These authors contributed equally to this work.
Inhibition of phosphodiesterase-4 promotes oligodendrocyte precursor cell differentiation and enhances CNS remyelination
Article first published online: 21 OCT 2013
© 2013 The Authors. Published by John Wiley and Sons, Ltd on behalf of EMBO
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
EMBO Molecular Medicine
Volume 5, Issue 12, pages 1918–1934, December 2013
How to Cite
Syed, Y. A., Baer, A., Hofer, M. P., González, G. A., Rundle, J., Myrta, S., Huang, J. K., Zhao, C., Rossner, M. J., Trotter, M. W. B., Lubec, G., Franklin, R. J. M. and Kotter, M. R. (2013), Inhibition of phosphodiesterase-4 promotes oligodendrocyte precursor cell differentiation and enhances CNS remyelination. EMBO Mol Med, 5: 1918–1934. doi: 10.1002/emmm.201303123
- Issue published online: 2 DEC 2013
- Article first published online: 21 OCT 2013
- Manuscript Accepted: 18 SEP 2013
- Manuscript Revised: 12 SEP 2013
- Manuscript Received: 3 JUN 2013
- Wings for Life
- Multiple Sclerosis Society
- BMBF. Grant Number: 01ES0812
- Mapk signalling;
- multiple sclerosis;
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.