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Effects of the ACE2 inhibitor GL1001 on acute dextran sodium sulfate-induced colitis in mice

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Abstract

Objective and design

Angiotensin-converting enzyme 2 (ACE2) is expressed in gastrointestinal tissue. Previous studies of GL1001, a potent and selective ACE2 inhibitor, have revealed anti-inflammatory activity in the mouse digestive tract. We hypothesized that GL1001 might also produce beneficial effects in a mouse DSS model of inflammatory bowel disease.

Materials

Female mice were used for study.

Treatment

Animals were treated for 5 days with 5% DSS in the drinking water to induce colitis. For the following 9 days, animals were treated twice daily with GL1001 (30, 100, 300 mg/kg, s.c.), sulfasalazine (150 mg/kg, p.o.), or vehicle.

Methods

Throughout the experiment, body weight, rectal prolapse, stool consistency, and fecal occult blood were monitored. At termination, colon length, histopathology, and myeloperoxidase activity were assessed.

Results

High-dose GL1001 ameliorated DSS-induced disease activity, including rectal prolapse and intestinal bleeding. The most robust effect of GL1001 was observed 48–96 h post DSS treatment and was comparable in magnitude to that of sulfasalazine. Colon pathology and myeloperoxidase activity were also markedly attenuated by high-dose GL1001 treatment, with the most profound effects observed in the distal segment.

Conclusions

The findings support the previously observed anti-inflammatory effects of ACE2 inhibition in gastrointestinal tissue and suggest that GL1001 may have therapeutic utility for inflammatory bowel disease.

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Abbreviations

IBD:

Inflammatory bowel disease

DSS:

Dextran sodium sulfate

Ang:

Angiotensin

Ang I:

Angiotensin I

Ang II:

Angiotensin II

ACE:

Angiotensin-converting enzyme

ACE2:

Angiotensin-converting enzyme 2

AT1 :

Angiotensin II receptor type 1

AT2 :

Angiotensin II receptor type 2

RAS:

Renin-angiotensin system

DAI:

Disease activity index

NSAID:

Nonsteroidal anti-inflammatory drug

MPO:

Myeloperoxidase

TNF-α:

Tumor necrosis factor α

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Authors and Affiliations

  1. Drug Repositioning and Selection, Ore Pharmaceuticals, Inc., 38 Sidney St., Cambridge, MA, 02139, USA

    John J. Byrnes, Stefan Gross, Courtney Ellard, Kelly Connolly, Stephen Donahue & Dominic Picarella

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  1. John J. Byrnes
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  2. Stefan Gross
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  3. Courtney Ellard
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  4. Kelly Connolly
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  6. Dominic Picarella
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Correspondence to John J. Byrnes.

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Responsible Editor: I. Ahnfelt-Rønne.

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Byrnes, J.J., Gross, S., Ellard, C. et al. Effects of the ACE2 inhibitor GL1001 on acute dextran sodium sulfate-induced colitis in mice. Inflamm. Res. 58, 819–827 (2009). https://doi.org/10.1007/s00011-009-0053-3

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  • DOI: https://doi.org/10.1007/s00011-009-0053-3

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