The sphingosine‐1‐phosphate receptor 1 modulator ponesimod repairs cuprizone‐induced demyelination and induces oligodendrocyte differentiation

Author:

Willems Emily12ORCID,Schepers Melissa123ORCID,Piccart Elisabeth1,Wolfs Esther4ORCID,Hellings Niels35ORCID,Ait‐Tihyaty Maria6,Vanmierlo Tim123ORCID

Affiliation:

1. Department of Neuroscience, Biomedical Research Institute, Faculty of Medicine and Life Sciences Hasselt University Diepenbeek Belgium

2. Department Psychiatry and Neuropsychology, School for Mental Health and Neuroscience Maastricht University Maastricht Netherlands

3. University MS Center (UMSC) Hasselt‐Pelt Hasselt Belgium

4. Department of Cardio and Organ Systems, Biomedical Research Institute Hasselt University Diepenbeek Belgium

5. Department of Immunology and Infection, Biomedical Research Institute Hasselt University Diepenbeek Belgium

6. Janssen Research & Development, LLC Titusville New Jersey USA

Abstract

AbstractSphingosine‐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.

Funder

Janssen Research and Development

Publisher

Wiley

Subject

Genetics,Molecular Biology,Biochemistry,Biotechnology

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