Inhibition of phosphodiesterase‐4 promotes oligodendrocyte precursor cell differentiation and enhances CNS remyelination
Open accessAbstract
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.
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In PBS-treated animals, inclusion of lesions smaller than 0.2 mm2, which were strongly populated with Plp-positive cells, resulted in a significant non-zero slope indicating an effect of lesion size on Plp-positive cell density.
“The inclusion of lesions smaller than 0.2 mm2, which were strongly populated with Plp-positive cells, resulted in a significant non-zero slope indicating an effect of the lesion size on the cell density, as shown in previous studies14.”
From Tamoxifen accelerates the repair of demyelinated lesions in the central nervous system (2016) · cites this paper as [14]
The Methods section (Induction of focal demyelination; page not provided) reports the analysis in PBS-treated animals and a significant non-zero slope for Plp-positive cell density. It gives the lesion-size cutoff as <0.4 mm², however, not <0.2 mm². (LLM, conf=0.90)
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References 67 · Cited by 58
- Authors
- 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., & Kotter, M. R.
- Affiliations
- Wellcome/MRC Cambridge Stem Cell Institute (GB)
- Medical University of Vienna (AT)
- Max Planck Institute of Experimental Medicine (DE)
- Corresponding author
- Franklin, Robin J. M.
- Kotter, Mark R.
- ORCID
- Venue
- EMBO Molecular Medicine
- Published
- 2013-10-21
- Volume
- 5
- Issue
- 12
- Pages
- 1918-1934
- ISSN
- 1757-4676 (ISSN-L)
- 1757-4684
- PMC
- PMC3914530
- OpenAlex
- W2163474372
- Cited by
- 58
- References
- 67
- Citations by year
- 2026: 1 · 2025: 7 · 2024: 4 · 2023: 8 · 2022: 7 · 2021: 1 · 2020: 4 · 2019: 5 · 2018: 4 · 2017: 6 · 2016: 3 · 2015: 6 · 2014: 2
- FWCI
- 2.75
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- EMBO Molecular Medicine (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- ORCA Online Research @Cardiff (Cardiff University) (acceptedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Max Planck Institute for Plasma Physics (submittedVersion)
- MPG.PuRe (Max Planck Society) (submittedVersion, other-oa)
- Funders
- Wings for Life
- Multiple Sclerosis Society
- BMBF (01ES0812)
- Topics
- Health Sciences › Medicine › Pathology and Forensic Medicine › Multiple Sclerosis Research Studies
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Phosphodiesterase function and regulation
- Keywords
- phosphodiesterase-4 inhibitors, oligodendrocyte precursor cells, oligodendrocyte differentiation, remyelination, multiple sclerosis, MAPK signaling, cyclic AMP, demyelination, disease-modifying drugs, regenerative medicine
- MeSH terms
- Cyclic AMP, Animals, Cell Differentiation, Cells, Cultured, Central Nervous System, Bucladesine, Humans, Immunity, Innate, Multiple Sclerosis, Myelin Sheath, Oligodendroglia, Rats, Sprague-Dawley, Mitogen-Activated Protein Kinases, Rats, Cyclic Nucleotide Phosphodiesterases, Type 4, Phosphodiesterase 4 Inhibitors, Transcriptome
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