The nitric oxide-donor molsidomine modulates the innate inflammatory response in a mouse model of muscular dystrophy.

Abstract

Inflammation plays a crucial role in muscle remodeling and repair after acute and chronic damage, in particular in muscular dystrophies, a heterogeneous group of genetic diseases leading to muscular degeneration. Defect of nitric oxide (NO) generation is a key pathogenic event in muscular dystrophies, thus NO donors have been explored as new therapeutics for this disease. We have investigated the immune-modulating effect of one of such drugs, molsidomine, able to slow the progression of muscular dystrophy in the α-Sarcoglican-null mice, a model for the limb girdle muscular dystrophy 2D, sharing several hallmarks of muscle degeneration with other muscular dystrophies. α-Sarcoglican-null mice were treated with molsidomine and drug effects on the inflammatory infiltrates and on muscle repair were assessed at selected time points. We found that molsidomine treatment modulates effectively the characteristics of the inflammatory infiltrate within dystrophic muscles, enhancing its healing function. Initially molsidomine amplified macrophage recruitment, promoting a more efficient clearance of cell debris and effective tissue regeneration. At a later stage molsidomine decreased significantly the extent of the inflammatory infiltrate, whose persistence exacerbates muscle damage: most of the remaining macrophages displayed characteristics of the transitional population, associated with reduced fibrosis and increased preservation of the muscle tissue. The dual action of molsidomine, the already known NO donation and the immunomodulatory function we now identified, suggests that it has a unique potential in tissue healing during chronic muscle damage. This, alongside its already approved use in human, makes molsidomine a drug with a significant therapeutic potential in muscular dystrophies.

• Authors: Paola Zordan, Clara Sciorati, Lara Campana, Lucia Cottone, Emilio Clementi, Patrizia-Rovere Querini, Silvia Brunelli
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 715 Issue 1-3 Pg. 296-303 (Sep 05 2013) ISSN: 1879-0712 [Electronic] Netherlands
• PMID: 23707352 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2013 Elsevier B.V. All rights reserved.

Chemical References

• Nitric Oxide
• Molsidomine

Topics

• Animals
• Disease Models, Animal
• Fibrosis
• Humans
• Immunity, Innate (drug effects)
• Inflammation (immunology, pathology)
• Mice
• Molsidomine (metabolism, pharmacology)
• Muscular Dystrophies (immunology, pathology)
• Nitric Oxide (metabolism)
• Phenotype