Drug Trial of Superoxide Dismutase in Duchenne's Muscular Dystrophy

Stern, Lawrence Z.; Ringel, Steven P.; Ziter, Fred A.; Menander-Huber, K B; Ionâşescu, Victor; Pellegrino, Richard J.; Snyder, Russell D.

doi:10.1001/archneur.1982.00510180020004

Cited by 45 publications

(21 citation statements)

References 25 publications

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“…This hypothesis is further supported by the finding that in vivo antioxidant treatments provide beneficial effects in mdx skeletal muscle (3,4,9). Unfortunately, clinical trials of antioxidants in DMD patients have shown no clear benefits (14,50). However, these trials have been limited in size and duration and have failed to provide evidence that the ROS status of cells was altered.…”

Section: Discussionmentioning

confidence: 92%

The role of reactive oxygen species in the hearts of dystrophin-deficient mdx mice

Williams

Allen²

2007

American Journal of Physiology-Heart and Circulatory Physiology

139

131

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Duchenne muscular dystrophy (DMD) is caused by deficiency of the cytoskeletal protein dystrophin. Oxidative stress is thought to contribute to the skeletal muscle damage in DMD; however, little is known about the role of oxidative damage in the pathogenesis of the heart failure that occurs in DMD patients. The dystrophin-deficient (mdx) mouse is an animal model of DMD that also lacks dystrophin. The current study investigates the role of the antioxidant N-acetylcysteine (NAC) on mdx cardiomyocyte function, Ca(2+) handling, and the cardiac inflammatory response. Treated mice received 1% NAC in their drinking water for 6 wk. NAC had no effect on wild-type (WT) mice. Immunohistochemistry experiments revealed that mdx mice had increased dihydroethidine (DHE) staining, an indicator of superoxide production; NAC-treatment reduced DHE staining in mdx hearts. NAC treatment attenuated abnormalities in mdx cardiomyocyte Ca(2+) handling. Mdx cardiomyocytes had decreased fractional shortening and decreased Ca(2+) sensitivity; NAC treatment returned mdx fractional shortening to WT values but did not affect the Ca(2+) sensitivity. Immunohistochemistry experiments revealed that mdx hearts had increased levels of collagen type III and the macrophage-specific protein, CD68; NAC-treatment returned collagen type III and CD68 expression close to WT values. Finally, mdx hearts had increased NADPH oxidase activity, suggesting it could be a possible source of increased reactive oxygen species in mdx mice. This study is the first to demonstrate that oxidative damage may be involved in the pathogenesis of the heart failure that occurs in mdx mice. Therapies designed to reduce oxidative damage might be beneficial to DMD patients with heart failure.

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Section: Discussionmentioning

confidence: 92%

The role of reactive oxygen species in the hearts of dystrophin-deficient mdx mice

Williams

Allen²

2007

American Journal of Physiology-Heart and Circulatory Physiology

139

131

View full text Add to dashboard Cite

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“…This early oxidative stress may lead to the initial necrotic bout seen in mdx skeletal muscle and may be an early causative event in initiation and progression of human DMD. While the free radical component of the disease has been well documented, numerous clinical trials using antioxidants have failed to attenuate disease symptoms (Mendell & Wiechers, 1979; Stern et al 1982; Tamari et al 1982; Hunter et al 1983; Gamstorp et al 1986; Fenichel et al 1988). This may indicate that oxidant damage has a role early in disease initiation or progression, but not later.…”

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confidence: 99%

Increased catalase expression improves muscle function inmdxmice

Selsby

2010

Experimental Physiology

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It has been well established that oxidative stress contributes to pathology associated with Duchenne muscular dystrophy (DMD). I hypothesized that overexpression of the antioxidant enzyme catalase would improve muscle function in the mdx mouse, the mouse model of DMD. To test this hypothesis, neonatal mdx mice were injected with a recombinant adeno-associated virus driving the catalase transgene. Animals were killed 4 or 6 weeks or 6 months following injection. Muscle function was generally improved by catalase overexpression. Four weeks following injection, extensor digitorum longus specific tension was improved twofold, while soleus was similar between groups. Resistance to contraction-induced injury was similar between groups; however, resistance to fatigue was increased 25% in catalase-treated soleus compared with control muscle. Six weeks following injection, extensor digitorum longus specific tension was increased 15%, while soleus specific tension was similar between treated and untreated limbs. Catalase overexpression reduced contraction-induced injury by 30–45% and fatigue by 20% compared with control limbs. Six months following injection, diaphragm specific tension was similar between groups, but resistance to contraction-induced injury was improved by 35% and fatigue by 25%. Taken together, these data indicate that catalase can improve a subset of parameters of muscle function in dystrophin-deficient skeletal muscle.

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“…Therefore, treatment of human disorders with human enzyme will probably also not yield any beneficial effects. Classically, bovine SOD was used for experimental research [12] as well as in early clinical trials to test SOD administration effects on several human disorders [18,19]. With the outbreak of Creutzfeldt-Jacob disease, bovine-derived products for human consumption were limited, and suitable alternatives were developed from plant-extracted forms of SOD.…”

Section: Superoxide Dismutasementioning

confidence: 99%

Therapeutic value of oral supplementation with melon superoxide dismutase and wheat gliadin combination

Romão

2015

Nutrition

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Dietary antioxidant supplementation has been popular in Western countries. Various supplements have been developed in recent years, and research has been gathered from both animal and clinical research trials. In this review, the therapeutic value of oral administration of a combination of melon superoxide dismutase (SOD) and a vegetable polymer (gliadin) is evaluated. Critical examination of the effects of SOD-gliadin supplementation is carried out, with an emphasis on its impact on oxidative stress levels and on endogenous antioxidant pathways. Overall analysis of peer-reviewed published data suggests that intake of SOD-gliadin might have advantageous health effects. These conclusions are dependent on the condition or pathology under consideration. In general, the authors, who analyzed SOD-gliadin supplementation, support the use of SOD-gliadin supplementation as a complementary treatment rather than a therapeutic treatment. To further clarify the importance of dietary SOD-gliadin administration, additional large-scale clinical trials are recommended.

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Drug Trial of Superoxide Dismutase in Duchenne's Muscular Dystrophy

Cited by 45 publications

References 25 publications

The role of reactive oxygen species in the hearts of dystrophin-deficient mdx mice

The role of reactive oxygen species in the hearts of dystrophin-deficient mdx mice

Increased catalase expression improves muscle function inmdxmice

Therapeutic value of oral supplementation with melon superoxide dismutase and wheat gliadin combination

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