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A regenerative approach to the treatment of multiple sclerosis

Author

Listed:
  • Vishal A. Deshmukh

    (The Scripps Research Institute, 10550, North Torrey Pines Road, La Jolla, California 92037, USA)

  • Virginie Tardif

    (The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA)

  • Costas A. Lyssiotis

    (The Scripps Research Institute, 10550, North Torrey Pines Road, La Jolla, California 92037, USA
    Present Address: Weill Cornell Medical College, 1300 York Avenue, New York, New York 10065, USA.)

  • Chelsea C. Green

    (The Scripps Research Institute, 10550, North Torrey Pines Road, La Jolla, California 92037, USA)

  • Bilal Kerman

    (Laboratory of Genetics, The Salk Institute for Biological Sciences, 10010 North Torrey Pines Road, La Jolla, California 92037, USA)

  • Hyung Joon Kim

    (Laboratory of Genetics, The Salk Institute for Biological Sciences, 10010 North Torrey Pines Road, La Jolla, California 92037, USA)

  • Krishnan Padmanabhan

    (Laboratory of Genetics, The Salk Institute for Biological Sciences, 10010 North Torrey Pines Road, La Jolla, California 92037, USA)

  • Jonathan G. Swoboda

    (The Scripps Research Institute, 10550, North Torrey Pines Road, La Jolla, California 92037, USA)

  • Insha Ahmad

    (The Scripps Research Institute, 10550, North Torrey Pines Road, La Jolla, California 92037, USA)

  • Toru Kondo

    (Institute for Genetic Medicine, Hokkaido University, Kita-15, Nishi- 7, Kita-ku, Sapporo 060-0815, Japan)

  • Fred H. Gage

    (Laboratory of Genetics, The Salk Institute for Biological Sciences, 10010 North Torrey Pines Road, La Jolla, California 92037, USA)

  • Argyrios N. Theofilopoulos

    (The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA)

  • Brian R. Lawson

    (The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA)

  • Peter G. Schultz

    (The Scripps Research Institute, 10550, North Torrey Pines Road, La Jolla, California 92037, USA
    The California Institute for Biomedical Research, 11119 North Torrey Pines Road)

  • Luke L. Lairson

    (The Scripps Research Institute, 10550, North Torrey Pines Road, La Jolla, California 92037, USA
    The California Institute for Biomedical Research, 11119 North Torrey Pines Road)

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.

Suggested Citation

  • Vishal A. Deshmukh & Virginie Tardif & Costas A. Lyssiotis & Chelsea C. Green & Bilal Kerman & Hyung Joon Kim & Krishnan Padmanabhan & Jonathan G. Swoboda & Insha Ahmad & Toru Kondo & Fred H. Gage & A, 2013. "A regenerative approach to the treatment of multiple sclerosis," Nature, Nature, vol. 502(7471), pages 327-332, October.
    • Handle: RePEc:nat:nature:v:502:y:2013:i:7471:d:10.1038_nature12647
    DOI: 10.1038/nature12647
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    Cited by:

    1. Giampiero Porcu & Eliseo Serone & Velia De Nardis & Daniele Di Giandomenico & Giuseppe Lucisano & Marco Scardapane & Anna Poma & Antonella Ragnini-Wilson, 2015. "Clobetasol and Halcinonide Act as Smoothened Agonists to Promote Myelin Gene Expression and RxRγ Receptor Activation," PLOS ONE, Public Library of Science, vol. 10(12), pages 1-22, December.
    2. Jaime Gonzalez Cardona & Matthew D Smith & Jingya Wang & Leslie Kirby & Jason T Schott & Todd Davidson & Jodi L Karnell & Katharine A Whartenby & Peter A Calabresi, 2019. "Quetiapine has an additive effect to triiodothyronine in inducing differentiation of oligodendrocyte precursor cells through induction of cholesterol biosynthesis," PLOS ONE, Public Library of Science, vol. 14(9), pages 1-19, September.

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