Co-administration of ibuprofen and nitric oxide is an effective experimental therapy for muscular dystrophy, with immediate applicability to humans.
OBJECTIVE
Current therapies for muscular dystrophy are based on corticosteroids. Significant side effects associated with these therapies have prompted several studies aimed at identifying possible alternative strategies. As inflammation and defects of nitric oxide (NO) generation are key pathogenic events in muscular dystrophies, we have studied the effects of combining the NO donor isosorbide dinitrate (ISDN) and the non-steroidal anti-inflammatory drug ibuprofen.


METHODS
alpha-Sarcoglycan-null mice were treated for up to 8 months with ISDN (30 mg.kg(-1)) plus ibuprofen (50 mg.kg(-1)) administered daily in the diet. Effects of ISDN and ibuprofen alone were assessed in parallel. Drug effects on animal motility and muscle function, muscle damage, inflammatory infiltrates and cytokine levels, as well as muscle regeneration including assessment of endogenous stem cell pool, were measured at selected time points.


RESULTS
Combination of ibuprofen and ISDN stimulated regeneration capacity, of myogenic precursor cells, reduced muscle necrotic damage and inflammation. Muscle function in terms of free voluntary movement and resistance to exercise was maintained throughout the time window analysed. The effects of ISDN and ibuprofen administered separately were transient and significantly lower than those induced by their combination.


CONCLUSIONS
Co-administration of NO and ibuprofen provided synergistic beneficial effects in a mouse model of muscular dystrophy, leading to an effective therapy. Our results open the possibility of immediate clinical testing of a combination of ISDN and ibuprofen in dystrophic patients, as both components are approved for use in humans, with a good safety profile.
Sciorati
Clara
C
San Raffaele Scientific Institute, Stem Cell Research Institute, Milan, Italy.
Buono
Roberta
R
Azzoni
Emanuele
E
Casati
Silvana
S
Ciuffreda
Pierangela
P
D'Angelo
Grazia
G
Cattaneo
Dario
D
Brunelli
Silvia
S
Clementi
Emilio
E
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D004357:Drug Synergism; D007052:Ibuprofen / Q000494:pharmacology*; D007548:Isosorbide Dinitrate / Q000494:pharmacology*; D051379:Mice; D018345:Mice, Knockout; D009137:Muscular Dystrophy, Animal / Q000188:drug therapy* / Q000503:physiopathology; D020030:Nitric Oxide Donors / Q000494:pharmacology*; D049031:Sarcoglycans / Q000235:genetics; D013234:Stem Cells / Q000378:metabolism
D000894:Anti-Inflammatory Agents, Non-Steroidal; D020030:Nitric Oxide Donors; D049031:Sarcoglycans; D007548:Isosorbide Dinitrate; D007052:Ibuprofen