Avaliação dos inibidores da anidrase carbônica em dois modelos experimentais de distrofia muscular

França - inibidores da anidrase carbônica são diuréticos usados no tratamento do glaucoma. Nesta pesquisa eles foram testados em um parasita deficiente em distrofina (C elegans) e no camundongo mdx. Nos dois modelos estudados as drogas reduziram as alterações patológicas dos músculos e aumentaram a força muscular.

O resumo em inglês pode ser lido abaixo:

(Hum. Mol. Genet., Nov 2009; 18:4089 - 4101) Evaluation of the therapeutic potential of carbonic anhydrase inhibitors in two animal models of dystrophin deficient muscular dystrophy

Jean Giacomotto1,, Cordula Pertl2,, Caroline Borrel1, Maggie C. Walter2, Stefanie Bulst2, Bob Johnsen3, David L. Baillie3, Hanns Lochmüller4, Christian Thirion2 and Laurent Ségalat1,*

1 Centre de Génétique Moléculaire et Cellulaire, UMR 5534, Université Lyon 1, 69622 Villeurbanne Cedex, France 2 Laboratory of Molecular Myology, Department of Neurology, Friedrich Baur Institute, Ludwig Maximilians University of Munich, Munich, Germany 3 Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, BC, Canada, V5A 1S6 4 Institute of Human Genetics, Newcastle University, Newcastle upon Tyne, UK

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.

Fonte: http://distrofiamuscular.net/noticias.htm