Mast Cell Stabilizer Ketotifen [4-(1-Methyl-4-piperidylidene)-4H-benzo[4,5]cyclohepta[1,2-b]thiophen-10(9H)-one Fumarate] Prevents Mucosal Mast Cell Hyperplasia and Intestinal Dysmotility in Experimental Trichinella spiralis Inflammation in the Rat

Abstract

Trichinella spiralis infection in rats induces hypermotility and an abnormal response to cholecystokinin (CCK) similar to motor disturbances observed in irritable bowel syndrome. Mast cell hyperplasia is also characteristic of this experimental model. The aim of our study was to correlate mast cell activity with the development of dysmotility and to demonstrate whether the mast cell stabilizer ketotifen [4-(1-methyl-4-piperidylidene)-4H-benzo [4,5]could prevent the development of intestine hypermotility. Sprague-Dawley rats were infected with T. spiralis and, 5 days after infection, treated with the mast-cell stabilizer ketotifen (10 mg/kg/day). Twelve days after infection, intestinal spontaneous motor activity and response to CCK were evaluated by means of strain-gauge transducers. Immunohistochemistry for rat mast cell protease II (RMCPII), cyclooxygenase (COX)-2, and inducible nitric-oxide synthase (iNOS) was performed in intestinal specimens. In addition, RMCPII and myeloperoxidase were determined in serum. Infected control rats showed hypermotility, mast cell hyperplasia, increased RMCPII levels, increased myeloperoxidase, and overexpression of COX-2 and iNOS. In contrast, ketotifen-treated rats showed spontaneous intestinal motility and CCK response similar to the noninfected control rats. Mast cell hyperplasia and RMCPII were reduced in ketotifen-treated rats. Inflammatory parameters were less modified by ketotifen, but those animals that received the longest ketotifen treatment showed a slight amelioration in these parameters. These results indicate that mast cells are implicated in the development of hypermotility. The treatment with ketotifen prevented hypermotility and mast cell hyperplasia and diminished mucosal mast cell activity.

PAR-2-mediated control of barrier function and motility differs between early and late phases of postinfectious gut dysfunction in the rat

“…Ketotifen solutions were freshly prepared every 2 days. Similar treatment protocols have been used before, both clinically and preclinically, showing effects consistent with a ketotifen-mediated modulation of MC degranulation (14,19,35,42,45) …”

“…In that respect, one of the main features of T. spiralis infection is a persistent MC infiltration, an important source of endogenous proteinases (10,28,35). In particular, MC-derived tryptase has been suggested as one of the main endogenous activators of PAR-2 (1).…”

“…Muscle-stage larvae of T. spiralis were obtained from infected CD1 mice as previously described (4,35,43). Rats were infected at 8 -9 wk of age by administration of 7,500 T. spiralis larvae suspended in 1 ml of saline by oral gavage, and studies were performed on days 14 and 30 postinfection.…”

“…For this purpose, we used Trichinella spiralis (T. spiralis)-infected rats, a validated model of MCassociated enteritis and gut dysfunction that is regarded as a valid model of IBS (7,10,35,43). We studied how intestinal function was affected under basal conditions and after PAR-2 activation in the early and the late postinfectious phases.…”

Expression of vasoactive intestinal polypeptide, substance P and neuropeptide Y in jejunal enteric nerves is altered in rabbits suffering from long term Trichinella spiralis infection: an immunohistochemical study

“…In the rat, on day 8 post infection (PI) with Nippostrongylus brasiliensis intestinal transit increases whereas on days 10, 12 and 14 no significant changes in relation to healthy animals are observed (Farmer, 1981). In Trichinella spiralis parasitized hosts, stimulation of mucosal mast cells to prolif-erate and release histamine causes local intestinal inflammation (Frieling et al, 1994) and hypermotility (Serna et al, 2006), symptoms which resemble those observed during irritable bowel syndrome. Notably, intense, long term infection of farm animals with trichinellosis (mainly in pigs, cattle and horses) frequently causes weight loss due to reduced productivity, high morbidity and also disqualifies meat intended for human consumption (Eckert, 1996).…”