title: 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 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.
authors.affiliation: Wellcome Trust and MRC Cambridge Stem Cell Institute, and Anne McLaren Laboratory for Regenerative Medicine, University of Cambridge, West Forvie Building, Forvie Site, Robinson Way, Cambridge, UK; Department of Neurosurgery, Medical University Vienna, Vienna, Austria; Max-Planck Institute for Experimental Medicine, Department of Neurogenetics, Goettingen, Germany.
authors.forename: Yasir A
authors.initials: YA
authors.lastname: Syed
authors.forename: Alexandra
authors.initials: A
authors.lastname: Baer
authors.forename: Matthias P
authors.initials: MP
authors.lastname: Hofer
authors.forename: Ginez A
authors.initials: GA
authors.lastname: González
authors.forename: Jon
authors.initials: J
authors.lastname: Rundle
authors.forename: Szymon
authors.initials: S
authors.lastname: Myrta
authors.forename: Jeffrey K
authors.initials: JK
authors.lastname: Huang
authors.forename: Chao
authors.initials: C
authors.lastname: Zhao
authors.forename: Moritz J
authors.initials: MJ
authors.lastname: Rossner
authors.forename: Matthew W B
authors.initials: MW
authors.lastname: Trotter
authors.forename: Gert
authors.initials: G
authors.lastname: Lubec
authors.forename: Robin J M
authors.initials: RJ
authors.lastname: Franklin
authors.forename: Mark R
authors.initials: MR
authors.lastname: Kotter
mesh_terms: D000818:Animals; D003994:Bucladesine / Q000737:chemistry / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D002490:Central Nervous System / Q000378:metabolism*; D000242:Cyclic AMP / Q000378:metabolism; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009103:Multiple Sclerosis / Q000378:metabolism / Q000473:pathology; D009186:Myelin Sheath / Q000737:chemistry / Q000378:metabolism*; D009836:Oligodendroglia / Q000166:cytology / Q000378:metabolism; D058988:Phosphodiesterase 4 Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D059467:Transcriptome
chemical_list: D058988:Phosphodiesterase 4 Inhibitors; D003994:Bucladesine; D000242:Cyclic AMP; D020928:Mitogen-Activated Protein Kinases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4
keywords: Mapk signalling; demyelination; multiple sclerosis; oligodendrocytes; remyelination