Investigation of Debio 025, a cyclophilin inhibitor, in the dystrophic mdx mouse, a model for Duchenne muscular dystrophy

摘要: Background and purpose: Duchenne muscular dystrophy (DMD) is a severe muscle wasting disorder caused by the absence of cytoskeletal protein dystrophin. This leads to cell death accompanied chronic inflammation. Cyclosporin A (CsA) powerful immunosuppressive drug, which has been proposed for DMD treatment. CsA also directly regulates mitochondrial permeability transition pore (mPTP), participates in pathways through inhibition cyclophilin D. Here, we evaluated whether Debio 025, inhibitor with no activity, improves dystrophic condition mouse model DMD, regulation mPTP. Experimental approach: The potency 025 protect cells against mitochondria-mediated was assessed caspase-3 activity calcium retention capacity assays. Mdx5Cv mice (3-week-old) were treated daily gavage 2 weeks (10, 30 or 100 mg kg−1), (10 mg kg−1) placebo. The effects on necrosis function measured. Key results: In vitro investigations showed protective effect low concentrations death. Histology demonstrated that partially protected diaphragm soleus muscles (10 100 mg kg−1, respectively). Hindlimb from receiving at 10 mg kg−1 relaxed faster, alteration stimulation frequency-dependent recruitment fibres displayed higher resistance mechanical stress. Conclusions implications: Debio improved structure muscle, suggesting therapies targeting mPTP may be helpful patients. British Journal Pharmacology (2008) 155, 574–584; doi:10.1038/bjp.2008.285; published online 21 July 2008