Inhibiting dipeptidyl peptidase activity partially ameliorates colitis in mice.
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.
School of Biological Sciences, Flinders University, Adelaide, South Australia, Australia.
Roger
R
Yazbeck
Gordon S
GS
Howarth
Mark S
MS
Geier
Hans-Ulrich
HU
Demuth
Catherine A
CA
Abbott
D000818:Animals; D003092:Colitis / Q000188:drug therapy* / Q000201:enzymology; D018819:Dipeptidyl Peptidase 4 / Q000097:blood*; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000627:therapeutic use*; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004195:Disease Models, Animal; D015212:Inflammatory Bowel Diseases / Q000188:drug therapy / Q000201:enzymology; D007700:Kinetics; D051379:Mice
D054873:Dipeptidyl-Peptidase IV Inhibitors; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; D018819:Dipeptidyl Peptidase 4