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. 2013 Dec;5(12):1918-34.
doi: 10.1002/emmm.201303123. Epub 2013 Oct 21.

Inhibition of phosphodiesterase-4 Promotes Oligodendrocyte Precursor Cell Differentiation and Enhances CNS Remyelination

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Free PMC article

Inhibition of phosphodiesterase-4 Promotes Oligodendrocyte Precursor Cell Differentiation and Enhances CNS Remyelination

Yasir A Syed et al. EMBO Mol Med. .
Free PMC article

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.

Keywords: Mapk signalling; demyelination; multiple sclerosis; oligodendrocytes; remyelination.

Figures

Figure 1
Figure 1
Inhibition of OPC differentiation by MAI is regulated by phosphorylation of Erk1/2, p38Mapk and Creb1.
Figure 2
Figure 2
Erk1/2, p38Mapk and Creb1 play a functional role during OPC differentiation.
Figure 3
Figure 3
In situ PLA confirms direct interactions of p-Erk1/2 and p-p38Mapk with p-Creb1 during OPC differentiation. To explore interactions between phosphorylated (p-) Creb1 to (p-) Erk1/2 and (p-) p38 an in situ PLA was conducted. Each interaction complex detected by PLA is visualized with a fluorescent signal. DNA was counterstained by Hoechst 33342 (blue).
Figure 4
Figure 4
Increasing cAMP levels by treatment with dbcAMP or inhibition of Pde4 by rolipram promotes OPC differentiation in the presence of MAIs.
Figure 5
Figure 5
Promoting OPC differentiation by inhibition of Pde4 depends on Erk1/2, p38Mapk and Creb1 activity.
Figure 6
Figure 6
Inhibition of Pde4 primes OPCs and promotes OPC differentiation.
Figure 7
Figure 7
Rolipram treatment does not affect OPC proliferation in remyelinating lesions.
Figure 8
Figure 8
Inhibition of Pde4 promotes CNS remyelination.
Figure 9
Figure 9
Pde4 inhibition does not alter the presence of microglia/macrophages in remyelinating lesions
Figure 10
Figure 10
Axonal injury following experimental demyelination is comparable between the groups.

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References

    1. Arnett HA, Fancy SP, Alberta JA, Zhao C, Plant SR, Kaing S, Raine CS, Rowitch DH, Franklin RJM, Stiles CD. bHLH transcription factor Olig1 is required to repair demyelinated lesions in the CNS. Science. 2004;306:2111–2115. - PubMed
    1. Baer AS, Syed YA, Kang SU, Mitteregger D, Vig R, Ffrench-Constant C, Franklin RJM, Altmann F, Lubec G, Kotter MR. Myelin-mediated inhibition of oligodendrocyte precursor differentiation can be overcome by pharmacological modulation of Fyn-RhoA and protein kinase C signalling. Brain. 2009;132:465–481. - PMC - PubMed
    1. Barkhof F, Hulst HE, Drulovic J, Uitdehaag BM, Matsuda K, Landin R. Ibudilast in relapsing-remitting multiple sclerosis: a neuroprotectant. Neurology. 2010;74:1033–1040. - PubMed
    1. Beaumont E, Whitaker CM, Burke DA, Hetman M, Onifer SM. Effects of rolipram on adult rat oligodendrocytes and functional recovery after contusive cervical spinal cord injury. Neuroscience. 2009;163:985–990. - PMC - PubMed
    1. Bitsch A, Schuchardt J, Bunkowski S, Kuhlmann T, Bruck W. Acute axonal injury in multiple sclerosis. Correlation with demyelination and inflammation. Brain. 2000;123:1174–1183. - PubMed

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