Teriflunomide Promotes Oligodendroglial 8,9-Unsaturated Sterol Accumulation and CNS Remyelination.
Animals
Animals, Newborn
Cells, Cultured
Central Nervous System Diseases
/ drug therapy
Cholesterol
/ metabolism
Crotonates
/ administration & dosage
Demyelinating Diseases
/ drug therapy
Disease Models, Animal
Hydroxybutyrates
/ administration & dosage
Immunosuppressive Agents
/ administration & dosage
Larva
Mice
Mice, Inbred C57BL
Mice, Transgenic
Nitriles
/ administration & dosage
Oligodendrocyte Precursor Cells
/ drug effects
Oligodendroglia
/ drug effects
Remyelination
/ drug effects
Toluidines
/ administration & dosage
Xenopus laevis
Journal
Neurology(R) neuroimmunology & neuroinflammation
ISSN: 2332-7812
Titre abrégé: Neurol Neuroimmunol Neuroinflamm
Pays: United States
ID NLM: 101636388
Informations de publication
Date de publication:
11 2021
11 2021
Historique:
received:
09
11
2020
accepted:
23
08
2021
entrez:
13
10
2021
pubmed:
14
10
2021
medline:
5
2
2022
Statut:
epublish
Résumé
To test whether low concentrations of teriflunomide (TF) could promote remyelination, we investigate the effect of TF on oligodendrocyte in culture and on remyelination in vivo in 2 demyelinating models. The effect of TF on oligodendrocyte precursor cell (OPC) proliferation and differentiation was assessed in vitro in glial cultures derived from neonatal mice and confirmed on fluorescence-activated cell sorting-sorted adult OPCs. The levels of the 8,9-unsaturated sterols lanosterol and zymosterol were quantified in TF- and sham-treated cultures. In vivo, TF was administered orally, and remyelination was assessed both in myelin basic protein-GFP-nitroreductase ( In cultures, low concentrations of TF down to 10 nM decreased OPC proliferation and increased their differentiation, an effect that was also detected on adult OPCs. Oligodendrocyte differentiation induced by TF was abrogated by the oxidosqualene cyclase inhibitor Ro 48-8071 and was mediated by the accumulation of zymosterol. In the demyelinated tadpole, TF enhanced the regeneration of mature oligodendrocytes up to 2.5-fold. In the mouse demyelinated spinal cord, TF promoted the differentiation of newly generated oligodendrocytes by a factor of 1.7-fold and significantly increased remyelination. TF enhances zymosterol accumulation in oligodendrocytes and CNS myelin repair, a beneficial off-target effect that should be investigated in patients with multiple sclerosis.
Sections du résumé
BACKGROUND AND OBJECTIVES
To test whether low concentrations of teriflunomide (TF) could promote remyelination, we investigate the effect of TF on oligodendrocyte in culture and on remyelination in vivo in 2 demyelinating models.
METHODS
The effect of TF on oligodendrocyte precursor cell (OPC) proliferation and differentiation was assessed in vitro in glial cultures derived from neonatal mice and confirmed on fluorescence-activated cell sorting-sorted adult OPCs. The levels of the 8,9-unsaturated sterols lanosterol and zymosterol were quantified in TF- and sham-treated cultures. In vivo, TF was administered orally, and remyelination was assessed both in myelin basic protein-GFP-nitroreductase (
RESULTS
In cultures, low concentrations of TF down to 10 nM decreased OPC proliferation and increased their differentiation, an effect that was also detected on adult OPCs. Oligodendrocyte differentiation induced by TF was abrogated by the oxidosqualene cyclase inhibitor Ro 48-8071 and was mediated by the accumulation of zymosterol. In the demyelinated tadpole, TF enhanced the regeneration of mature oligodendrocytes up to 2.5-fold. In the mouse demyelinated spinal cord, TF promoted the differentiation of newly generated oligodendrocytes by a factor of 1.7-fold and significantly increased remyelination.
DISCUSSION
TF enhances zymosterol accumulation in oligodendrocytes and CNS myelin repair, a beneficial off-target effect that should be investigated in patients with multiple sclerosis.
Identifiants
pubmed: 34642237
pii: 8/6/e1091
doi: 10.1212/NXI.0000000000001091
pmc: PMC8515201
pii:
doi:
Substances chimiques
Crotonates
0
Hydroxybutyrates
0
Immunosuppressive Agents
0
Nitriles
0
Toluidines
0
teriflunomide
1C058IKG3B
Cholesterol
97C5T2UQ7J
zymosterol
PU2755PT4O
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Informations de copyright
Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.
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