Transient receptor potential ankyrin 1 agonists improve intestinal transit in a murine model of postoperative ileus.
BACKGROUND
Stimulation of transient receptor potential ankyrin 1 (TRPA1), which abundantly expressed in enterochromaffin cells (ECC), has been reported to exert apparently contradictory results in in vitro contractility and in vivo gastrointestinal (GI) transit evaluations. The pharmaceutical-grade Japanese traditional medicine daikenchuto (TU-100) has been reported to be beneficial for postoperative ileus (POI) and accelerate GI transit in animals and humans. TU-100 was recently shown to increase intestinal blood flow via stimulation of TRPA1 in the epithelial cells of the small intestine (SI).


METHODS
The effects of various TRPA1 agonists on motility were examined in a manipulation-induced murine POI model, in vitro culture of SI segments and an ECC model cell line, RIN-14B.


RESULTS
Orally administered TRPA1 agonists, aryl isothiocyanate (AITC) and cinnamaldehyde (CA), TU-100 ingredients, [6]-shogaol (6S) and γ-sanshool (GS), improved SI transit in a POI model. The effects of AITC, 6S and GS but not CA were abrogated in TRPA1-deficient mice. SI segments show periodic peristaltic motor activity whose periodicity disappeared in TRPA1-deficient mice. TU-100 augmented the motility. AITC, CA and 6S increased 5-HT release from isolated SI segments and the effects of all these compounds except for CA were lost in TRPA1-deficient mice. 6S and GS induced a release of 5-HT from RIN-14B cells in a dose- and TRPA1-dependent manner.


CONCLUSIONS
Intraluminal TRPA1 stimulation is a potential therapeutic strategy for GI motility disorders. Further investigation is required to determine whether 5-HT and/or ECC are involved in the effect of TRPA1 on motility.
Tsumura Research Laboratories, Tsumura & Co., Ibaraki, Japan.
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K
Tsuchiya
Tsumura Research Laboratories, Tsumura & Co., Ibaraki, Japan.
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K
Kubota
Tsumura Research Laboratories, Tsumura & Co., Ibaraki, Japan.
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K
Ohbuchi
Tsumura Research Laboratories, Tsumura & Co., Ibaraki, Japan.
A
A
Kaneko
Tsumura Research Laboratories, Tsumura & Co., Ibaraki, Japan.
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N
Ohno
Tsumura Research Laboratories, Tsumura & Co., Ibaraki, Japan.
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A
Mase
Tsumura Research Laboratories, Tsumura & Co., Ibaraki, Japan.
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H
Matsushima
Tsumura Research Laboratories, Tsumura & Co., Ibaraki, Japan.
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http://orcid.org/0000-0002-3066-6044
M
Yamamoto
Division of Cancer Pathophysiology, National Cancer Center Research Institute, Tokyo, Japan.
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K
Miyano
Division of Cancer Pathophysiology, National Cancer Center Research Institute, Tokyo, Japan.
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Y
Uezono
Laboratory of Pathophysiology & Therapeutics, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan.|Center for Clinical and Biomedical Research, Sapporo Higashi Tokushukai Hospital, Sapporo, Japan.
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T
Kono
D000171:Acrolein / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D000577:Amides / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005772:Gastrointestinal Transit / Q000187:drug effects* / Q000502:physiology*; D045823:Ileus / Q000188:drug therapy* / Q000503:physiopathology; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D009285:Naphthoquinones / Q000494:pharmacology / Q000627:therapeutic use; D009924:Organ Culture Techniques; D000074025:TRPA1 Cation Channel / Q000819:agonists* / Q000502:physiology*
C559645:12,13-dihydro-N-methyl-6,11,13-trioxo-5H-benzo(4,5)cyclohepta(1,2-b)naphthalen-5,12-imine; D000577:Amides; D009285:Naphthoquinones; D000074025:TRPA1 Cation Channel; C475685:Trpa1 protein, mouse; C100574:sanshool; D000171:Acrolein; C012843:cinnamaldehyde
aryl isothiocyanate; daikenchuto; enterochromaffin cells; shogaol; γ-sanshool