Investigation of Debio 025, a cyclophilin inhibitor, in the dystrophic mdx mouse, a model for Duchenne muscular dystrophy.
OBJECTIVE
Duchenne muscular dystrophy (DMD) is a severe muscle wasting disorder caused by the absence of the cytoskeletal protein dystrophin. This leads to muscle cell death accompanied by chronic inflammation. Cyclosporin A (CsA) is a powerful immunosuppressive drug, which has been proposed for DMD treatment. CsA also directly regulates the mitochondrial permeability transition pore (mPTP), which participates in cell death pathways through the inhibition of cyclophilin D. Here, we evaluated whether Debio 025, a cyclophilin inhibitor with no immunosuppressive activity, improves the dystrophic condition in a mouse model of DMD, through regulation of mPTP.


METHODS
The potency of Debio 025 to protect mouse dystrophic cells against mitochondria-mediated death was assessed by caspase-3 activity and calcium retention capacity assays. Mdx(5Cv) mice (3-week-old) were treated daily by gavage for 2 weeks with Debio 025 (10, 30 or 100 mg kg(-1)), CsA (10 mg kg(-1)) or placebo. The effects on muscle necrosis and function were measured.


RESULTS
In vitro investigations showed protective effect of low concentrations of Debio 025 against cell death. Histology demonstrated that Debio 025 partially protected the diaphragm and soleus muscles against necrosis (10 and 100 mg kg(-1), respectively). Hindlimb muscles from mice receiving Debio 025 at 10 mg kg(-1) relaxed faster, showed alteration in the stimulation frequency-dependent recruitment of muscle fibres and displayed a higher resistance to mechanical stress.


CONCLUSIONS
Debio 025 partially improved the structure and the function of the dystrophic mouse muscle, suggesting that therapies targeting the mPTP may be helpful to DMD patients.
Reutenauer
J
J
Laboratory of Pharmacology, Geneva-Lausanne School of Pharmaceutical Sciences, University of Geneva, Geneva, Switzerland.
Dorchies
O M
OM
Patthey-Vuadens
O
O
Vuagniaux
G
G
Ruegg
U T
UT
D000818:Animals; D000831:Animals, Newborn; D016923:Cell Death / Q000187:drug effects; D021983:Cyclophilins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016572:Cyclosporine / Q000008:administration & dosage / Q000494:pharmacology*; D003964:Diaphragm / Q000378:metabolism / Q000503:physiopathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D016503:Drug Delivery Systems; D005260:Female; D006614:Hindlimb; D008297:Male; D051379:Mice; D018101:Mice, Inbred mdx; D033681:Mitochondrial Membrane Transport Proteins / Q000187:drug effects / Q000378:metabolism; D000083162:Mitochondrial Permeability Transition Pore; D018482:Muscle, Skeletal / Q000378:metabolism / Q000503:physiopathology; D009137:Muscular Dystrophy, Animal / Q000188:drug therapy*; D020388:Muscular Dystrophy, Duchenne / Q000188:drug therapy*; D009336:Necrosis / Q000188:drug therapy / Q000209:etiology
D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D016572:Cyclosporine; D021983:Cyclophilins; C499715:alisporivir