Long-term treatment with naproxcinod significantly improves skeletal and cardiac disease phenotype in the mdx mouse model of dystrophy.
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, we 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, we evaluated in vitro force contraction, optical imaging of inflammation, echocardiography and blood pressure (BP) at the 9-month endpoint prior to sacrifice. We found that 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, we found significant improvement in heart function, as evidenced by improved fraction shortening, ejection fraction and systolic BP. 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, our results indicate that naproxcinod has significant potential as a safe therapeutic option for the treatment of muscular dystrophies.
Research Center for Genetic Medicine, Children's National Medical Center, Washington, DC, USA.
Kitipong
K
Uaesoontrachoon
Research Center for Genetic Medicine, Children's National Medical Center, Washington, DC, USA.
James L
JL
Quinn
Research Center for Genetic Medicine, Children's National Medical Center, Washington, DC, USA.
Kathleen S
KS
Tatem
Research Center for Genetic Medicine, Children's National Medical Center, Washington, DC, USA.
Jack H
JH
Van Der Meulen
Research Center for Genetic Medicine, Children's National Medical Center, Washington, DC, USA.
Qing
Q
Yu
Research Center for Genetic Medicine, Children's National Medical Center, Washington, DC, USA.
Aditi
A
Phadke
Research Center for Genetic Medicine, Children's National Medical Center, Washington, DC, USA.
Brittany K
BK
Miller
Research Center for Genetic Medicine, Children's National Medical Center, Washington, DC, USA Department of Integrative Systems Biology, George Washington University School of Medicine and Health Sciences, Washington, DC, USA.
Heather
H
Gordish-Dressman
Nicox Research Institute, Via Ariosto 21-20091, Bresso Milano, Italy.
Ennio
E
Ongini
Nicox Research Institute, Via Ariosto 21-20091, Bresso Milano, Italy.
Daniela
D
Miglietta
Research Center for Genetic Medicine, Children's National Medical Center, Washington, DC, USA Department of Integrative Systems Biology, George Washington University School of Medicine and Health Sciences, Washington, DC, USA knagaraju@childrensnational.org.
Kanneboyina
K
Nagaraju
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000627:therapeutic use; D001835:Body Weight / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006334:Heart Function Tests / Q000187:drug effects*; D006614:Hindlimb / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D018101:Mice, Inbred mdx; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000503:physiopathology; D020388:Muscular Dystrophy, Duchenne / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology*; D009288:Naproxen / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D020030:Nitric Oxide Donors / Q000008:administration & dosage* / Q000627:therapeutic use; D011239:Prednisolone / Q000008:administration & dosage / Q000627:therapeutic use
D000893:Anti-Inflammatory Agents; D020030:Nitric Oxide Donors; C111751:naproxen-n-butyl nitrate; D009288:Naproxen; D011239:Prednisolone