title: Co-administration of ibuprofen and nitric oxide is an effective experimental therapy for muscular dystrophy, with immediate applicability to humans.
abstract: 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.
authors.affiliation: San Raffaele Scientific Institute, Stem Cell Research Institute, Milan, Italy.
authors.forename: Clara
authors.initials: C
authors.lastname: Sciorati
authors.forename: Roberta
authors.initials: R
authors.lastname: Buono
authors.forename: Emanuele
authors.initials: E
authors.lastname: Azzoni
authors.forename: Silvana
authors.initials: S
authors.lastname: Casati
authors.forename: Pierangela
authors.initials: P
authors.lastname: Ciuffreda
authors.forename: Grazia
authors.initials: G
authors.lastname: D'Angelo
authors.forename: Dario
authors.initials: D
authors.lastname: Cattaneo
authors.forename: Silvia
authors.initials: S
authors.lastname: Brunelli
authors.forename: Emilio
authors.initials: E
authors.lastname: Clementi
mesh_terms: 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
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D020030:Nitric Oxide Donors; D049031:Sarcoglycans; D007548:Isosorbide Dinitrate; D007052:Ibuprofen