A dual acting compound releasing nitric oxide (NO) and ibuprofen, NCX 320, shows significant therapeutic effects in a mouse model of muscular dystrophy.
Clara Scioratia, Corresponding Author Contact Information, E-mail The Corresponding Author, Daniela Migliettab, Roberta Buonoa, c, Viviana Pisaa, b, c, d, e, Dario Cattaneoc, Emanuele Azzonia, e, Silvia Brunellia, e and Emilio Clementic
a San Raffaele Scientific Institute, Division of Regenerative Medicine, Via Olgettina 58, 20132, Milan, Italy
b Nicoxnext term Research Institute, Via Ariosto 21, 20091 Bresso, Milan, Italy
c Unit of Clinical Pharmacology - CNR Neuroscience Institute, Department of Clinical Sciences, University Hospital “Luigi Sacco”, Università degli Studi di Milano, 20157 Milan, Italy
d Dept. of Experimental Medicine, University of Milano-Bicocca, 20052 Monza, Italy
e E. Medea Scientific Institute, 23842 Bosisio Parini, Italy
Received 29 March 2011;
revised 5 May 2011;
accepted 5 May 2011.
Available online 12 May 2011.
A resolutive therapy for muscular dystrophies, a heterogeneous group of genetic diseases leading to muscular degeneration and in the severe forms to death, is still lacking. Since inflammation and defects in nitric oxide generation are recognized key pathogenic events in muscular dystrophy, we have analysed the effects of a derivative of ibuprofen, NCX 320, belonging to the class of cyclooxygenase inhibiting nitric oxide donator (CINOD), in the α-sarcoglycan null mice, a severe mouse model of dystrophy. NCX 320 was administered daily in the diet for 8 months starting 1 month from weaning. Muscle functional recovery was evaluated by free wheel and treadmill tests at 8 months. Serum creatine kinase activity, as well as the number of diaphragm inflammatory infiltrates and necrotic fibres, was measured as indexes of skeletal muscle damage. Muscle regeneration was evaluated in diaphragm and tibialis anterior muscles, measuring the numbers of centronucleated fibres and of myogenic precursor cells. NCX 320 mitigated muscle damage, reducing significantly serum creatine kinase activity, the number of necrotic fibres and inflammatory infiltrates. Moreover, NCX 320 stimulated muscle regeneration increasing significantly the number of myogenic precursor cells and regenerating fibres. All these effects concurred in inducing a significant improvement of muscle function, as assessed by both free wheel and treadmill tests. These results describe the properties of a new compound incorporating nitric oxide donation together with anti-inflammatory properties, showing that it is effective in slowing muscle dystrophy progression long term. Of importance, this new compound deserves specific attention for its potential in the therapy of muscular dystrophy given that ibuprofen is well tolerated in paediatric patients and with a profile of safety that makes it suitable for chronic treatment such as the one required in muscular dystrophies.
Keywords: (6): Nitric oxide; Inflammation; Muscular Dystrophy; Skeletal muscle regeneration; NCX 320; Ibuprofen.