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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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Sahakian, L, Filippone, RT, Stavely, R, Robinson, AM, Yan, XS, Abalo, R, Eri, R ORCID: 0000-0003-1688-8043, Bornstein, JC, Kelley, MR and Nurgali, K 2020 , 'Inhibition of APE1/Ref-1 redox signaling alleviates intestinal dysfunction and damage to myenteric neurons in a mouse model of spontaneous chronic colitis' , Inflammatory Bowel Diseases , pp. 1-19 , doi: 10.1093/ibd/izaa161.

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Abstract

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 tooxidative stress. In this study, we aimed to determine whether an APE1/Ref-1 redox domain inhibitor, APX3330, alleviates inflammation-inducedoxidative 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. Invivo 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 inneuroprotective 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 forthe treatment of IBD.

Item Type: Article
Authors/Creators:Sahakian, L and Filippone, RT and Stavely, R and Robinson, AM and Yan, XS and Abalo, R and Eri, R and Bornstein, JC and Kelley, MR and Nurgali, K
Keywords: APE1/Ref-1, APX3330, enteric nervous system, chronic intestinal inflammation, IBD, oxidative stress, DNA damage
Journal or Publication Title: Inflammatory Bowel Diseases
Publisher: Lippincott Williams & Wilkins
ISSN: 1078-0998
DOI / ID Number: 10.1093/ibd/izaa161
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© 2020 Crohn’s & Colitis Foundation.

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