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Nature. 2013 Oct 17;502(7471):327-332. doi: 10.1038/nature12647. Epub 2013 Oct 9.

A regenerative approach to the treatment of multiple sclerosis.

Author information

1
Department of Chemistry, The Scripps Research Institute, 10550, North Torrey Pines Road, La Jolla, California 92037, USA.
2
Department of Immunology and Microbial Science, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.
3
Laboratory of Genetics, The Salk Institute for Biological Sciences, 10010 North Torrey Pines Road, La Jolla, California 92037, USA.
4
Division of Stem Cell Biology, Institute for Genetic Medicine, Hokkaido University, Kita-15, Nishi- 7, Kita-ku, Sapporo 060-0815, Japan.
5
The California Institute for Biomedical Research, 11119 North Torrey Pines Road, La Jolla, California 92037, USA.
#
Contributed equally

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.

PMID:
24107995
PMCID:
PMC4431622
DOI:
10.1038/nature12647
[Indexed for MEDLINE]
Free PMC Article

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