Drug reprofiling using zebrafish identifies novel compounds with potential pro-myelination effects.
Treatment of the autoimmune demyelinating disease multiple sclerosis (MS) requires therapies that both limit and repair damage. While several immunomodulatory treatments exist to limit damage there are currently no treatments that promote the regenerative process of remyelination. A rapid way of screening potential pro-remyelination compounds is therefore required. The use of larval zebrafish in a drug reprofiling screen allows rapid in vivo screening and has been used successfully in the past as an efficient way of identifying new indications for existing drugs. A novel screening platform for potential pro-myelination compounds was developed using zebrafish larvae. Two percent of compounds screened from reprofiling libraries altered oligodendrocyte lineage cell recruitment and/or proliferation, as measured by the numbers of dorsally migrated spinal cord olig2(+) cells. Selective screening identified three compounds that altered levels of myelination, as measured by whole larvae myelin basic protein (mbp) transcript levels; the src family kinase inhibitor PP2, a biogenic amine and a thioxanthene. As well as many previously unrecognised compounds, identified compounds included those with previously known effects on myelin and/or the oligodendrocyte lineage, such as a PPAR agonist, steroid hormones and src family kinase inhibitors. As well as providing methods for further assessment of potentially beneficial compounds, this screen has highlighted 25 targets that are able to alter oligodendrocyte lineage cell recruitment or proliferation and/or mbp transcript levels in vivo and are worthy of further investigation for their potential effects on remyelination.
Buckley
Clare E
CE
MRC Centre for Stem Cell Biology and Regenerative Medicine and Department of Veterinary Medicine, University of Cambridge, Madingley Road, Cambridge CB3 0ES, UK. clare.buckley@kcl.ac.uk
Marguerie
Anita
A
Roach
Alan G
AG
Goldsmith
Paul
P
Fleming
Angeleen
A
Alderton
Wendy K
WK
Franklin
Robin J M
RJ
D000704:Analysis of Variance; D000818:Animals; D030801:Animals, Genetically Modified; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D002452:Cell Count / Q000379:methods; D002454:Cell Differentiation / Q000187:drug effects* / Q000502:physiology; D004353:Drug Evaluation, Preclinical; D004625:Embryo, Nonmammalian; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects* / Q000502:physiology; D049452:Green Fluorescent Proteins / Q000235:genetics; D023421:Models, Animal; D004676:Myelin Basic Protein / Q000235:genetics / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D000076104:Oligodendrocyte Transcription Factor 2; D009836:Oligodendroglia / Q000187:drug effects / Q000378:metabolism*; D010894:Piroxicam / Q000031:analogs & derivatives / Q000494:pharmacology; D013116:Spinal Cord / Q000166:cytology; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism
D000894:Anti-Inflammatory Agents, Non-Steroidal; D051792:Basic Helix-Loop-Helix Proteins; D004791:Enzyme Inhibitors; D049452:Green Fluorescent Proteins; D004676:Myelin Basic Protein; D009419:Nerve Tissue Proteins; D000076104:Oligodendrocyte Transcription Factor 2; D010894:Piroxicam; D029961:Zebrafish Proteins; C465361:olig2 protein, zebrafish; C013580:isoxicam