Suramin affects metalloproteinase‐9 activity and increases beta‐dystroglycan levels in the diaphragm of the dystrophin‐deficient <i>mdx</i> MOUSE

Taniguti, Ana Paula Tiemi; Matsumura, Cíntia Yuri; Rodrigues‐Simioni, Léa; Neto, Humberto Santo; Marques, Maria Júlia

doi:10.1002/mus.23468

Cited by 12 publications

(14 citation statements)

References 39 publications

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“…b‐DG, which is reduced in the dystrophic fibres, is a main component of the dystrophin‐protein complex that links the cytoskeleton to the extracellular matrix, protects muscle fibres from mechanical stress and confers sarcolemmal reliance during contraction . Therefore, it is possible to suggest that the combined therapy improved sarcolemma stability by significantly increasing the levels of b‐DG, in agreement to other reports . The increase in b‐DG observed here may be related to the actions of both therapies (primarily the combined) in decreasing the levels of MMP‐9 because DFZ and DOX have anti‐MMP‐9 activity and b‐DG is a substrate of MMP‐9 …”

Section: Discussionsupporting

confidence: 89%

Co‐administration of deflazacort and doxycycline: a potential pharmacotherapy for Duchenne muscular dystrophy

Pereira

Marques

Neto

2015

Clin Exp Pharma Physio

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The standard therapy used in the treatment of Duchenne muscle dystrophy (DMD) is corticoids, such as deflazacort and prednisone. However, they have limited therapeutic value, and their combination with drugs already in use to treat other human diseases could potentially increase corticoid outcomes in DMD. In the present study, we evaluated whether a combined therapy of the corticoid deflazacort with doxycycline could result in greater improvement in mdx dystrophy than deflazacort alone. Deflazacort alone or deflazacort/doxycycline were administered for 36 days (starting on postnatal day 0) in drinking water. Histopathological, biochemical (creatine kinase), functional (forelimb muscle grip strength and fatigue) parameters and inflammatory markers (MMP-9, TNF-α, NF-kB) were evaluated in biceps brachii and diaphragm muscles of the mdx mice. The combined therapy was superior in improving the dystrophic phenotype compared to monotherapy. The primary results were observed in attenuating muscle fatigue, decreasing muscle total calcium and inflammatory markers and increasing β-dystroglycan, a main component of the dystrophin-protein complex. Furthermore, the combined therapy was effective in preventing the loss of body mass observed with deflazacort alone at this very early stage of therapy. The present study offers preclinical data to support further studies with deflazacort/doxycycline combined therapy in DMD clinical trials.

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Section: Discussionsupporting

confidence: 89%

Co‐administration of deflazacort and doxycycline: a potential pharmacotherapy for Duchenne muscular dystrophy

Pereira

Marques

Neto

2015

Clin Exp Pharma Physio

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“…Late‐stage therapy with the anti‐fibrotic drug suramin can ameliorate the diaphragm dysfunction (Taniguti et al . ). The present results suggest that early therapy with anti‐fibrotic drugs may protect the mdx diaphragm muscle against fibrosis, which is of relevance to DMD therapy because patients eventually suffer from respiratory failure due to extensive fibrosis.…”

Section: Discussionmentioning

confidence: 97%

Changes in calsequestrin, TNF‐α, TGF‐β and MyoD levels during the progression of skeletal muscle dystrophy in mdx mice: a comparative analysis of the quadriceps, diaphragm and intrinsic laryngeal muscles

Maranhão

Moreira

Maurício

et al. 2015

Int J Experimental Path

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In Duchenne muscular dystrophy (DMD), the search for new biomarkers to follow the evolution of the disease is of fundamental importance in the light of the evolving gene and pharmacological therapies. In addition to the lack of dystrophin, secondary events including changes in calcium levels, inflammation and fibrosis greatly contribute to DMD progression and the molecules involved in these events may represent potential biomarkers. In this study, we performed a comparative evaluation of the progression of dystrophy within muscles that are differently affected by dystrophy (diaphragm; DIA and quadriceps; QDR) or spared (intrinsic laryngeal muscles) using the mdx mice model of DMD. We assessed muscle levels of calsequestrin (calcium-related protein), tumour necrosis factor (TNF-α; pro-inflammatory cytokine), tumour growth factor (TGF-β; pro-fibrotic factor) and MyoD (muscle proliferation) vs. histopathology at early (1 and 4 months of age) and late (9 months of age) stages of dystrophy. Fibrosis was the primary feature in the DIA of mdx mice (9 months: 32% fibrosis), which was greater than in the QDR (9 months: 0.6% fibrosis). Muscle regeneration was the primary feature in the QDR (9 months: 90% of centrally nucleated fibres areas vs. 33% in the DIA). The QDR expressed higher levels of calsequestrin than the DIA. Laryngeal muscles showed normal levels of TNF-α, TGF-β and MyoD. A positive correlation between histopathology and cytokine levels was observed only in the diaphragm, suggesting that TNF-α and TGF-β serve as markers of dystrophy primarily for the diaphragm.

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“…Intraperitoneal injection of suramin in 6-month old mdx mice has been shown to increase MMP-2 and MMP-9 activity 96 , decrease creatine kinase, and to attenuate fibrosis in skeletal muscle, but not cardiac muscle 97 . In 8-month old mdx mice, however, suramin did improve cardiomyopathy and decrease myocardial fibrosis, inflammation, and myonecrosis 98 .…”

Section: Drugs Targeting Fibrosismentioning

confidence: 99%

Pharmacological therapeutics targeting the secondary defects and downstream pathology of Duchenne muscular dystrophy

Spinazzola

Kunkel

2016

Expert Opinion on Orphan Drugs

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Introduction Since the identification of the dystrophin gene in 1986, a cure for Duchenne muscular dystrophy (DMD) has yet to be discovered. Presently, there are a number of genetic-based therapies in development aimed at restoration and/or repair of the primary defect. However, growing understanding of the pathophysiological consequences of dystrophin absence has revealed several promising downstream targets for the development of therapeutics. Areas covered In this review, we discuss various strategies for DMD therapy targeting downstream consequences of dystrophin absence including loss of muscle mass, inflammation, fibrosis, calcium overload, oxidative stress, and ischemia. The rationale of each approach and the efficacy of drugs in preclinical and clinical studies are discussed. Expert opinion For the last 30 years, effective DMD drug therapy has been limited to corticosteroids, which are associated with a number of negative side effects. Our knowledge of the consequences of dystrophin absence that contribute to DMD pathology has revealed several potential therapeutic targets. Some of these approaches may have potential to improve or slow disease progression independently or in combination with genetic-based approaches. The applicability of these pharmacological therapies to DMD patients irrespective of their genetic mutation, as well as the potential benefits even for advanced stage patients warrants their continued investigation.

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Suramin affects metalloproteinase‐9 activity and increases beta‐dystroglycan levels in the diaphragm of the dystrophin‐deficient mdx MOUSE

Abstract: These results show the potential benefits of suramin in maintaining the structure of the dystrophin-glycoprotein complex.

Cited by 12 publications

References 39 publications

Co‐administration of deflazacort and doxycycline: a potential pharmacotherapy for Duchenne muscular dystrophy

Co‐administration of deflazacort and doxycycline: a potential pharmacotherapy for Duchenne muscular dystrophy

Changes in calsequestrin, TNF‐α, TGF‐β and MyoD levels during the progression of skeletal muscle dystrophy in mdx mice: a comparative analysis of the quadriceps, diaphragm and intrinsic laryngeal muscles

Pharmacological therapeutics targeting the secondary defects and downstream pathology of Duchenne muscular dystrophy

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