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Uso de um inibidor da ciclofilina, Debio-025, em um modelo especial de distrofia muscular em camundongos

Itália - nesta pesquisa os autores utilizaram camundongos com defeito no colágeno VI, simulando a distrofia muscular congênita de Ulrich e a miopatia de Bethlem. Os animais foram tratados com um inibidor da ciclofilina, Debio-025. O tratamento com a droga normalizou a função mitocondrial, reduziu a morte celular e as alterações ultrestruturais dos músculos indicando um potencial para utilização no tratamento destas formas de distrofia. A droga já foi testada também em outros modelos de camundongos também com bons resultados.

O resumo em inglês pode ser lido abaixo:

(British Journal of Pharmacology, 2009) The cyclophilin inhibitor Debio 025 normalizes mitochondrial function, muscle apoptosis and ultrastructural defects in Col6a1−/− myopathic mice

T Tiepolo, A Angelin, E Palma, P Sabatelli, L Merlini, L Nicolosi, F Finetti, P Braghetta, G Vuagniaux, J-M Dumont, CT Baldari, P Bonaldo, P Bernardi
Background and purpose: We have investigated the therapeutic effects of the selective cyclophilin inhibitor D-MeAla3-EtVal4-cyclosporin (Debio 025) in myopathic Col6a1−/− mice, a model of muscular dystrophies due to defects of collagen VI.Experimental approach: We studied calcineurin activity based on NFAT translocation; T cell activation based on expression of CD69 and CD25; propensity to open the permeability transition pore in mitochondria and skeletal muscle fibres based on the ability to retain Ca2+ and on membrane potential, respectively; muscle ultrastructure by electronmicroscopy; and apoptotic rates by terminal deoxynucleotidyl transferase-mediated dUTP nick end labelling assays in Col6a1−/− mice before after treatment with Debio 025.Key results: Debio 025 did not inhibit calcineurin activity, yet it desensitizes the mitochondrial permeability transition pore in vivo. Treatment with Debio 025 prevented the mitochondrial dysfunction and normalized the apoptotic rates and ultrastructural lesions of myopathic Col6a1−/− mice.Conclusions and implications: Desensitization of the mitochondrial permeability transition pore can be achieved by selective inhibition of matrix cyclophilin D without inhibition of calcineurin, resulting in an effective therapy of Col6a1−/− myopathic mice. These findings provide an important proof of principle that collagen VI muscular dystrophies can be treated with Debio 025. They represent an essential step towards an effective therapy for Ullrich Congenital Muscular Dystrophy and Bethlem Myopathy, because Debio 025 does not expose patients to the potentially harmful effects of immunosuppression.

 

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