Role of neurokinin 1 receptors in dextran sulfate-induced colitis: studies with gene-deleted mice and the selective receptor antagonist netupitant
- 358 Downloads
Objective and design
The function of the neurokinin 1 (NK1) receptor was investigated in the DSS-induced mouse colitis model using NK1 receptor-deficient mice and the selective antagonist netupitant.
Colitis was induced by oral administration of 20 mg/ml DSS solution for 7 days in C57BL/6 and Tacr1 KO animals (n = 5–7).
During the induction, one-half of the C57BL/6 and Tacr1 KO group received one daily dose of 6 mg/kg netupitant, administered intraperitoneally, the other half of the group received saline, respectively.
Disease activity index (DAI), on the basis of stool consistency, blood and weight loss, was determined over 7 days. Histological evaluation, myeloperoxidase (MPO) measurement, cytokine concentrations and receptor expression analysis were performed on the colon samples.
NK1 receptors are up-regulated in the colon in response to DSS treatment. DSS increased DAI, histopathological scores, BLC, sICAM-1, IFN-γ, IL-16 and JE in wildtype mice, which were significantly reduced in NK1 receptor-deficient ones. NK1 receptor antagonism with netupitant significantly diminished DAI, inflammatory histopathological alterations, BLC, IFN-γ, IL-13 and IL-16 in wildtype mice, but not in the NK1-deficient ones. MPO was similarly elevated and netupitant significantly decreased its activity in both groups.
NK1 receptor antagonism could be beneficial for colitis via inhibiting different inflammatory mechanisms.
KeywordsNeurogenic inflammation Tachykinins Inflammatory bowel disease Edema NK1 receptor antagonist
This work was supported by SROP-4.2.2.A-11/1/KONV-2012-0024, SROP-4.2.1.B-10/2/KONV-2010-0002, SROP-4.2.2.B-10/1/2010-0029. Alexandra Berger and Christopher J. Paige were supported by Terry Fox Program Project Grant (National Cancer Institute of Canada #015005), Canadian Institute of Health Research (#9862).
- 10.Renzi D, Mantellini P, Calabrò A, Panerai C, Amorosi A, Paladini I, et al. Substance P and vasoactive intestinal polypeptide but not calcitonin gene-related peptide concentrations are reduced in patients with moderate and severe ulcerative colitis. Ital J Gastroenterol Hepatol. 1998;30:62–70.PubMedGoogle Scholar
- 16.Mazelin L, Theodorou V, More J, Emonds-Alt X, Fioramonti J, Bueno L, et al. Comparative effects of nonpeptide tachykinin receptor agonists on experimental gut inflammation in rats and guinea-pigs. Tachykin Gut Inflamm. 1998;63:293–304.Google Scholar
- 21.Rees V, Dieleman LA, Palmen MJHJ, Akol H, Bloemena E, Pena SGMM AS. Chronic experimental colitis induced by dextran sulphate sodium (DSS) is characterized by Th1 and Th2 cytokines. Clin Exp Immunol. 2001;2:385–91.Google Scholar
- 24.Scheiffele F, Fuss IJ (2002) Induction of TNBS colitis in mice. Curr. Protoc. Immunol. Chapter 15:Unit 15.19.Google Scholar
- 32.Von Euler US, Gaddum JH. An unidentified depressor substance in certain tissue extracts. J Physiol. 1931;72(1):74–86.Google Scholar
- 39.Biolow M, Shigemoto R, Yokota Y, Tsuchida K, Nakanishi S. Cloning and expression of a rat neuromedin K receptor cDNA. J Biol Chem. 1990;265:623–8.Google Scholar