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Abstract

Progressive phases of multiple sclerosis are associated with inhibited differentiation of the progenitor cell population that generates the mature oligodendrocytes required for remyelination and disease remission. To identify selective inducers of oligodendrocyte differentiation, we performed an image-based screen for myelin basic protein (MBP) expression using primary rat optic-nerve-derived progenitor cells. Here we show that among the most effective compounds identifed was benztropine, which significantly decreases clinical severity in the experimental autoimmune encephalomyelitis (EAE) model of relapsing-remitting multiple sclerosis when administered alone or in combination with approved immunosuppressive treatments for multiple sclerosis. Evidence from a cuprizone-induced model of demyelination, in vitro and in vivo T-cell assays and EAE adoptive transfer experiments indicated that the observed efficacy of this drug results directly from an enhancement of remyelination rather than immune suppression. Pharmacological studies indicate that benztropine functions by a mechanism that involves direct antagonism of M1 and/or M3 muscarinic receptors. These studies should facilitate the development of effective new therapies for the treatment of multiple sclerosis that complement established immunosuppressive approaches.

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Acknowledgements

This work was supported by the Skaggs Institute for Chemical Biology and the California Institute for Regenerative Medicine grant TR3-05617 (to P.G.S), the California Institute for Regenerative Medicine (TG2-01165) and National Science Foundation pre-doctoral fellowships (to V.A.D and C.A.L, respectively). We are grateful to T. Hasnat, M. Chadwell, W. Kiosses and M. Wood for technical support. This is manuscript number 21786 of The Scripps Research Institute.

Author information

Author notes

    • Costas A. Lyssiotis

    Present Address: Weill Cornell Medical College, 1300 York Avenue, New York, New York 10065, USA.

    • Brian R. Lawson
    • , Peter G. Schultz
    •  & Luke L. Lairson

    These authors contributed equally to this work.

Affiliations

  1. Department of Chemistry, The Scripps Research Institute, 10550, North Torrey Pines Road, La Jolla, California 92037, USA

    • Vishal A. Deshmukh
    • , Costas A. Lyssiotis
    • , Chelsea C. Green
    • , Jonathan G. Swoboda
    • , Insha Ahmad
    • , Peter G. Schultz
    •  & Luke L. Lairson
  2. Department of Immunology and Microbial Science, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA

    • Virginie Tardif
    • , Argyrios N. Theofilopoulos
    •  & Brian R. Lawson
  3. Laboratory of Genetics, The Salk Institute for Biological Sciences, 10010 North Torrey Pines Road, La Jolla, California 92037, USA

    • Bilal Kerman
    • , Hyung Joon Kim
    • , Krishnan Padmanabhan
    •  & Fred H. Gage
  4. Division of Stem Cell Biology, Institute for Genetic Medicine, Hokkaido University, Kita-15, Nishi- 7, Kita-ku, Sapporo 060-0815, Japan

    • Toru Kondo
  5. The California Institute for Biomedical Research, 11119 North Torrey Pines Road, La Jolla, California 92037, USA

    • Peter G. Schultz
    •  & Luke L. Lairson

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Contributions

L.L.L., P.G.S., C.A.L. and V.A.D. initiated the project and developed strategy. V.A.D., V.T., C.C.G., B.K., H.J.K., K.P., J.G.S. and I.A. performed the experiments. L.L.L., P.G.S. and V.A.D.wrote the manuscript. B.R.L., C.A.L., A.N.T., F.H.G. and T.K. contributed essential ideas and comments.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Brian R. Lawson or Peter G. Schultz or Luke L. Lairson.

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DOI

https://doi.org/10.1038/nature12647

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