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

Abstract

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)-kappaB. We showed that NF-kappaB 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-kappaB 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-alpha, p-38, JNK1 expression was evaluated in muscle by western blot analysis. NF-kappaB 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-kappaB 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-kappaB, MAPKs and COX/5-LOX pathways in the dystrophic process and show that flavocoxid is more effective in mdx mice than methylprednisolone.

• Authors: Sonia Messina, Alessandra Bitto, M'hammed Aguennouz, Anna Mazzeo, Alba Migliorato, Francesca Polito, Natasha Irrera, Domenica Altavilla, Gian Luca Vita, Massimo Russo, Antonino Naro, Maria Grazia De Pasquale, Emanuele Rizzuto, Antonio Musarò, Francesco Squadrito, Giuseppe Vita
• Journal: Experimental neurology (Exp Neurol) Vol. 220 Issue 2 Pg. 349-58 (Dec 2009) ISSN: 1090-2430 [Electronic] United States
• PMID: 19786019 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Inflammatory Agents
• Cytokines
• Drug Combinations
• NF-kappa B
• flavocoxid
• Catechin
• DNA
• Hydrogen Peroxide
• Peroxidase
• Arachidonate 5-Lipoxygenase
• Prostaglandin-Endoperoxide Synthases
• Creatine Kinase
• Methylprednisolone

Topics

• Animals
• Anti-Inflammatory Agents (therapeutic use)
• Arachidonate 5-Lipoxygenase (metabolism)
• Catechin (therapeutic use)
• Creatine Kinase (metabolism)
• Cytokines (biosynthesis)
• DNA (metabolism)
• Drug Combinations
• Electrophoretic Mobility Shift Assay
• Hydrogen Peroxide (metabolism)
• Immunohistochemistry
• Male
• Methylprednisolone (therapeutic use)
• Mice
• Mice, Inbred C57BL
• Mice, Inbred mdx
• Muscle, Skeletal (pathology)
• Muscular Dystrophies (drug therapy, pathology)
• NF-kappa B (physiology)
• Necrosis
• Peroxidase (metabolism)
• Prostaglandin-Endoperoxide Synthases (physiology)
• Signal Transduction (genetics, physiology)