Co-administration of ibuprofen and nitric oxide is an effective experimental therapy for muscular dystrophy, with immediate applicability to humans
Article first published online: 22 APR 2010
© 2010 The Authors. Journal compilation © 2010 The British Pharmacological Society
British Journal of Pharmacology
Volume 160, Issue 6, pages 1550–1560, July 2010
How to Cite
Sciorati, C., Buono, R., Azzoni, E., Casati, S., Ciuffreda, P., D'Angelo, G., Cattaneo, D., Brunelli, S. and Clementi, E. (2010), Co-administration of ibuprofen and nitric oxide is an effective experimental therapy for muscular dystrophy, with immediate applicability to humans. British Journal of Pharmacology, 160: 1550–1560. doi: 10.1111/j.1476-5381.2010.00809.x
- Issue published online: 25 JUN 2010
- Article first published online: 22 APR 2010
- Received 30 November 2009; revised 8 March 2010; accepted 11 March 2010
- nitric oxide;
- muscular dystrophy;
- skeletal muscle regeneration
Background and purpose: 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.
Experimental approach: α-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.
Key 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 and implications: 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.