Suramin attenuates dystrophin‐deficient cardiomyopathy in the <i>mdx</i> mouse model of duchenne muscular dystrophy

Moreira, Drielen de Oliveira; Pereira, Juliana Vianna; Taniguti, Ana Paula Tiemi; Matsumura, Cíntia Yuri; Ramos, Luis Alberto Ferreira; Áreas, Miguel Arcanjo; Neto, Humberto Santo; Marques, Maria Júlia

doi:10.1002/mus.23858

Cited by 11 publications

(6 citation statements)

References 44 publications

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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 . Imatinib mesylate inhibited TFG-β pro-fibrogenic activity, decreased creatine kinase 99 , reduced fibrosis, and improve hind limb grip strength 100 in mdx mice.…”

Section: Drugs Targeting Fibrosismentioning

confidence: 81%

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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Section: Drugs Targeting Fibrosismentioning

confidence: 81%

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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“…The dosage of suramin (60 mg/kg twice weekly i.p.) was selected according to previous studies that effectively reduce myocardial fibrosis, inflammation, and myonecrosis in the mdx mouse model of Duchenne muscular dystrophy [ 28 , 29 , 30 ]. As shown in Figure 2 B and Supplementary Table S1 , the suramin-treated Pkd1 -miR Tg mice tended to have reduced kidney weights compared with saline-treated mutant mice, but the kidney-to-body weight ratios were not significantly different between the control and treatment groups ( Figure 2 C), possibly due to lower body weights found in the suramin-treated mice.…”

Section: Resultsmentioning

confidence: 99%

“…A recent study showed that suramin may induce phospholipidosis via the inhibition of lysosomal phospholipase A2 [ 51 ]. The dose of suramin used in the current study is still within the non-cytotoxic concentration range according to previous studies in mouse models of cardiac fibrosis and lung injury [ 28 , 29 , 30 ]. Although further studies using other animal models for PKD and different dosing schedules are needed to confirm our results, our findings raised an important safety concern about using suramin in the setting of PKD due to drug-induced kidney injury and lysosomal damage.…”

Section: Discussionmentioning

confidence: 99%

Effects of Suramin on Polycystic Kidney Disease in a Mouse Model of Polycystin-1 Deficiency

Chang

Hsu

et al. 2022

IJMS

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The aberrant activation of the purinergic signaling pathway has been shown to promote cyst growth and fluid secretion in autosomal dominant polycystic kidney disease (ADPKD). Suramin is an anti-parasitic drug that has strong anti-purinergic properties. Whether suramin could have a therapeutic effect on ADPKD has not been fully investigated. We examined the effect of suramin on cyst progression in a Pkd1 microRNAs transgenic mouse model that presented stable Pkd1 knockdown and moderate disease progression. The Pkd1-deficient mice were treated with suramin (60 mg/kg) by intraperitoneal injection twice a week from postnatal days 35 to 90. Kidney-to-body weight ratios, cyst indices, and blood urea nitrogen (BUN) levels were measured. Cell proliferation and macrophage infiltration were determined by immunohistochemistry. The suramin-treated group had significantly lower renal cyst densities, cell proliferation, and macrophage infiltration compared with saline-treated controls. Suramin significantly inhibited ERK phosphorylation and the expression of Il1b, Il6, Nlrp3, Tgfb, Fn1, P2rx7, and P2ry2 mRNAs in the kidneys. However, BUN levels remained high despite the reduction in cyst growth. Furthermore, plasma cystatin C and neutrophil gelatinase-associated lipocalin (NGAL) levels were significantly higher in the suramin-treated group compared with the control group. Periodic acid-Schiff staining revealed degenerative changes and epithelial cell vacuolation in the non-cystic renal tubules, which indicated phospholipidosis following suramin treatment. These results suggest that suramin may reduce renal cyst growth and inflammation, but the associated tubular cell injuries could limit its therapeutic potential. Other purinergic receptor antagonists with less nephrotoxicity may deserve further investigation for the treatment of ADPKD.

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“…The corresponding clinical trials were terminated. Suramin is a TGF-β inhibitor that has shown antifibrotic function in mdx mice ( De Oliveira Moreira et al, 2013 ). The treatment of Suramin reduces the level of creatine kinase and attenuates fibrosis in skeletal muscles in mdx mice ( De Oliveira Moreira et al, 2013 , 2017 ).…”

Section: Therapeutic Strategies Targeting the Secondary Downstream Pathological Mechanismsmentioning

confidence: 99%

“…Suramin is a TGF-β inhibitor that has shown antifibrotic function in mdx mice ( De Oliveira Moreira et al, 2013 ). The treatment of Suramin reduces the level of creatine kinase and attenuates fibrosis in skeletal muscles in mdx mice ( De Oliveira Moreira et al, 2013 , 2017 ). Besides, Suramin can protect muscles against exercise-induced damage in mdx mice ( Taniguti et al, 2011 ).…”

Section: Therapeutic Strategies Targeting the Secondary Downstream Pathological Mechanismsmentioning

confidence: 99%

Current Pharmacological Strategies for Duchenne Muscular Dystrophy

Yao

Chen

et al. 2021

Front. Cell Dev. Biol.

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Duchenne muscular dystrophy (DMD) is a lethal, X-linked neuromuscular disorder caused by the absence of dystrophin protein, which is essential for muscle fiber integrity. Loss of dystrophin protein leads to recurrent myofiber damage, chronic inflammation, progressive fibrosis, and dysfunction of muscle stem cells. There is still no cure for DMD so far and the standard of care is principally limited to symptom relief through glucocorticoids treatments. Current therapeutic strategies could be divided into two lines. Dystrophin-targeted therapeutic strategies that aim at restoring the expression and/or function of dystrophin, including gene-based, cell-based and protein replacement therapies. The other line of therapeutic strategies aims to improve muscle function and quality by targeting the downstream pathological changes, including inflammation, fibrosis, and muscle atrophy. This review introduces the important developments in these two lines of strategies, especially those that have entered the clinical phase and/or have great potential for clinical translation. The rationale and efficacy of each agent in pre-clinical or clinical studies are presented. Furthermore, a meta-analysis of gene profiling in DMD patients has been performed to understand the molecular mechanisms of DMD.

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Suramin attenuates dystrophin‐deficient cardiomyopathy in the mdx mouse model of duchenne muscular dystrophy

Abstract: These findings suggest that suramin may be a new adjunctive therapy to help improve cardiomyopathy in DMD.

Cited by 11 publications

References 44 publications

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

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

Effects of Suramin on Polycystic Kidney Disease in a Mouse Model of Polycystin-1 Deficiency

Current Pharmacological Strategies for Duchenne Muscular Dystrophy

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