Duchenne muscular dystrophy (DMD) is the most common muscular dystrophy caused by mutations in the dystrophin gene. DMD is characterized by progressive muscle wasting and weakness, with the onset of symptoms occurring in the early childhood and consequently leading to paralysis and death for respiratory or cardiac failure. There is no cure and glucocorticoids are used to control the progression of the disease. In Duchenne muscular dystrophy (DMD) patients and the mouse model of DMD, mdx, dystrophin deficiency causes a decrease and mislocalization of muscle-specific neuronal nitric oxide synthase (nNOSμ), leading to functional impairments. Previous studies have shown that nitric oxide (NO) donation associated with anti-inflammatory action has beneficial effects in dystrophic mouse models. In this study, the authors have systematically investigated the effects of naproxcinod, an NO-donating naproxen derivative, on the skeletal and cardiac disease phenotype in mdx mice. Four-week-old mdx and C57BL/10 mice were treated with four different concentrations (0, 10, 21, and 41 mg/kg) of naproxcinod and 0.9 mg/kg of prednisolone in their food for 9 months. All mice were subjected to twice-weekly treadmill sessions, and functional and behavioral parameters were measured at 3, 6, and 9 months of treatment. In addition, in vitro force contraction, optical imaging of inflammation, echocardiography, and blood pressure at the 9-month endpoint were evaluated prior to sacrifice. Naproxcinod treatment at 21 mg/kg resulted in significant improvement in hindlimb grip strength and a 30% decrease in inflammation in the fore- and hindlimbs of mdx mice. Furthermore, significant improvement in heart function, as evidenced by improved fraction shortening, ejection fraction, and systolic blood pressure was observed. In addition, the long-term detrimental effects of prednisolone typically seen in mdx skeletal and heart function were not observed at the effective dose of naproxcinod. In conclusion, naproxcinod showed significant and persistent therapeutic effects improving muscle function, reducing muscle inflammation and improving heart function. Thus, naproxcinod seems to have significant potential as a safe therapeutic option for the treatment of muscular dystrophies.
