Abstract
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 (Mbp:GFP-NTR) transgenic Xenopus laevis demyelinated by metronidazole and in adult mice demyelinated by lysolecithin.
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.
Glossary
- ANOVA=
- analysis of variance;
- APC=
- adenomatous polyposis coli;
- BBB=
- blood brain barrier;
- Br=
- brain;
- BrdU=
- bromodeoxyuridine;
- DHODH=
- dihydroorotate dehydrogenase;
- DIV=
- days in vitro;
- EBP=
- emopamil binding protein;
- FACS=
- fluorescence-activated cell sorting;
- IFNγ=
- interferon-gamma;
- IL-17=
- interleukin-17;
- Li=
- liver;
- LPC=
- lysophosphatidylcholine;
- MBP=
- myelin basic protein;
- Mbp:GFP-NTR=
- myelin basic protein–GFP-nitroreductase;
- MOG=
- myelin oligodendrocyte glycoprotein;
- MS=
- multiple sclerosis;
- MTT=
- 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide;
- MTZ=
- metronidazole;
- OPC=
- oligodendrocyte precursor cell;
- PBS=
- phosphate-buffered saline;
- PDGFα::GFP=
- platelet derived growth factor receptor-alpha/green fluorescent protein;
- PFA=
- paraformaldehyde;
- SC=
- spinal cord;
- Sp=
- spleen;
- TF=
- teriflunomide
Footnotes
Go to Neurology.org/NN for full disclosures. Funding information is provided at the end of the article.
↵* These authors contributed equally to this work.
The Article Processing Charge was funded by the authors.
- Received November 9, 2020.
- Accepted in final form August 23, 2021.
- Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.
This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.
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