Evaluation of the therapeutic potential of carbonic anhydrase inhibitors in two animal models of dystrophin deficient muscular dystrophy.
Duchenne Muscular Dystrophy is an inherited muscle degeneration disease for which there is still no efficient treatment. However, compounds active on the disease may already exist among approved drugs but are difficult to identify in the absence of cellular models. We used the Caenorhabditis elegans animal model to screen a collection of 1000 already approved compounds. Two of the most active hits obtained were methazolamide and dichlorphenamide, carbonic anhydrase inhibitors widely used in human therapy. In C. elegans, these drugs were shown to interact with CAH-4, a putative carbonic anhydrase. The therapeutic efficacy of these compounds was further validated in long-term experiments on mdx mice, the mouse model of Duchenne Muscular Dystrophy. Mice were treated for 120 days with food containing methazolamide or dichlorphenamide at two doses each. Musculus tibialis anterior and diaphragm muscles were histologically analyzed and isometric muscle force was measured in M. extensor digitorum longus. Both substances increased the tetanic muscle force in the treated M. extensor digitorum longus muscle group, dichlorphenamide increased the force significantly by 30%, but both drugs failed to increase resistance of muscle fibres to eccentric contractions. Histological analysis revealed a reduction of centrally nucleated fibers in M. tibialis anterior and diaphragm in the treated groups. These studies further demonstrated that a C. elegans-based screen coupled with a mouse model validation strategy can lead to the identification of potential pharmacological agents for rare diseases.
Giacomotto
Jean
J
Centre de Génétique Moléculaire et Cellulaire, UMR 5534, Université Lyon 1, 69622 Villeurbanne Cedex, France.
Pertl
Cordula
C
Borrel
Caroline
C
Walter
Maggie C
MC
Bulst
Stefanie
S
Johnsen
Bob
B
Baillie
David L
DL
Lochmüller
Hanns
H
Thirion
Christian
C
Ségalat
Laurent
L
D000818:Animals; D017173:Caenorhabditis elegans / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism; D002257:Carbonic Anhydrase Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D002256:Carbonic Anhydrases / Q000235:genetics / Q000378:metabolism; D004005:Dichlorphenamide / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D016189:Dystrophin / Q000172:deficiency* / Q000235:genetics; D006801:Humans; D008704:Methazolamide / Q000494:pharmacology; D051379:Mice; D018101:Mice, Inbred mdx; D009043:Motor Activity; D009119:Muscle Contraction / Q000187:drug effects; D018482:Muscle, Skeletal / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D009137:Muscular Dystrophy, Animal / Q000235:genetics / Q000503:physiopathology / Q000517:prevention & control*; D034622:RNA Interference; D013997:Time Factors
D029742:Caenorhabditis elegans Proteins; D002257:Carbonic Anhydrase Inhibitors; D016189:Dystrophin; D002256:Carbonic Anhydrases; D004005:Dichlorphenamide; D008704:Methazolamide