Flavocoxid counteracts muscle necrosis and improves functional properties in mdx mice: A comparison study with methylprednisolone

Muscle degeneration in dystrophic muscle is exacerbated by the endogenous inflammatory response and increased oxidative stress. A key role is played by nuclear factor(NF)-κB. We showed that NF-κB inhibition through compounds with also antioxidant properties has beneficial effects in mdx mice, the mu...

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Published in:Experimental neurology 2009-12, Vol.220 (2), p.349-358
Main Authors: Messina, Sonia, Bitto, Alessandra, Aguennouz, M'hammed, Mazzeo, Anna, Migliorato, Alba, Polito, Francesca, Irrera, Natasha, Altavilla, Domenica, Vita, Gian Luca, Russo, Massimo, Naro, Antonino, De Pasquale, Maria Grazia, Rizzuto, Emanuele, Musarò, Antonio, Squadrito, Francesco, Vita, Giuseppe
Format: Article
Language:English
Subjects:
Animals
Anti-Inflammatory Agents - therapeutic use
Arachidonate 5-Lipoxygenase - metabolism
Biological and medical sciences
Catechin - therapeutic use
Creatine Kinase - metabolism
Cytokines - biosynthesis
Diseases of striated muscles. Neuromuscular diseases
DNA - metabolism
Drug Combinations
Duchenne muscular dystrophy
Electrophoretic Mobility Shift Assay
Flavocoxid
Hydrogen Peroxide - metabolism
Immunohistochemistry
Limbrel
Male
Medical food
Medical sciences
Methylprednisolone
Methylprednisolone - therapeutic use
Mice
Mice, Inbred C57BL
Mice, Inbred mdx
Muscle, Skeletal - pathology
Muscular Dystrophies - drug therapy
Muscular Dystrophies - pathology
Necrosis
Neurology
NF-kappa B - physiology
NF-κB, mdx mice
Oxidative stress
Peroxidase - metabolism
Prostaglandin-Endoperoxide Synthases - physiology
Signal Transduction - genetics
Signal Transduction - physiology
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Summary:Muscle degeneration in dystrophic muscle is exacerbated by the endogenous inflammatory response and increased oxidative stress. A key role is played by nuclear factor(NF)-κB. We showed that NF-κB inhibition through compounds with also antioxidant properties has beneficial effects in mdx mice, the murine model of Duchenne muscular dystrophy (DMD), but these drugs are not available for clinical studies. We evaluated whether flavocoxid, a mixed flavonoid extract with anti-inflammatory, antioxidant and NF-κB inhibiting properties, has beneficial effects in mdx mice in comparison with methylprednisolone, the gold standard treatment for DMD patients. Five-week-old mdx mice were treated for 5 weeks with flavocoxid, methylprednisolone or vehicle. The evaluation of in vivo and ex vivo functional properties and morphological parameters was performed. Serum samples were assayed for oxidative stress markers, creatine-kinase (CK) and leukotriene B-4. Cyclooxygenase-2 (COX-2), 5-lipoxygenase (5-LOX), tumor necrosis factor-α, p-38, JNK1 expression was evaluated in muscle by western blot analysis. NF-κB binding activity was investigated by electrophoresis mobility shift assay. The administration of flavocoxid: (1) ameliorated functional properties in vivo and ex vivo; (2) reduced CK; (3) reduced the expression of oxidative stress markers and of inflammatory mediators; (4) inhibited NF-κB and mitogen-activated protein kinases (MAPKs) signal pathways; (5) reduced muscle necrosis and enhanced regeneration. Our results highlight the detrimental effects of oxidative stress and NF-κB, MAPKs and COX/5-LOX pathways in the dystrophic process and show that flavocoxid is more effective in mdx mice than methylprednisolone.
ISSN:0014-4886
1090-2430
DOI:10.1016/j.expneurol.2009.09.015