Vanilloid receptor 1 antagonists attenuate disease severity in dextran sulphate sodium-induced colitis in mice
Vanilloid receptor 1 antagonists attenuate disease severity in dextran sulphate sodium-induced colitis in mice
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DOI：
10.1111/j.1365-2982.2004.00549.x
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发表时间：
2004-12-01
影响因子：
3.5
通讯作者：
Hornby, PJ
中科院分区：
文献类型：
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作者：
Kimball, ES;Wallace, NH;Hornby, PJ
神经原性机制与炎症性肠病（IBD）的诱导有关。在支配胃肠道的内源性和外源性传入神经元的神经末梢上已经观察到1型香草酸受体（TRPV 1），并且局部施用TRPV 1拮抗剂辣椒平降低了大鼠中葡聚糖硫酸钠（DSS）诱导的结肠炎的严重程度（Gut 2003; 52：713-9（1））。我们的目的是测试是否全身或口服给药TRPV 1拮抗剂减弱Balb/c小鼠中由5%DSS诱导的实验性结肠炎。腹腔注射辣椒平（2.5 mg/kg，bid），与溶剂处理组相比，显著降低了整体宏观损伤的严重程度（80%抑制，P < 0.05）;然而，对髓过氧化物酶（MPO）水平没有影响。口服TRPV 1拮抗剂对DSS诱导的结肠炎进行了试验，结果表明，在0.5和5.0 mg/kg的剂量下，TRPV 1拮抗剂可逆转肉眼可见的损伤评分。显微镜下评估的上皮损伤显著减少。MPO水平降低了约50%，腹泻评分降低了70%。这些结果表明，TRPV 1的药理学调节减弱小鼠实验性结肠炎的指数，口服活性TRPV 1拮抗剂的开发可能具有治疗IBD的治疗潜力。
Neurogenic mechanisms have been implicated in the induction of inflammatory bowel disease (IBD). Vanilloid receptor type 1 (TRPV1) has been visualized on nerve terminals of intrinsic and extrinsic afferent neurones innervating the gastrointestinal tract and local administration of a TRPV1 antagonist, capsazepine, reduces the severity of dextran sulphate sodium (DSS)-induced colitis in rats (Gut 2003; 52: 713-9(1)). Our aim was to test whether systemically or orally administered TRPV1 antagonists attenuate experimental colitis induced by 5% DSS in Balb/c mice. Intraperitoneal capsazepine (2.5 mg kg(-1), bid), significantly reduced the overall macroscopic damage severity compared with vehicle-treated animals (80% inhibition, P < 0.05); however, there was no effect on myeloperoxidase (MPO) levels. An experimental TRPV1 antagonist given orally was tested against DSS-induced colitis, and shown to reverse the macroscopic damage score at doses of 0.5 and 5.0 mg kg(-1). Epithelial damage assessed microscopically was significantly reduced. MPO levels were attenuated by approximately 50%, and diarrhoea scores were reduced by as much as 70%. These results suggest that pharmacological modulation of TRPV1 attenuates indices of experimental colitis in mice, and that development of orally active TRPV1 antagonists might have therapeutic potential for the treatment of IBD.