Debio-025 is more effective than prednisone in reducing muscular pathology in mdx mice

Abstract

Muscular dystrophy results in the progressive wasting and necrosis of skeletal muscle. Glucocorticoids such as prednisone have emerged as a front-line treatment for many forms of this disease. Recently, Debio-025, a cyclophilin inhibitor that desensitizes the mitochondrial permeability pore and subsequent cellular necrosis, was shown to improve pathology in three different mouse models of muscular dystrophy. However it is not known if Debio-025 can work in conjunction with prednisone, or how it compares against prednisone in mitigating disease in dystrophic mouse models. Here we show that Debio-025 reduced the variations in myofiber cross-sectional areas, decreased fibrosis, and decreased infiltration of activated macrophages more efficiently than prednisone. However the use of prednisone and Debio-025 together had no additional effect on these histopathological indexes. Orally administered Debio-025 also reduced creatine kinase blood levels and improved grip strength in mdx mice after 6 weeks of treatment, and the combination of Debio-025 with prednisone increased muscle function slightly better than prednisone alone. Thus, our results suggest that Debio-025 is as, effective as or slightly better than, prednisone in mitigating muscular dystrophy in the mdx mouse model of disease.