Siponimod ameliorates metabolic oligodendrocyte injury via the sphingosine-1 phosphate receptor 5.
Animals
Azetidines
/ pharmacology
Benzyl Compounds
/ pharmacology
Cuprizone
Disease Models, Animal
Homeodomain Proteins
/ genetics
Mice
Mice, Inbred C57BL
Multiple Sclerosis, Chronic Progressive
/ drug therapy
Oligodendroglia
/ drug effects
Sphingosine
/ pharmacology
Sphingosine-1-Phosphate Receptors
/ metabolism
S1PR5
cuprizone
multiple sclerosis
oligodendrocyte
siponimod
Journal
Proceedings of the National Academy of Sciences of the United States of America
ISSN: 1091-6490
Titre abrégé: Proc Natl Acad Sci U S A
Pays: United States
ID NLM: 7505876
Informations de publication
Date de publication:
04 10 2022
04 10 2022
Historique:
entrez:
26
9
2022
pubmed:
27
9
2022
medline:
28
9
2022
Statut:
ppublish
Résumé
Multiple sclerosis (MS), an autoimmune-driven, inflammatory demyelinating disease of the central nervous system (CNS), causes irreversible accumulation of neurological deficits to a variable extent. Although there are potent disease-modifying agents for its initial relapsing-remitting phase, immunosuppressive therapies show limited efficacy in secondary progressive MS (SPMS). Although modulation of sphingosine-1 phosphate receptors has proven beneficial during SPMS, the underlying mechanisms are poorly understood. In this project, we followed the hypothesis that siponimod, a sphingosine-1 phosphate receptor modulator, exerts protective effects by direct modulation of glia cell function (i.e., either astrocytes, microglia, or oligodendrocytes). To this end, we used the toxin-mediated, nonautoimmune MS animal model of cuprizone (Cup) intoxication. On the histological level, siponimod ameliorated cuprizone-induced oligodendrocyte degeneration, demyelination, and axonal injury. Protective effects were evident as well using GE180 translocator protein 18-kDa (TSPO) imaging with positron emission tomography (PET)/computed tomography (CT) imaging or next generation sequencing (NGS). Siponimod also ameliorated the cuprizone-induced pathologies in
Identifiants
pubmed: 36161894
doi: 10.1073/pnas.2204509119
pmc: PMC9546621
doi:
Substances chimiques
Azetidines
0
Benzyl Compounds
0
Homeodomain Proteins
0
Sphingosine-1-Phosphate Receptors
0
RAG-1 protein
128559-51-3
Cuprizone
5N16U7E0AO
Sphingosine
NGZ37HRE42
siponimod
RR6P8L282I
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
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