Department of Pharmacology and Pharmacotherapy, University of Pécs, Pécs, Hungary.
Inflamm Res. 2014 May;63(5):399-409. doi: 10.1007/s00011-014-0712-x. Epub 2014 Jan 28.
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.
使用 NK1 受体缺陷小鼠和选择性拮抗剂奈妥吡坦研究神经激肽 1（NK1）受体在 DSS 诱导的小鼠结肠炎模型中的作用。
C57BL/6 和 Tacr1 KO 动物通过口服 20mg/ml DSS 溶液 7 天诱导结肠炎（n=5-7）。
在诱导过程中，一半 C57BL/6 和 Tacr1 KO 组每天接受一次 6mg/kg 奈妥吡坦腹膜内给药，另一半组接受生理盐水。
在 7 天内测定疾病活动指数（DAI），根据粪便稠度、血液和体重减轻确定。对结肠样本进行组织学评估、髓过氧化物酶（MPO）测量、细胞因子浓度和受体表达分析。
NK1 受体在 DSS 治疗后在结肠中上调。DSS 增加了野生型小鼠的 DAI、组织病理学评分、BLC、sICAM-1、IFN-γ、IL-16 和 JE，而在 NK1 受体缺陷型小鼠中则显著降低。奈妥吡坦对 NK1 受体的拮抗作用显著减轻了野生型小鼠的 DAI、炎症性组织病理学改变、BLC、IFN-γ、IL-13 和 IL-16，但对 NK1 缺陷型小鼠则无明显影响。MPO 也显著升高，奈妥吡坦显著降低了两组的活性。
NK1 受体拮抗作用可能通过抑制不同的炎症机制对结肠炎有益。
