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

Syed, Yasir Ahmed, Baer, Alexandra, Hofer, Matthias P., González, Ginez A., Rundle, Jon, Myrta, Szymon, Huang, Jeffrey K., Zhao, Chao, Rossner, Moritz J., Trotter, Matthew W. B., Lubec, Gert, Franklin, Robin J. M. and Kotter, Mark R. 2013. Inhibition of phosphodiesterase-4 promotes oligodendrocyte precursor cell differentiation and enhances CNS remyelination. EMBO Molecular Medicine 5 (12) , pp. 1918-1934. 10.1002/emmm.201303123

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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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Biosciences
Publisher: John Wiley & Sons
ISSN: 1757-4676
Date of First Compliant Deposit: 21 February 2017
Date of Acceptance: 18 September 2013
Last Modified: 04 Jun 2017 09:43

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