Scientific Abstract
Proposal No. IBD-0013
Principal Investigator: Daniel S. Straus, Ph.D.
Applicant Organization: University of California, Riverside (U.S.A.)
Project Title: Trial of anti-inflammatory prostaglandins for treatment of inflammatory bowel disease in IL-10 knockout mice
Period of Award: August 1, 2002 - July 31, 2004
The purpose of this project is to test the activity of the cyclopentenone prostaglandin 15d-PGJ2 and analogs of this compound for treatment of mouse models for inflammatory bowel disease (IBD). The principal model to be used is the IL-10 knockout (IL-10o/o) mouse, which develops IBD spontaneously at an early age.
The etiology of IBD in humans is poorly understood, but it is characterized by an aberrant inflammatory response leading ultimately to severe tissue damage in the inflamed region of the intestines. In view of the devastating nature of IBD and the limited effectiveness of current therapies, it would be extremely helpful to have more potent anti-inflammatory drugs with fewer side effects.
We and others have recently demonstrated strong anti-inflammatory activity of 15d-PGJ2 in cell culture model systems. 15d-PGJ2 is a high affinity ligand for the nuclear receptor PPARγ and modulates transcription by binding to this receptor. Other activities of 15d-PGJ2 are mediated by the reactive a,b-unsaturated carbonyl group located in the cyclopentenone ring. The transcription factor NF-κB and its activating kinase are key targets for the anti-inflammatory activity of 15d-PGJ2, which inhibits NF-κB-mediated transcriptional activation by PPARγ-dependent and independent mechanisms.
In the proposed project, 15d-PGJ2 will be administered subcutaneously, intraperitoneally, or rectally, in order to evaluate its therapeutic effect in IBD caused by IL-10 deficiency in mice. A number of endpoints will be examined, including disease activity, histopathology, the presence of cells with activated NF-κB, and the levels of inflammatory cytokines in the cecum and colon. My collaborator, Dr. Kay Brummond, is synthesizing 15d-PGJ2 in adequate quantities for the testing in mice and will also synthesize several analogs of 15d-PGJ2 predicted to have increased anti-inflammatory activity. These compounds have an electron withdrawing substituent in the cyclopentenone ring, which is predicted to increase anti-inflammatory potency. Positive results in these experiments would provide a rationale for further testing of 15d-PGJ2 or its analogs for treatment of humans with IBD.