethacin-induced small intestinal lesions was examined in rats. Animals without fasting were given indomethacin (10 mg/kg, s.c.) and sacrificed 24 h later. Irsogladine (1-10 mg/kg) or 16,16-dimethyl prostaglandin E2 (dmPGE2 0.03 mg/kg) was given p.o. twice, 0.5 before and 6 h after indomethacin, while ampicillin (800 mg/kg) was given twice, 18 and 0.5 h before. Indomethacin caused severe lesions in the small intestine, mainly the jejunum and ileum, accompanied by intestinal hypermotility, the up-regulation of inducible nitric oxide synthase (iNOS) expression, and an increase of myeloperoxidase (MPO) activity as well as enterobacterial invasion in the mucosa. These events were all prevented by both dmPGE2 and ampicillin, except the intestinal hypermotility which was only prevented by dmPGE2. Likewise, irsogladine also significantly and dose-dependently prevented these lesions at > 1 mg/kg. This agent alone increased mucus secretion and significantly suppressed the decreased mucus response to indomethacin, resulting in a suppression of the bacterial invasion as well as the increase in MPO activity and iNOS expression. The protective effect of irsogladine was mimicked by isobutylmethylxanthine, a nonselective inhibitor of phosphodiesterase (PDE), as well as rolipram, a selective PDE4 inhibitor. These results suggest that irsogladine protects the small intestine against indomethacin-induced lesions, and this effect may be associated with the increased mucus secretion, probably due to the inhibitory actions of PDE, resulting in suppression of enterobacterial invasion and iNOS expression.

Present status and strategy of NSAIDs-induced small bowel injury

“…PAS staining increased with lafutidine, roxatidine, and irsogladine (Fig. 5) pretreatment as described in previous reports [56,57]. These results suggest that different inhibitory mechanisms may be operating with these effective drugs.…”

Lafutidine Protects the NSAID-Induced Small Intestinal Lesions Mediated by Capsaicin-Sensitive Afferent Neurons

“…Since lafutidine was found to prevent bacterial invasion, probably by up-regulating Muc2/mucus expression, it would be understandable that this agent suppressed the increase of iNOS expression in the small intestine following loxoprofen treatment. We previously reported that the mucosal protective drugs, such as irsogladine, rebamipide and teprenone, all significantly increased mucus secretion and suppressed bacterial invasion and iNOS expression, thereby reduced the severity of intestinal lesions produced by indomethacin [33]. These results together support a causeeffect relationship between changes in the above three events; ie., mucus secretion, bacterial invasion, and iNOS expression.…”

A wider view on gastric erosion: detailed evaluation of complex somatic and behavioral changes in rats treated with indomethacin at gastric ulcerogenic dose

“…To produce injury to the stomach, IM is usually injected to fasting rats or mice (Kato et al 2009;Rios et al 2010;Zelena and Filaretova 2010). On the contrary, for induction of injury to the small intestine IM is injected to fed animals (Kamei et al 2008;Yoda et al 2010;Kawahara et al 2011). The results of the present and our previous ) studies demon- strate that a single IM injection to fasting rats at gastric ulcerogenic dose may sequentially induce damage to the stomach and then, after refeeding, to the small intestine as well.…”