Inhibition of phosphodiesterase‐4 promotes oligodendrocyte precursor cell differentiation and enhances CNS remyelination

Inhibition of phosphodiesterase‐4 promotes oligodendrocyte precursor cell differentiation and enhances CNS remyelination

Abstract The increasing effectiveness of new disease‐modifying drugs that suppress disease activity in multiple sclerosis has opened up opportunities for regenerative medicines that enhance remyelination and potentially slow disease progression. Although several new targets for therapeutic enhanceme...

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Main Authors: Yasir A. Syed, Alexandra Baer, Matthias P. Hofer, Ginez A. González, Jon Rundle, Szymon Myrta, Jeffrey K. Huang, Chao Zhao, Moritz J. Rossner, Matthew W. B. Trotter, Gert Lubec, Robin J. M. Franklin, Mark R. Kotter
Format: Article
Language:English
Published: Springer Nature 2013-10-01
Series:EMBO Molecular Medicine
Subjects:
demyelination
Mapk signalling
multiple sclerosis
oligodendrocytes
remyelination
Online Access:https://doi.org/10.1002/emmm.201303123
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Summary:Abstract The increasing effectiveness of new disease‐modifying drugs that suppress disease activity in multiple sclerosis has opened up opportunities for regenerative medicines that enhance remyelination and potentially slow disease progression. Although several new targets for therapeutic enhancement of remyelination have emerged, few lend themselves readily to conventional drug development. Here, we used transcription profiling to identify mitogen‐activated protein kinase (Mapk) signalling as an important regulator involved in the differentiation of oligodendrocyte progenitor cells (OPCs) into oligodendrocytes. We show in tissue culture that activation of Mapk signalling by elevation of intracellular levels of cyclic adenosine monophosphate (cAMP) using administration of either dibutyryl‐cAMP or inhibitors of the cAMP‐hydrolysing enzyme phosphodiesterase‐4 (Pde4) enhances OPC differentiation. Finally, we demonstrate that systemic delivery of a Pde4 inhibitor leads to enhanced differentiation of OPCs within focal areas of toxin‐induced demyelination and a consequent acceleration of remyelination. These data reveal a novel approach to therapeutic enhancement of remyelination amenable to pharmacological intervention and hence with significant potential for translation.
ISSN:1757-4676
1757-4684

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