Therapeutic treatment with a novel hypoxia-inducible factor hydroxylase inhibitor (TRC160334) ameliorates murine colitis

Abstract

Background and aim

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.

Conclusion

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.

Keywords:

• IBD
• hypoxia-inducible factor
• HIF activation

Supplementary figures

Figure S1 Treatment with TRC160334 resulted in improvement in the mean percent change body weight profile of male BALB/c mice made colitic using 2,4,6-trinitrobenzene sulfonic acid.

Notes: Data represent mean ± standard error of the mean. *denotes P<0.05 versus vehicle using Student’s t-test.

Abbreviation: TNBS, 2,4,6-trinitrobenzene sulfonic acid.

Figure S2 Treatment with TRC160334 resulted in improvement in mean disease activity index scores of female BALB/c mice made colitic using dextran sulfate sodium.

Notes: Data represent mean ± standard error of the mean. *denotes P<0.05 versus the dextran sulfate sodium group using analysis of variance followed by Dunnett’s post hoc analysis.

Abbreviations: DSS, dextran sulfate sodium; DAI, disease activity index.

Figure S3 Treatment with TRC160334 showing trends of reduction in mRNA expression of proinflammatory cytokines tumor necrosis factor α and interferon γ and elevation in the expression of the anti-inflammatory cytokine interleukin-10.

Note: Data represent mean ± standard error of the mean.

Abbreviations: DSS, dextran sulfate sodium; IL-10, interleukin-10; INFγ, interferon γ; TNFα, tumor necrosis factor α.

Figure S4 Treatment with TRC160334 resulted in improvement in the mean percent change body weight profile of female BALB/c mice made colitic using dextran sulfate sodium.

Note: Data represent mean ± standard error of the mean.

Abbreviation: DSS, dextran sulfate sodium.

Acknowledgments

The authors would like to thank Mr Prakash Dhamecha and Ms Kinjal Patel for assisting in the experimental work and Mr Ajay Shivalkar for statistical analysis.

Disclosure

The authors declare that no conflict of interest exists and they are all employees of Torrent Pharmaceuticals Ltd, India. The study is supported by Torrent Pharmaceuticals Ltd, India.