ZFIN ID: ZDB-PUB-110328-7
Drug screening in a zebrafish model of Duchenne muscular dystrophy
Kawahara, G., Karpf, J.A., Myers, J.A., Alexander, M.S., Guyon, J.R., and Kunkel, L.M.
Date: 2011
Source: Proceedings of the National Academy of Sciences of the United States of America   108(13): 5331-6 (Journal)
Registered Authors: Guyon, Jeff, Kawahara, Genri, Kunkel, Louis M.
Keywords: phosphodiesterase inhibitor, chemical treatment
MeSH Terms:
  • Animals
  • Animals, Genetically Modified
  • Disease Models, Animal
  • Drug Evaluation, Preclinical*
  • Dystrophin/genetics*
  • Dystrophin/metabolism
  • Humans
  • Muscular Dystrophy, Duchenne/drug therapy*
  • Muscular Dystrophy, Duchenne/pathology
  • Muscular Dystrophy, Duchenne/physiopathology*
  • Oligonucleotides, Antisense
  • Pharmaceutical Preparations*
  • Phenotype
  • Small Molecule Libraries
  • Zebrafish/genetics*
  • Zebrafish/metabolism
  • Zebrafish Proteins/genetics*
  • Zebrafish Proteins/metabolism
PubMed: 21402949 Full text @ Proc. Natl. Acad. Sci. USA
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.