The sphingosine-1-phosphate receptor 1 modulator ponesimod repairs cuprizone-induced demyelination and induces oligodendrocyte differentiation.
cuprizone
multiple sclerosis
oligodendrocyte precursor
remyelination
visual evoked potentials
Journal
FASEB journal : official publication of the Federation of American Societies for Experimental Biology
ISSN: 1530-6860
Titre abrégé: FASEB J
Pays: United States
ID NLM: 8804484
Informations de publication
Date de publication:
31 Jan 2024
31 Jan 2024
Historique:
revised:
20
12
2023
received:
01
08
2023
accepted:
26
12
2023
medline:
20
1
2024
pubmed:
20
1
2024
entrez:
20
1
2024
Statut:
ppublish
Résumé
Sphingosine-1-phosphate receptor (S1PR) modulators are clinically used to treat relapse-remitting multiple sclerosis (MS) and the early phase of progressive MS when inflammation still prevails. In the periphery, S1PR modulators prevent lymphocyte egress from lymph nodes, hence hampering neuroinflammation. Recent findings suggest a role for S1PR modulation in remyelination. As the Giα-coupled S1P1 subtype is the most prominently expressed S1PR in oligodendrocyte precursor cells (OPCs), selective modulation (functional antagonism) of S1P1 may have direct effects on OPC functionality. We hypothesized that functional antagonism of S1P1 by ponesimod induces remyelination by boosting OPC differentiation. In the cuprizone mouse model of demyelination, we found ponesimod to decrease the latency time of visual evoked potentials compared to vehicle conditions, which is indicative of functional remyelination. In addition, the Y maze spontaneous alternations test revealed that ponesimod reversed cuprizone-induced working memory deficits. Myelin basic protein (MBP) immunohistochemistry and transmission electron microscopy of the corpus callosum revealed an increase in myelination upon ponesimod treatment. Moreover, treatment with ponesimod alone or in combination with A971432, an S1P5 monoselective modulator, significantly increased primary mouse OPC differentiation based on O4 immunocytochemistry. In conclusion, S1P1 functional antagonism by ponesimod increases remyelination in the cuprizone model of demyelination and significantly increases OPC differentiation in vitro.
Identifiants
pubmed: 38243760
doi: 10.1096/fj.202301557RR
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
e23413Subventions
Organisme : Janssen Research and Development (JRD)
Informations de copyright
© 2024 The Authors. The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.
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