Therapeutic treatment with a novel hypoxia-inducible factor hydroxylase inhibitor (TRC160334) ameliorates murine colitis.
OBJECTIVE
Mucosal healing in inflammatory bowel disease (IBD) can be achieved by improvement of intestinal barrier protection. Activation of hypoxia-inducible factor (HIF) has been identified as a critical factor for barrier protection during mucosal insult and is linked with improvement in symptoms of colitis. Although prophylactic efficacy of HIF hydroxylase inhibitors in murine colitis have been established, its therapeutic efficacy in clinically relevant therapeutic settings have not been established. In the present study we aim to establish therapeutic efficacy of TRC160334, a novel HIF hydroxylase inhibitor, in animal models of colitis.


METHODS
The efficacy of TRC160334 was evaluated in two different mouse models of colitis by oral route. A prophylactic efficacy study was performed in a 2,4,6-trinitrobenzene sulfonic acid-induced mouse model of colitis representing human Crohn's disease pathology. Additionally, a therapeutic efficacy study was performed in a dextran sulfate sodium-induced mouse model of colitis, a model simulating human ulcerative colitis.


RESULTS
TRC160334 treatment resulted in significant improvement in disease end points in both models of colitis. TRC160334 treatment resulted into cytoprotective heatshock protein 70 induction in inflamed colon. TRC160334 successfully attenuated the rate of fall in body weight, disease activity index, and macroscopic and microscopic scores of colonic damage leading to overall improvement in study outcome.


CONCLUSIONS
Our findings are the first to demonstrate that therapeutic intervention with a HIF hydroxylase inhibitor ameliorates IBD in disease models. These findings highlight the potential of TRC160334 for its clinical application in the treatment of IBD.
Department of Pharmacology, Torrent Pharmaceuticals Ltd, Gandhinagar, Gujarat, India.
Ram
R
Gupta
Cellular and Molecular Biology, Torrent Pharmaceuticals Ltd, Gandhinagar, Gujarat, India.
Anita R
AR
Chaudhary
Department of Pharmacology, Torrent Pharmaceuticals Ltd, Gandhinagar, Gujarat, India.
Binita N
BN
Shah
Preclinical Safety Evaluation, Torrent Pharmaceuticals Ltd, Gandhinagar, Gujarat, India.
Avinash V
AV
Jadhav
Department of Pharmacology, Torrent Pharmaceuticals Ltd, Gandhinagar, Gujarat, India.
Shitalkumar P
SP
Zambad
Discovery, Torrent Research Centre, Torrent Pharmaceuticals Ltd, Gandhinagar, Gujarat, India.
Ramesh Chandra
RC
Gupta
Discovery, Torrent Research Centre, Torrent Pharmaceuticals Ltd, Gandhinagar, Gujarat, India.
Shailesh
S
Deshpande
Discovery, Torrent Research Centre, Torrent Pharmaceuticals Ltd, Gandhinagar, Gujarat, India.
Vijay
V
Chauthaiwale
Discovery, Torrent Research Centre, Torrent Pharmaceuticals Ltd, Gandhinagar, Gujarat, India.
Chaitanya
C
Dutt
HIF activation; IBD; hypoxia-inducible factor