Naproxcinod shows significant advantages over naproxen in the mdx model of Duchenne Muscular Dystrophy

Abstract

BackgroundIn dystrophin-deficient muscles of Duchenne Muscular Dystrophy (DMD) patients and the mdx mouse model, nitric oxide (NO) signalling is impaired. Previous studies have shown that NO-donating drugs are beneficial in dystrophic mouse models. Recently, a long-term treatment (9 months) of mdx mice with naproxcinod, an NO-donating naproxen, has shown a significant improvement of the dystrophic phenotype with beneficial effects present throughout the disease progression. It remains however to be clearly dissected out which specific effects are due to the NO component compared with the anti-inflammatory activity associated with naproxen. Understanding the contribution of NO vs the anti-inflammatory effect is important, in view of the potential therapeutic perspective, and this is the final aim of this study.MethodsFive-week-old mdx mice received either naproxcinod (30 mg/kg) or the equimolar dose of naproxen (20 mg/kg) in the diet for 6 months. Control mdx mice were used as reference. Treatments (or vehicle for control groups) were administered daily in the diet. For the first 3 months the study was performed in sedentary animals, then all mice were subjected to exercise until the sixth month. Skeletal muscle force was assessed by measuring whole body tension in sedentary animals as well as in exercised mice and resistance to fatigue was measured after 3 months of running exercise. At the end of 6 months of treatment, animals were sacrificed for histological analysis and measurement of naproxen levels in blood and skeletal muscle.ResultsNaproxcinod significantly ameliorated skeletal muscle force and resistance to fatigue in sedentary as well as in exercised mice, reduced inflammatory infiltrates and fibrosis deposition in both cardiac and diaphragm muscles. Conversely, the equimolar dose of naproxen showed no effects on fibrosis and improved muscle function only in sedentary mice, while the beneficial effects in exercised mice were lost demonstrating a limited and short-term effect.ConclusionIn conclusion, this study shows that NO donation may have an important role, in addition to anti-inflammatory activity, in slowing down the progression of the disease in the mdx mouse model therefore positioning naproxcinod as a promising candidate for treatment of DMD.Electronic supplementary materialThe online version of this article (doi:10.1186/s13023-015-0311-0) contains supplementary material, which is available to authorized users.

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“…However, it may not be the end for naproxcinod clinical development, since it recently received from FDA and European Medicines Agency (EMA) the orphan drug designation for the treatment of Duchenne muscular dystrophy . In fact, some animal studies have already shown the naproxcinod potential to delay the progression of muscular dystrophies . Furthermore, a recent agreement between NicOx and Fera Pharmaceuticals (USA) gives hope to the further development of naproxcinod to be commercialized in USA…”

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“…The advancement also of NO-releasing prodrugs of other NSAIDs, such as Naproxen (compound 24, Figure 11) into late-stage clinical evaluation [54] illustrates the potential application of NO-releasing aspirin prodrugs if such a compound could be identified. Indeed, in 2015 compound 24 secured orphan drug designation from the FDA as a potential treatment for Duchenne Muscular Dystrophy [55,56].…”

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