University Of Tasmania
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Inhibition of APE1/Ref-1 redox signaling alleviates intestinal dysfunction and damage to myenteric neurons in a mouse model of spontaneous chronic colitis

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posted on 2023-05-20, 16:24 authored by Sahakian, L, Filippone, RT, Stavely, R, Robinson, AM, Yan, XS, Abalo, R, Rajaraman Eri, Bornstein, JC, Kelley, MR, Nurgali, K

Background:Inflammatory bowel disease (IBD) associates with damage to the enteric nervous system (ENS), leading to gastrointestinal (GI) dysfunction. Oxidative stress is important for the pathophysiology of inflammation-induced enteric neuropathy and GI dysfunction. Apurinic/ apyrimidinic endonuclease 1/redox factor-1 (APE1/Ref-1) is a dual functioning protein that is an essential regulator of the cellular response to oxidative stress. In this study, we aimed to determine whether an APE1/Ref-1 redox domain inhibitor, APX3330, alleviates inflammation-induced oxidative stress that leads to enteric neuropathy in the Winnie murine model of spontaneous chronic colitis.

Methods: Winnie mice received APX3330 or vehicle via intraperitoneal injections over 2 weeks and were compared with C57BL/6 controls. In vivo disease activity and GI transit were evaluated. Ex vivo experiments were performed to assess functional parameters of colonic motility, immune cell infiltration, and changes to the ENS.

Results: Targeting APE1/Ref-1 redox activity with APX3330 improved disease severity, reduced immune cell infiltration, restored GI function ,and provided neuroprotective effects to the enteric nervous system. Inhibition of APE1/Ref-1 redox signaling leading to reduced mitochondrial superoxide production, oxidative DNA damage, and translocation of high mobility group box 1 protein (HMGB1) was involved in neuroprotective effects of APX3330 in enteric neurons.

Conclusions: This study is the first to investigate inhibition of APE1/Ref-1’s redox activity via APX3330 in an animal model of chronic intestinal inflammation. Inhibition of the redox function of APE1/Ref-1 is a novel strategy that might lead to a possible application of APX3330 for the treatment of IBD.


Publication title

Inflammatory Bowel Diseases








School of Health Sciences


Lippincott Williams & Wilkins

Place of publication

530 Walnut St, Philadelphia, USA, Pa, 19106-3621

Rights statement

© 2020 Crohn’s & Colitis Foundation.

Repository Status

  • Restricted

Socio-economic Objectives

Clinical health not elsewhere classified