Role of neurokinin 1 receptors in dextran sulfate-induced colitis: studies with gene-deleted mice and the selective receptor antagonist netupitant
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- 作者：István Szitter (1) (2)
Erika Pintér (1) (2) (3)
Anikó Perkecz (1) (2)
ágnes Kemény (1) (2)
József Kun (1) (2)
László Kereskai (4)
Claudio Pietra (5)
John P. Quinn (6)
Andreas Zimmer (7)
Alexandra Berger (8) (9)
Christopher J. Paige (8) (9)
Zsuzsanna Helyes (1) (2) (3) - 关键词：Neurogenic inflammation ; Tachykinins ; Inflammatory bowel disease ; Edema ; NK1 receptor antagonist
- 刊名：Inflammation Research
- 出版年：2014
- 出版时间：May 2014
- 年：2014
- 卷：63
- 期：5
- 页码：399-409
- 全文大小：1,909 KB
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Erika Pintér (1) (2) (3)
Anikó Perkecz (1) (2)
ágnes Kemény (1) (2)
József Kun (1) (2)
László Kereskai (4)
Claudio Pietra (5)
John P. Quinn (6)
Andreas Zimmer (7)
Alexandra Berger (8) (9)
Christopher J. Paige (8) (9)
Zsuzsanna Helyes (1) (2) (3)
1. Department of Pharmacology and Pharmacotherapy, University of Pécs, Pécs, Hungary
2. János Szentágothai Research Centre, Pécs, Hungary
3. PharmInVivo Ltd., Pécs, Hungary
4. Department of Pathology, University of Pécs, Pécs, Hungary
5. Helsinn Healthcare SA, Preclinical R&D, Pambio-Noranco, Lugano, Switzerland
6. Department of Molecular and Clinical Pharmacology, Institute of Translation, University of Liverpool, Liverpool University, Liverpool, UK
7. Institute of Molecular Psychiatry, University of Bonn, Bonn, Germany
8. Ontario Cancer Institute, University Health Network, Toronto, Canada
9. Department of Immunology, University of Toronto, Toronto, Canada - ISSN：1420-908X
文摘
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. Subjects Colitis was induced by oral administration of 20?mg/ml DSS solution for 7?days in C57BL/6 and Tacr1 KO animals (n?=?5-). Treatment 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. Methods 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. Results 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. Conclusions NK1 receptor antagonism could be beneficial for colitis via inhibiting different inflammatory mechanisms.