Drug screening in a zebrafish model of Duchenne muscular dystrophy

作者：Kawahara Genri; Karpf Jeremy A; Myers Jennifer A; Alexander Matthew S; Guyon Jeffrey R; Kunkel Louis M^*

来源：Proceedings of the National Academy of Sciences, 2011, 108(13): 5331-5336.

DOI：10.1073/pnas.1102116108

• phosphodiesterase inhibitor
• chemical treatment

Two known zebrafish dystrophin mutants, sapje and sapje-like (sap(c/100)), represent excellent small-animal models of human muscular dystrophy. Using these dystrophin-null zebrafish, we have screened the Prestwick chemical library for small molecules that modulate the muscle phenotype in these fish. With a quick and easy birefringence assay, we have identified seven small molecules that influence muscle pathology in dystrophin-null zebrafish without restoration of dystrophin expression. Three of seven candidate chemicals restored normal birefringence and increased survival of dystrophin-null fish. One chemical, aminophylline, which is known to be a nonselective phosphodiesterase (PDE) inhibitor, had the greatest ability to restore normal muscle structure and up-regulate the cAMP-dependent PKA pathway in treated dystrophin-deficient fish. Moreover, other PDE inhibitors also reduced the percentage of affected sapje fish. The identification of compounds, especially PDE inhibitors, that moderate the muscle phenotype in these dystrophin-null zebrafish validates the screening protocol described here and may lead to candidate molecules to be used as therapeutic interventions in human muscular dystrophy.

• 出版日期2011-3-29