A regenerative approach to the treatment of multiple sclerosis

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, Argyrios N. Theofilopoulos, Brian R. Lawson, Peter G. Schultz, Luke L. Lairson

Research output: Contribution to journalArticle

215 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)327-332
Number of pages6
JournalNature
Volume502
Issue number7471
DOIs
StatePublished - Oct 10 2013

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Benztropine
Multiple Sclerosis
Autoimmune Experimental Encephalomyelitis
Oligodendroglia
Immunosuppressive Agents
Cuprizone
Stem Cells
Muscarinic M3 Receptors
Muscarinic M1 Receptors
Relapsing-Remitting Multiple Sclerosis
Myelin Basic Protein
Adoptive Transfer
Demyelinating Diseases
Optic Nerve
Therapeutics
Pharmacology
T-Lymphocytes
Pharmaceutical Preparations
Population

ASJC Scopus subject areas

  • General

Cite this

Deshmukh, V. A., Tardif, V., Lyssiotis, C. A., Green, C. C., Kerman, B., Kim, H. J., ... Lairson, L. L. (2013). A regenerative approach to the treatment of multiple sclerosis. Nature, 502(7471), 327-332. https://doi.org/10.1038/nature12647

A regenerative approach to the treatment of multiple sclerosis. / Deshmukh, Vishal A.; Tardif, Virginie; Lyssiotis, Costas A.; Green, Chelsea C.; Kerman, Bilal; Kim, Hyung Joon; Padmanabhan, Krishnan; Swoboda, Jonathan G.; Ahmad, Insha; Kondo, Toru; Gage, Fred H.; Theofilopoulos, Argyrios N.; Lawson, Brian R.; Schultz, Peter G.; Lairson, Luke L.

In: Nature, Vol. 502, No. 7471, 10.10.2013, p. 327-332.

Research output: Contribution to journalArticle

Deshmukh, VA, Tardif, V, Lyssiotis, CA, Green, CC, Kerman, B, Kim, HJ, Padmanabhan, K, Swoboda, JG, Ahmad, I, Kondo, T, Gage, FH, Theofilopoulos, AN, Lawson, BR, Schultz, PG & Lairson, LL 2013, 'A regenerative approach to the treatment of multiple sclerosis', Nature, vol. 502, no. 7471, pp. 327-332. https://doi.org/10.1038/nature12647
Deshmukh VA, Tardif V, Lyssiotis CA, Green CC, Kerman B, Kim HJ et al. A regenerative approach to the treatment of multiple sclerosis. Nature. 2013 Oct 10;502(7471):327-332. https://doi.org/10.1038/nature12647
Deshmukh, Vishal A. ; Tardif, Virginie ; Lyssiotis, Costas A. ; Green, Chelsea C. ; Kerman, Bilal ; Kim, Hyung Joon ; Padmanabhan, Krishnan ; Swoboda, Jonathan G. ; Ahmad, Insha ; Kondo, Toru ; Gage, Fred H. ; Theofilopoulos, Argyrios N. ; Lawson, Brian R. ; Schultz, Peter G. ; Lairson, Luke L. / A regenerative approach to the treatment of multiple sclerosis. In: Nature. 2013 ; Vol. 502, No. 7471. pp. 327-332.
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