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Glia. 2019 Jul;67(7):1320-1332. doi: 10.1002/glia.23606. Epub 2019 Feb 28.

Inhibition of MAPK/ERK pathway promotes oligodendrocytes generation and recovery of demyelinating diseases.

Suo N1,2, Guo YE1,2, He B1,2,3, Gu H1, Xie X1,3,4.

Author information

1
CAS Key Laboratory of Receptor Research, the National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
2
University of Chinese Academy of Sciences, Graduate School, Beijing, China.
3
School of Life Science and Technology, ShanghaiTech University, Shanghai, China.
4
Stake Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.

Abstract

Oligodendrocytes (OLs) are the myelinating glia of the central nervous system. Injury to OLs causes myelin loss. In demyelinating diseases, such as multiple sclerosis, the remyelination is hindered principally due to a failure of the oligodendrocyte precursor cells (OPCs) to differentiate into mature OLs. To identify inducers of OPC to OL differentiation, a high-throughput screening based on myelin basic protein expression using neural progenitor cells-derived OPCs has been performed and, PD0325901-an MEK (MAPK kinase) inhibitor-is found to significantly enhance OPC to OL differentiation in a dose- and time-dependent manner. Other MEK inhibitors also display similar effect, indicating blockade of MAPK-ERK signaling is sufficient to induce OPC differentiation into OLs. PD0325901 facilitates the formation of myelin sheaths in OPC-neuron co-culture in vitro. And in experimental autoimmune encephalomyelitis model and cuprizone-induced demyelination model, PD0325901 displays significant therapeutic effect by promoting myelin regeneration. Our results suggest that targeting the MAPK-ERK pathway might be an intriguing way to develop new therapies for demyelinating diseases.

KEYWORDS:

ERK; MAPK; MEK inhibitor; differentiation; myelin; oligodendrocyte; oligodendrocyte progenitor cell; remyelination

PMID:
30815939
PMCID:
PMC6593996
DOI:
10.1002/glia.23606
[Indexed for MEDLINE]
Free PMC Article

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