Abstract |
Duchenne muscular dystrophy (DMD) is a progressive muscle- wasting disease resulting from lack of the sarcolemmal protein dystrophin. However, the mechanism leading to the final disease status is not fully understood. Several lines of evidence suggest a role for nuclear factor ( NF)-kappaB in muscle degeneration as well as regeneration in DMD patients and mdx mice. We investigated the effects of blocking NF-kappaB by inhibition of oxidative stress/lipid peroxidation on the dystrophic process in mdx mice. Five-week-old mdx mice received three times a week for 5 weeks either IRFI-042 (20 mg/kg), a strong antioxidant and lipid peroxidation inhibitor, or its vehicle. IRFI-042 treatment increased forelimb strength (+22%, P < 0.05) and strength normalized to weight (+23%, P < 0.05) and decreased fatigue (-45%, P < 0.05). It also reduced serum creatine kinase levels (P < 0.01) and reduced muscle-conjugated diene content and augmented muscle- reduced glutathione (P < 0.01). IRFI-042 blunted NF-kappaB DNA-binding activity and tumor necrosis factor-alpha expression in the dystrophic muscles (P < 0.01), reducing muscle necrosis (P < 0.01) and enhancing regeneration (P < 0.05). Our data suggest that oxidative stress/lipid peroxidation represents one of the mechanisms activating NF-kappaB and the consequent pathogenetic cascade in mdx muscles. Most importantly, these new findings may have clinical implications for the pharmacological treatment of patients with DMD.
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Authors | Sonia Messina, Domenica Altavilla, M'hammed Aguennouz, Paolo Seminara, Letteria Minutoli, Maria C Monici, Alessandra Bitto, Anna Mazzeo, Herbert Marini, Francesco Squadrito, Giuseppe Vita |
Journal | The American journal of pathology
(Am J Pathol)
Vol. 168
Issue 3
Pg. 918-26
(Mar 2006)
ISSN: 0002-9440 [Print] United States |
PMID | 16507907
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Antioxidants
- Benzofurans
- IRFI 042
- NF-kappa B
- Tumor Necrosis Factor-alpha
- DNA
- Creatine Kinase
- Glutathione
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Topics |
- Animals
- Antioxidants
(pharmacology)
- Benzofurans
(pharmacology)
- Body Weight
- Creatine Kinase
(analysis)
- DNA
(metabolism)
- Forelimb
(physiology)
- Glutathione
(analysis)
- Lipid Peroxidation
(drug effects)
- Male
- Mice
- Mice, Inbred mdx
- Muscle Fatigue
(physiology)
- Muscle, Skeletal
(chemistry, pathology, physiopathology)
- Muscular Dystrophy, Duchenne
(metabolism, pathology, physiopathology)
- NF-kappa B
(metabolism)
- Tumor Necrosis Factor-alpha
(metabolism)
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