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Lipid peroxidation inhibition blunts nuclear factor-kappaB activation, reduces skeletal muscle degeneration, and enhances muscle function in mdx mice.

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.
AuthorsSonia Messina, Domenica Altavilla, M'hammed Aguennouz, Paolo Seminara, Letteria Minutoli, Maria C Monici, Alessandra Bitto, Anna Mazzeo, Herbert Marini, Francesco Squadrito, Giuseppe Vita
JournalThe American journal of pathology (Am J Pathol) Vol. 168 Issue 3 Pg. 918-26 (Mar 2006) ISSN: 0002-9440 [Print] United States
PMID16507907 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Antioxidants
  • Benzofurans
  • IRFI 042
  • NF-kappa B
  • Tumor Necrosis Factor-alpha
  • DNA
  • Creatine Kinase
  • Glutathione
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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