Dipeptidyl peptidase 4 inhibitor sitagliptin protected against dextran sulfate sodium-induced experimental colitis by potentiating the action of GLP-2  

作　　者：Meng-meng Ning Wen-ji Yang Wen-bo Guan Yi-pei Gu Ying Feng Ying Leng 

机构地区：[1]State Key Laboratory of Drug Research,Shanghai Institute of Materia Medica,Chinese Academy of Sciences,Shanghai 201203,China [2]University of Chinese Academy of Sciences,Beijing 100049,China

出　　处：《Acta Pharmacologica Sinica》2020年第11期1446-1456,共11页中国药理学报（英文版）

基　　金：supported by a grant from the National Natural Science Foundation of China(no.81872922).

摘　　要：Dipeptidyl peptidase 4(DPP4),a ubiquitously expressed protease that cleaves off the N-terminal dipeptide from proline and alanineon the penultimate position,has important roles in many physiological processes.In the present study,experimental colitis wasinduced in mice receiving 3%dextran sulfate sodium(DSS)in drinking water.We found that mice with DSS-induced colitis hadsignificantly increased intestinal DPP activity and decreased serum DPP activity,suggesting a probable correlation of DPP4 withexperimental colitis.Then,we investigated whether sitagliptin,a specific DPP4 inhibitor could protect against DSS-induced colitis.We showed that oral administration of single dose of sitagliptin(30 mg/kg) on D7 remarkably inhibited DPP enzyme activity in bothserum and intestine of DSS-induced colitic mice.Repeated administration of sitagliptin(10,30 mg/kg,bid,from D0 to D8)significantly ameliorated DSs-induced colitis,including reduction of disease activity index(DAl)and body weight loss,improvementof histological score and colon length.Sitagliptin administration dose-dependently increased plasma concentrations of active formof GLP-1 and colonic expression of GLP-2R.Co-administration of GLP-2R antagonist GLP-23(500 μg/kg,bid,sc)abolished theprotective effects of sitagliptin in DSS-induced colitic mice.Moreover,sitagliptin administration significantly decreased the ratio ofapoptotic cells and increased the ratio of proliferative cels in colon epithelium of DSs-induced colitic mice,and this effect was alsoblocked by GLP-2^3-33.Taken together,our results demonstrate that sitagliptin could attenuate DSS-induced experimental colits andthe effects can be attributed to the enhancement of GLP-2 action and the subsequent protective effects on intestinal barier byinhibiting epithelial cells apoptosis and promoting their proliferation.These findings suggest sitagliptin as a novel therapeuticapproach for the treatment of ulcerative colitis.

关 键 词：ulcerative colitis dextran sulfate sodium dipeptidyl peptidase 4 SITAGLIPTIN glucagon-like peptide-2 GLP-2^3-33 APOPTOSIS PROLIFERATION 

分 类 号：R96[医药卫生—药理学]