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Inhibition of phosphodiesterase-4 promotes oligodendrocyte precursor cell differentiation and enhances CNS remyelination
- Source :
- EMBO Molecular Medicine, Embo Molecular Medicine
- Publication Year :
- 2013
-
Abstract
- The increasing effectiveness of new disease-modifying drugs that suppress\ud disease activity in multiple sclerosis has opened up opportunities for\ud regenerative medicines that enhance remyelination and potentially slow disease\ud progression. Although several new targets for therapeutic enhancement of\ud remyelination have emerged, few lend themselves readily to conventional drug\ud development. Here, we used transcription profiling to identify mitogen-activated\ud protein kinase (Mapk) signalling as an important regulator involved in the\ud differentiation of oligodendrocyte progenitor cells (OPCs) into oligodendrocytes.\ud We show in tissue culture that activation of Mapk signalling by elevation of\ud intracellular levels of cyclic adenosine monophosphate (cAMP) using administration\ud of either dibutyryl-cAMP or inhibitors of the cAMP-hydrolysing enzyme\ud phosphodiesterase-4 (Pde4) enhances OPC differentiation. Finally, we demonstrate\ud that systemic delivery of a Pde4 inhibitor leads to enhanced differentiation\ud of OPCs within focal areas of toxin-induced demyelination and a consequent\ud acceleration of remyelination. These data reveal a novel approach to therapeutic\ud enhancement of remyelination amenable to pharmacological intervention and\ud hence with significant potential for translation.
- Subjects :
- MAPK/ERK pathway
Central Nervous System
Multiple Sclerosis
Cellular differentiation
Regulator
oligodendrocytes
Biology
Rats, Sprague-Dawley
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
medicine
Cyclic AMP
Animals
Humans
Cyclic adenosine monophosphate
Remyelination
Protein kinase A
Cells, Cultured
Myelin Sheath
Research Articles
030304 developmental biology
0303 health sciences
Bucladesine
Mapk signalling
Cell Differentiation
Immunity, Innate
3. Good health
Cell biology
Cyclic Nucleotide Phosphodiesterases, Type 4
Rats
Oligodendroglia
medicine.anatomical_structure
remyelination
chemistry
Immunology
Molecular Medicine
Phosphodiesterase 4 Inhibitors
demyelination
Mitogen-Activated Protein Kinases
Transcriptome
030217 neurology & neurosurgery
Intracellular
medicine.drug
Subjects
Details
- ISSN :
- 17574684 and 17574676
- Volume :
- 5
- Issue :
- 12
- Database :
- OpenAIRE
- Journal :
- EMBO molecular medicine
- Accession number :
- edsair.doi.dedup.....43cc7e0fba01047d720978a6b785c8ec