Résumé :
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Screening of drugs in mdx miceCorinne Huchet-Cadiou2,Ma Carre-Pierrat1, Aude Lafoux2, Antoine Roux2, Guillaume Tanniou3, Lucie Chambonnier1 and Laurent Slat11 CGMC, CNRS-UMR 5534, Universitaude Bernard Lyon-1, 69622 Villeurbanne, France; 2 UMR INSERM U915 Institut du Thorax, Universit Nantes, 44322 Nantes, France, 3 AFM-Gthon, 1 rue de l'Internationale, BP59, 91002 Evry, France.Muscular dystrophies refer to a heterogeneous group of degenerative muscle genetic diseases. The most frequent and severe form of degenerative muscle disease is DMD. Caused by mutations in the dystrophin gene and affecting 1 in 3500 male births, DMD is characterized by progressive muscle weakness and degeneration. So far there is no corrective therapy for any muscular dystrophies. Current conventional therapies as surgery, corticosteroid administration for muscle weakness, medication to counter cardiomyopathy partially alleviate signs and symptoms but do not directly targeted the disease mechanism, nor reverse the phenotype. With progress made in the knowledge of the genetics, molecular biology, vectorology and muscle physiology of muscular dystrophies, several new strategies based on pharmacology and gene therapy are currently being developed and hold promise in a near future.Although great hopes are attached to gene and cell therapies, identification of active small molecules remains a valid option for new treatments. We have studied the effect of 20 approved pharmaceutical compounds on the muscles of dystrophin-deficient mdx5cv mice. These compounds were selected as the result of a prior screen of 800 approved molecules on a dystrophin mutant of the invertebrate animal model Crhabditis elegans. Drugs were administered to the mice through maternal feeding since 2 weeks of life and mixed in their food after the 3rd week of life. The effects of the drugs on mice were evaluated both at 6 weeks and 16 weeks. Each drug was tested at two concentrations. Prednisone was added to the molecule list as a positive control. To investigate treatment efficiency, more than 30 histological, biochemical and functional parameters were recorded. This extensive study reveals that tricyclics (Imipramine, Amitriptyline) and benzodiazepine (Tetrazepam)are beneficial to the fast muscles of mdx mice. It also highlights a great variability of responses according to time, muscles and assays.
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