Idebenone Protects against Acute Murine Colitis via Antioxidant and Anti-Inflammatory Mechanisms

Abstract

Oxidative stress is a key player of the inflammatory cascade responsible for the initiation of ulcerative colitis (UC). Although the short chain quinone idebenone is considered a potent antioxidant and a mitochondrial electron donor, emerging evidence suggests that idebenone also displays anti-inflammatory activity. This study evaluated the impact of idebenone in the widely used dextran sodium sulphate (DSS)-induced mouse model of acute colitis. Acute colitis was induced in C57BL/6J mice via continuous exposure to 2.5% DSS over 7 days. Idebenone was co-administered orally at a dose of 200 mg/kg body weight. Idebenone significantly prevented body weight loss and improved the disease activity index (DAI), colon length, and histopathological score. Consistent with its reported antioxidant function, idebenone significantly reduced the colonic levels of malondialdehyde (MDA) and nitric oxide (NO), and increased the expression of the redox factor NAD(P)H (nicotinamide adenine dinucleotide phosphate) dehydrogenase quinone-1 (NQO-1) in DSS-exposed mice. Immunohistochemistry revealed a significantly increased expression of tight junction proteins, which protect and maintain paracellular intestinal permeability. In support of an anti-inflammatory activity, idebenone significantly attenuated the elevated levels of pro-inflammatory cytokines in colon tissue. These results suggest that idebenone could represent a promising therapeutic strategy to interfere with disease pathology in UC by simultaneously inducing antioxidative and anti-inflammatory pathways.

Idebenone Protects against Spontaneous Chronic Murine Colitis by Alleviating Endoplasmic Reticulum Stress and Inflammatory Response

“…Based on this evidence and on our previous results [ 46 ], we hypothesized that idebenone would also confer protection against chronic colitis in the Winnie mouse model of spontaneous colitis. The current study highlights the protective role of idebenone in UC to ameliorate chronic inflammation by simultaneously suppressing ER stress and pro-inflammatory cytokine levels.…”

“…Immunohistochemical analysis was performed to detect the localization of mucin MUC2 proteins using an HRP/DAB Detection IHC kit (ab64621, Abcam, Victoria, Australia), as mentioned previously [ 46 , 50 ]. Briefly, tissue section slides were dewaxed in xylene and rehydrated through a series of graded ethanol before incubating in citrate buffer (pH 6) for antigen retrieval process in a decloaking chamber at 121 °C for 4 min.…”

“…The amount of malondialdehyde (MDA) levels present in colonic tissue was determined using lipid peroxidation colorimetric/fluorometric assay kit (K739, Bio Vision, New South Wales, Australia) as described previously [ 46 , 52 ]. The colon tissues were homogenized in the lysis buffer provided in the kit, followed by centrifugation at 13,000× g to collect supernatant.…”

“…Idebenone is well tolerated and safe for human use as either acute or chronic treatment [ 45 ]. Previously, in a dextran sodium sulfate (DSS)-induced mouse model of acute colitis [ 46 ], idebenone ameliorated intestinal inflammation by an indirect antioxidant effect via upregulating NAD(P)H dehydrogenase quinone 1/superoxide dismutase (NQO-1/SOD) detoxifying enzymes, which was associated with reduced lipid peroxidation. In the same study, idebenone also preserved the expression of the barrier integrity proteins occludin and zona-occludin 1.…”

“…In the same study, idebenone also preserved the expression of the barrier integrity proteins occludin and zona-occludin 1. In this colitis model, idebenone also reduced the levels of several pro-inflammatory cytokines and chemokines down to levels found in healthy animals [ 46 ]. This activity was also reported in a rat model of titanium-dioxide-induced kidney toxicity, where idebenone reduced the levels of interleukins 1, 6 (IL-1, IL-6) and tumor necrosis factor alpha (TNF-α), which was associated with improved kidney function [ 47 ].…”