Duchenne muscular dystrophy (DMD) is a progressive muscle-
wasting disease due to a mutation in the
dystrophin gene and the consequential
protein deficiency in muscle. How the lack of the sarcolemmal
protein dystrophin gives rise to the final disease status is still not clear. Several evidences suggest a role of
nuclear factor kappa-B (
NF-kappaB), a pleiotropic
transcription factor, in muscle degeneration and regeneration in DMD patients and mdx mice. We investigated the effects of
NF-kappaB blocking by
pyrrolidine dithiocarbamate (
PDTC), a well-known
NF-kappaB inhibitor, on dystrophic process in mdx mice. Five-week-old mdx and wild-type mice received three times a week for 5 weeks either
PDTC (50 mg/kg) or its vehicle.
PDTC treatment: (i) increased forelimb strength (+20%; P < 0.05) and strength normalized to weight (+24%; P < 0.05) and a decreased
fatigue percentage (-61%; P < 0.05) in mdx mice, (ii) blunted the augmented
NF-kappaB nuclear binding activity and the enhanced
TNF-alpha expression in dystrophic muscles (P < 0.01), (iii) at a quantitative morphological evaluation of extensor digitorum longus (EDL) and biceps muscles, increased area with normal fibers (P < 0.05, in EDL), reduced muscle
necrosis (P < 0.05 in biceps; P < 0.01 in EDL), and enhanced muscle regeneration (P < 0.01, in biceps). Our data support the hypothesis that
NF-kappaB contributes to the perpetuation of the dystrophic damage and show that its blockade produces beneficial effects on functional, biochemical, and morphological parameters in mdx mice. Most importantly, these new findings may have clinical implications for the pharmacological treatment of patients with DMD.