title: Drug screening in a zebrafish model of Duchenne muscular dystrophy.
abstract: 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.
authors.affiliation: Division of Genetics, Program in Genomics, Children's Hospital, Boston, MA 02115, USA.
authors.forename: Genri
authors.initials: G
authors.lastname: Kawahara
authors.forename: Jeremy A
authors.initials: JA
authors.lastname: Karpf
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Myers
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Alexander
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Guyon
authors.forename: Louis M
authors.initials: LM
authors.lastname: Kunkel
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D016189:Dystrophin / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D020388:Muscular Dystrophy, Duchenne / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology*; D016376:Oligonucleotides, Antisense; D004364:Pharmaceutical Preparations; D010641:Phenotype; D054852:Small Molecule Libraries; D015027:Zebrafish / Q000235:genetics* / Q000378:metabolism; D029961:Zebrafish Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D016189:Dystrophin; D016376:Oligonucleotides, Antisense; D004364:Pharmaceutical Preparations; D054852:Small Molecule Libraries; D029961:Zebrafish Proteins