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Drug reprofiling using zebrafish identifies novel compounds with potential pro-myelination effects
Clare E Buckley1, Anita Marguerie, Alan G Roach
1MRC 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
Researchers developed a novel zebrafish screening platform to identify compounds that promote remyelination in multiple sclerosis (MS). This screen identified promising drug candidates, including PP2, a biogenic amine, and a thioxanthene, for further investigation.
Area of Science:
- Neuroscience
- Pharmacology
- Developmental Biology
Background:
- Multiple sclerosis (MS) is an autoimmune demyelinating disease requiring therapies for damage limitation and repair.
- Current MS treatments focus on immunomodulation to limit damage, but lack agents promoting remyelination.
- A rapid in vivo screening method is needed to discover pro-remyelination compounds.
Purpose of the Study:
- To develop and implement a novel screening platform using zebrafish larvae to identify compounds that promote remyelination.
- To screen existing drug libraries for compounds that enhance oligodendrocyte lineage cell recruitment, proliferation, and myelination.
- To identify novel therapeutic targets for promoting remyelination in demyelinating diseases.
Main Methods:
- A novel screening platform was established using larval zebrafish for high-throughput in vivo screening.
- Compounds from drug reprofiling libraries were screened for their effects on oligodendrocyte lineage cell (olig2+) recruitment and proliferation.
- Myelination levels were assessed by measuring myelin basic protein (mbp) transcript levels in whole zebrafish larvae.
Main Results:
- Two percent of screened compounds modulated oligodendrocyte lineage cell recruitment and/or proliferation.
- Three compounds, including the src family kinase inhibitor PP2, a biogenic amine, and a thioxanthene, significantly altered myelination levels.
- The screen identified known myelin-modulating compounds (e.g., PPAR agonist, steroid hormones) and novel candidates, highlighting 25 potential targets for remyelination therapies.
Conclusions:
- The developed zebrafish screening platform is effective for identifying pro-remyelination compounds.
- Several compounds, including PP2, a biogenic amine, and a thioxanthene, show potential for promoting remyelination.
- The study identified 25 novel targets worthy of further investigation for MS therapeutic development.
