Mo1312 Transient Receptor Potential Ankyrin 1 (TRPA1) Agonists Improve Intestinal Transit in Murine Postoperative Ileus Model

Abstract

Background/Aim: Transient receptor potential ankyrin 1 (TRPA1) locates in the cell membrane of enterochromaffin cells (EC), and TRPA1 stimulation on EC is proposed to modulate intestinalmotility via release of serotonin (5-HT). Although a previous study has demonstrated that TRPA1 agonists produce a contractile response in isolated intestinal muscle strips in vitro, apparently contradictory results have been reported for gastrointestinal (GI) transit in vivo. The Japanese traditional medicine daikenchuto (TU-100), which is being investigated as a new drug in the US and is used for the treatment of postoperative ileus (POI) in Japan, was reported to accelerate GI transit in animals and humans. TU-100 has recently been shown to increase intestinal blood flow via stimulation of TRPA1 located on the epithelial cells of the small intestine. The present study investigates the effects of TU-100, TU-100 ingredients, and TRPA1 agonists on dysregulated intestinal transit in an established murine POI model. Methods: The POI model, which involves manipulation of colon and small intestinal transit, was evaluated by calculating the geometric center of distribution of fluorescent-labeled dextran markers. The in vitro motility of isolated mouse small intestine in an organ bath was evaluated by video imaging and intraluminal pressure was measured by a strain gauge transducer. 5-HT release from isolated small intestinal segments or a rat pancreatic endocrine cell line RIN-14B, which is supposed to have common properties with EC, was measured by ELISA and/or HPLC. The tested compounds included the well known TRPA1 agonists aryl isothiocyanate (AITC) and cinnamaldehyde (CA), as well as TU-100 and its ingredients shogaol and hydroxy-α-sanshool, which stimulate TRPA1. TRPA1 KO mice were also studied. Results: Orally administered TRPA1 agonists, TU-100, and TU100 ingredients improved small intestinal transit in the POI model. Incubation of small intestinal segments with TRPA1 agonists and TU-100 ingredients resulted in an increase in the level of 5-HT in the culture supernatant. The effects of AITC and TU-100 ingredients, but not CA, were abrogated in TRPA1 KO mice. All agents induced the release of 5-HT from RIN14B cells Conclusion: TRPA1 stimulation by TU-100 may be involved in its beneficial effect on POI. The role of TRPA1 in GI motility deserves further extensive investigation with the aim of developing a novel therapeutic strategy to treat GI motility disorders.