Siponimod ameliorates metabolic oligodendrocyte injury via the sphingosine-1 phosphate receptor 5.

Abstract

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 Rag1-deficient mice, demonstrating that the protection is independent of T and B cell modulation. Proinflammatory responses in primary mixed astrocytes/microglia cell cultures were not modulated by siponimod, suggesting that other cell types than microglia and astrocytes are targeted. Of note, siponimod completely lost its protective effects in S1pr5-deficient mice, suggesting direct protection of degenerating oligodendrocytes. Our study demonstrates that siponimod exerts protective effects in the brain in a S1PR5-dependent manner. This finding is not just relevant in the context of MS but in other neuropathologies as well, characterized by a degeneration of the axon-myelin unit.

• Authors: Newshan Behrangi, Leo Heinig, Linda Frintrop, Emily Santrau, Jens Kurth, Bernd Krause, Dimitrinka Atanasova, Tim Clarner, Athanassios Fragoulis, Markus Joksch, Henrik Rudolf, Sven G Meuth, Sarah Joost, Markus Kipp
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 119 Issue 40 Pg. e2204509119 (10 04 2022) ISSN: 1091-6490 [Electronic] United States
• PMID: 36161894 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Azetidines
• Benzyl Compounds
• Homeodomain Proteins
• Sphingosine-1-Phosphate Receptors
• RAG-1 protein
• Cuprizone
• Sphingosine
• siponimod

Topics

• 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, therapeutic use)
• Sphingosine-1-Phosphate Receptors (metabolism)