| ironjustice@aol.com 2006-03-22, 3:40 pm |
| Lipid Peroxidation Inhibition Blunts Nuclear Factor-{kappa}B
Activation, Reduces Skeletal Muscle Degeneration, and Enhances Muscle
Function in mdx Mice.
Messina S, Altavilla D, Aguennouz M, Seminara P, Minutoli L, Monici MC,
Bitto A, Mazzeo A, Marini H, Squadrito F, Vita G
Am J Pathol. 2006 Mar ; 168(3): 918-26
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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