Yazbeck Roger, Howarth Gordon S, Geier Mark S, Demuth Hans-Ulrich, Abbott Catherine A
School of Biological Sciences, Flinders University, Adelaide, South Australia, Australia.
Front Biosci. 2008 May 1;13:6850-8. doi: 10.2741/3193.
New treatment strategies are required for the debilitating inflammatory bowel diseases (IBD), Crohn's Disease and Ulcerative Colitis. DP inhibitors can prolong the bioactivity of the potent intestinotrophic growth factor glucagon-like peptide-2 (GLP-2(1-33)). We investigated whether novel inhibitors of DP activity could modify the course of disease activity in the dextran sulfate sodium (DSS) model of colitis. C57BL/6 mice consumed 2 percent DSS in drinking water for 6 days. Mice were orally gavaged twice daily with 0.9% saline, 10 mg/kg isoleucyl-cyano-pyrrolidine (P59/99) or isoleucyl-thiazolidine (P32/98). Assessment of disease severity incorporated a disease activity index (DAI), together with histological assessment of crypt area and depth in the distal colon. DP activity was significantly inhibited at all time points. The DAI was significantly lower in the P59/99 and P32/98 treatment groups compared to saline treatment in all three time courses. Crypt hyperplasia (p<0.05) was observed in the saline group compared to P32/98 treatment at day 9. This preliminary study shows that novel inhibitors of DP activity may provide a new treatment strategy for IBD.
对于使人衰弱的炎症性肠病（IBD）、克罗恩病和溃疡性结肠炎，需要新的治疗策略。二肽基肽酶（DP）抑制剂可以延长强效肠道营养生长因子胰高血糖素样肽-2（GLP-2(1-33)）的生物活性。我们研究了新型DP活性抑制剂是否能改变葡聚糖硫酸钠（DSS）诱导的结肠炎模型中的疾病活动进程。C57BL/6小鼠饮用含2% DSS的水6天。小鼠每天经口灌胃两次，分别给予0.9%生理盐水、10 mg/kg异亮氨酰-氰基-吡咯烷（P59/99）或异亮氨酰-噻唑烷（P32/98）。疾病严重程度评估包括疾病活动指数（DAI），以及对远端结肠隐窝面积和深度的组织学评估。在所有时间点，DP活性均受到显著抑制。在所有三个时间进程中，P59/99和P32/98治疗组的DAI均显著低于生理盐水治疗组。与第9天P32/98治疗组相比，生理盐水组观察到隐窝增生（p<0.05）。这项初步研究表明，新型DP活性抑制剂可能为炎症性肠病提供一种新的治疗策略。
