Metformin promotes CNS remyelination and improves social interaction following focal demyelination through CBP Ser436 phosphorylation.
Animals
Demyelinating Diseases
/ drug therapy
Female
Histone Acetyltransferases
/ metabolism
Hypoglycemic Agents
/ pharmacology
Male
Metformin
/ pharmacology
Mice
Mice, Inbred C57BL
Mice, Transgenic
Oligodendroglia
/ drug effects
Phosphorylation
/ drug effects
Remyelination
/ drug effects
Serine
/ metabolism
Social Interaction
/ drug effects
CBP S436 phosphorylation
Differentiation
Mature oligodendrocytes
Metformin
Myelin
Oligodendrocyte precursors
Social interaction
White matter demyelinating disease
Journal
Experimental neurology
ISSN: 1090-2430
Titre abrégé: Exp Neurol
Pays: United States
ID NLM: 0370712
Informations de publication
Date de publication:
12 2020
12 2020
Historique:
received:
12
03
2020
revised:
15
08
2020
accepted:
26
08
2020
pubmed:
3
9
2020
medline:
11
3
2021
entrez:
3
9
2020
Statut:
ppublish
Résumé
Individuals with demyelinating diseases often experience difficulties during social interactions that are not well studied in preclinical models. Here, we describe a novel juvenile focal corpus callosum demyelination murine model exhibiting a social interaction deficit. Using this preclinical murine demyelination model, we discover that application of metformin, an FDA-approved drug, in this model promotes oligodendrocyte regeneration and remyelination and improves the social interaction. This beneficial effect of metformin acts through stimulating Ser436 phosphorylation in CBP, a histone acetyltransferase. In addition, we found that metformin acts through two distinct molecular pathways to enhance oligodendrocyte precursor (OPC) proliferation and differentiation, respectively. Metformin enhances OPC proliferation through early-stage autophagy inhibition, while metformin promotes OPC differentiation into mature oligodendrocytes through activating CBP Ser436 phosphorylation. In summary, we identify that metformin is a promising remyelinating agent to improve juvenile demyelination-associated social interaction deficits by promoting oligodendrocyte regeneration and remyelination.
Identifiants
pubmed: 32877653
pii: S0014-4886(20)30285-5
doi: 10.1016/j.expneurol.2020.113454
pii:
doi:
Substances chimiques
Hypoglycemic Agents
0
Serine
452VLY9402
Metformin
9100L32L2N
Histone Acetyltransferases
EC 2.3.1.48
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
113454Subventions
Organisme : NIDDK NIH HHS
ID : R01 DK107641
Pays : United States
Informations de copyright
Copyright © 2020 Elsevier Inc. All rights reserved.