Dystrophic phenotype improvement in the diaphragm muscle of mdx mice by diacerhein.

Rafael Dias Mâncio,Daniela Sayuri Mizobuti,Túlio De Almeida Hermes,Elaine Minatel,Ian Feller Rupcic,Aline Barbosa Macedo,Atsushi Asakura

doi:10.1371/journal.pone.0182449

Rafael Dias Mâncio, Daniela Sayuri Mizobuti + Show 5 more

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https://doi.org/10.1371/journal.pone.0182449

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Journal: PloS one	Publication Date: Aug 7, 2017
Citations: 15	License type: CC BY 4.0

Affiliation: Universidade Estadual de Campinas

Abstract

Chronic inflammation and oxidative stress are striking features of Duchenne muscular dystrophy disease. Diacerhein is an anthraquinone, which exhibits anti-inflammatory and antioxidant properties. Based on their actions, the present study evaluated the effects of diacerhein against myonecrosis, oxidative stress and inflammatory response in the diaphragm muscle of mdx mice and compared these results to current treatment widely used in DMD patients, with a main focus on the impact of prednisone. The results demonstrated that diacerhein treatment prevented muscle damage indicated by a decrease in the IgG uptake by muscle fibers, lower CK levels in serum, reduction of fibers with central nuclei with a concomitant increase in fibers with peripheral nuclei. It also had an effect on the inflammatory process, decreasing the inflammatory area, macrophage staining and TNF-α and IL-1β content. Regarding oxidative stress, diacerhein treatment was effective in reducing the ROS and lipid peroxidation in the diaphragm muscle from mdx mice. Compared to prednisone treatment, our findings demonstrated that diacerhein treatment improved the dystrophic phenotype in the diaphragm muscle of mdx mice similar to that of glucocorticoid therapy. In this respect, this work suggests that diacerhein has a potential use as an alternative drug in dystrophinopathy treatment and recommends that its anti-inflammatory and antioxidants properties in the dystrophic muscle should be better understood.

Highlights

Duchenne muscular dystrophy (DMD) is a lethal and X-linked muscle disease characterized by cycles of muscle degeneration and regeneration, chronic inflammation and an oxidative stress state, which affects 1 in 3500–6000 live male birth [1,2,3,4].Regarding the inflammatory process, it has been reported that inflammatory cytokines such as tumor necrosis factor α (TNF-α) and interleukin-1β (IL-1β) play a major role in the DMD phenotype [5]
The control (C57BL/10) group and saline, prednisone- and diacerhein-treated mdx groups presented weight gain during the experimental period and there was no significant difference between them (Table 1)
We evaluated the effects of diacerhein, an established drug used for osteoarthritis with important anti-inflammatory and antioxidant properties [20, 28], in mdx mice, focusing on the morphological and molecular alterations of the diaphragm muscle

Summary

Introduction

Duchenne muscular dystrophy (DMD) is a lethal and X-linked muscle disease characterized by cycles of muscle degeneration and regeneration, chronic inflammation and an oxidative stress state, which affects 1 in 3500–6000 live male birth [1,2,3,4]. It has been reported that inflammatory cytokines such as tumor necrosis factor α (TNF-α) and interleukin-1β (IL-1β) play a major role in the DMD phenotype [5]. The experimental model of DMD [6], the TNF-α content has been well characterized and shown to have increased in the diaphragm muscle where inflammation is generally greater in this model [7,8,9]. The IL-1β contributes towards muscular dystrophy, leading to the initiation and continuation of the muscle pathology in DMD [10].

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