P.11.2 Naproxcinod, a nitric oxide-donating anti-inflammatory compound, is effective in two mouse models of muscle dystrophy

Abstract

Nitric oxide (NO) plays a critical role in skeletal muscle function, including control of blood flow and muscle repair. In muscular dystrophies, synthesis of NO in the skeletal muscle is known to be defective therefore contributing to damage progression. In the present study, we evaluated the effects of naproxcinod, an NO-donating anti-inflammatory compound, in two models of muscular dystrophy, the alpha-sarcoglycan (alpha-SG) null mice, a model for limb-girdle muscle dystrophy, and the mdx mouse model for Duchenne muscle dystrophy (DMD). Naproxcinod (10 and 30 mg/kg/day) was orally administered for 7 months to mdx mice and for 4 months to alpha-SG null mice starting at 4 weeks of age. Muscle function was assessed by treadmill test at 4 months (both mdx and alpha-SG null mice) and 7 months of treatment (mdx mice). Serum creatine kinase (CK) was measured as index of skeletal muscle damage. Inflammatory infiltrates, as well as muscle regeneration were studied in diaphragm and tibialis anterior muscles. In mdx mice 30 mg/kg/day of naproxcinod significantly improved muscle function in terms of resistance to exercise with a recovery score of 12%; significantly reduced skeletal muscle inflammation and serum CK activity; and increased muscle regeneration. Likewise in alpha-SG null mice, 4 months of naproxcinod treatment led to a significant improvement of resistance to fatigue (recovery score of 59%), and to reduction of muscle inflammation and damage. Furthermore, both diaphragm and tibialis anterior muscles appeared fully regenerated, thus supporting the marked beneficial effects observed for muscle function. The results demonstrate that naproxcinod, through NO donation together with anti-inflammatory activity, produces significant and persistent therapeutic effects improving muscle function, reducing muscle inflammation and maintaining regeneration capacity of the muscle in two models of muscular dystrophies.