Résumé :
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Duchenne muscular dystrophy is a relatively common disease that affects skeletal muscle leading to progressive paralysis and death. There is currently no resolutive therapy. We have developed a novel strategy based on the combination of nitric oxide (NO), which has beneficial effects in skeletal muscle, with non steroidal anti-inflammatory drugs (NSAIDs). To this end we used a new class of NO-releasing NSAIDs (NO-NSAIDs). We report the results of long term (one-year) oral treatment in the mouse model for limb girdle muscular dystrophy (?-sarcoglycan null mice) with two such NO-NSAIDs, nitroibuprofen and nitroparacetamol. Both drugs significantly ameliorated the morphological, biochemical and functional phenotype in the absence of secondary effects, efficiently slowing down disease progression and were significantly more effective than the corticosteroid prednisolone analyzed in parallel. NO-NSAIDs acted by reducing inflammation, preventing muscle damage and preserving the number and function of satellite cells. To assess the mechanisms of NO-NSAID action we dissected the contribution of NO and NSAID activities, by analyzing the effects of the NSAID ibuprofen and of isosorbide dinitrate that release NO with a pharmacokinetic profile similar to that of NO-NSAIDs. The NO-NSAIDs were significantly more effective than either isosorbide dinitrate or ibuprofen. Of importance, the NO-NSAIDs were more effective therapeutic agents also with respect to the combination of isosorbide dinitrate and ibuprofen, suggesting that NO-NSAIDs have properties additional to NO release and NSAID activity. The new therapeutic strategy we propose is not selective for a subset of mutations, provides ground for immediate clinical experimentation with NO-NSAIDS, which are approved for use in humans.
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