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)-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.
Messina
Sonia
S
Department of Neurosciences, Psychiatry and Anaesthesiology, Unit of Neurology and Neuromuscular Diseases, AOU Policlinico G. Martino, 98125 Messina, Italy. messinasonia@libero.it
Bitto
Alessandra
A
Aguennouz
M'hammed
M
Mazzeo
Anna
A
Migliorato
Alba
A
Polito
Francesca
F
Irrera
Natasha
N
Altavilla
Domenica
D
Vita
Gian Luca
GL
Russo
Massimo
M
Naro
Antonino
A
De Pasquale
Maria Grazia
MG
Rizzuto
Emanuele
E
Musarò
Antonio
A
Squadrito
Francesco
F
Vita
Giuseppe
G
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use*; D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism; D002392:Catechin / Q000627:therapeutic use*; D003402:Creatine Kinase / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis; D004247:DNA / Q000378:metabolism; D004338:Drug Combinations; D024202:Electrophoretic Mobility Shift Assay; D006861:Hydrogen Peroxide / Q000378:metabolism; D007150:Immunohistochemistry; D008297:Male; D008775:Methylprednisolone / Q000627:therapeutic use*; D051379:Mice; D008810:Mice, Inbred C57BL; D018101:Mice, Inbred mdx; D018482:Muscle, Skeletal / Q000473:pathology*; D009136:Muscular Dystrophies / Q000188:drug therapy* / Q000473:pathology; D016328:NF-kappa B / Q000502:physiology; D009336:Necrosis; D009195:Peroxidase / Q000378:metabolism; D011451:Prostaglandin-Endoperoxide Synthases / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology
D000893:Anti-Inflammatory Agents; D016207:Cytokines; D004338:Drug Combinations; D016328:NF-kappa B; C544478:flavocoxid; D002392:Catechin; D004247:DNA; D006861:Hydrogen Peroxide; D009195:Peroxidase; D001094:Arachidonate 5-Lipoxygenase; D011451:Prostaglandin-Endoperoxide Synthases; D003402:Creatine Kinase; D008775:Methylprednisolone