Siponimod supports remyelination in the non-supportive environment
Abstract Inflammatory demyelination, a hallmark of multiple sclerosis (MS) lesions, leads to functional impairments and progressive axonal loss over time. Although remyelination is thought to protect axons, endogenous regenerative processes are often incomplete or fail entirely in many MS patients....
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Nature Portfolio
2025-02-01
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| Online Access: | https://doi.org/10.1038/s41598-025-87825-8 |
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| author | Johann Krüger Newshan Behrangi David Schliep Leo Heinig Elise Vankriekelsvenne Nicole Wigger Markus Kipp |
| author_facet | Johann Krüger Newshan Behrangi David Schliep Leo Heinig Elise Vankriekelsvenne Nicole Wigger Markus Kipp |
| author_sort | Johann Krüger |
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| description | Abstract Inflammatory demyelination, a hallmark of multiple sclerosis (MS) lesions, leads to functional impairments and progressive axonal loss over time. Although remyelination is thought to protect axons, endogenous regenerative processes are often incomplete or fail entirely in many MS patients. While the precise reasons for remyelination failure remain unclear, repeated demyelination in previously affected white matter regions is a recognized contributing factor. In a previous study, we demonstrated that the sphingosine-1-phosphate modulator Siponimod ameliorates metabolic oligodendrocyte injury in an MS animal model. In this study, we explored the potential of Siponimod to enhance remyelination in a non-supportive environment. To this end, male mice were subjected to Cuprizone intoxication for seven weeks. From the onset of the fifth week, when oligodendrocyte progenitor cells begin to differentiate, mice were administered either a vehicle or Siponimod solution. Post-treatment, brain specimens were processed for (immune-) histochemical analyses. After four weeks of Cuprizone intoxication, staining intensities for various myelination markers, were significantly reduced. At the end of week seven, loss of myelin staining intensities was still pronounced, but anti-myelin basic protein (MBP) and myelin-associated glycoprotein (MAG) expression was significantly higher in Siponimod- versus vehicle-treated mice. Consistent with this finding, densities of OLIG2+ oligodendrocytes significantly recovered in Siponimod-treated but not in vehicle-treated mice. This enhanced recovery was paralleled by the trend of lower densities of Ki67+ proliferating oligodendrocyte progenitor cells. Our findings suggest that Siponimod has modest pro-regenerative capacities, partly explaining the amelioration of disease progression in secondary progressive MS patients. |
| format | Article |
| id | doaj-art-e6e4597b9b99442c965f9ee4418551ea |
| institution | Kabale University |
| issn | 2045-2322 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Nature Portfolio |
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| series | Scientific Reports |
| spelling | doaj-art-e6e4597b9b99442c965f9ee4418551ea2025-02-09T12:34:26ZengNature PortfolioScientific Reports2045-23222025-02-0115111210.1038/s41598-025-87825-8Siponimod supports remyelination in the non-supportive environmentJohann Krüger0Newshan Behrangi1David Schliep2Leo Heinig3Elise Vankriekelsvenne4Nicole Wigger5Markus Kipp6Institute of Anatomy, Rostock University Medical CenterInstitute of Anatomy, Rostock University Medical CenterInstitute of Anatomy, Rostock University Medical CenterInstitute of Anatomy, Rostock University Medical CenterInstitute of Anatomy, Rostock University Medical CenterInstitute of Anatomy, Rostock University Medical CenterInstitute of Anatomy, Rostock University Medical CenterAbstract Inflammatory demyelination, a hallmark of multiple sclerosis (MS) lesions, leads to functional impairments and progressive axonal loss over time. Although remyelination is thought to protect axons, endogenous regenerative processes are often incomplete or fail entirely in many MS patients. While the precise reasons for remyelination failure remain unclear, repeated demyelination in previously affected white matter regions is a recognized contributing factor. In a previous study, we demonstrated that the sphingosine-1-phosphate modulator Siponimod ameliorates metabolic oligodendrocyte injury in an MS animal model. In this study, we explored the potential of Siponimod to enhance remyelination in a non-supportive environment. To this end, male mice were subjected to Cuprizone intoxication for seven weeks. From the onset of the fifth week, when oligodendrocyte progenitor cells begin to differentiate, mice were administered either a vehicle or Siponimod solution. Post-treatment, brain specimens were processed for (immune-) histochemical analyses. After four weeks of Cuprizone intoxication, staining intensities for various myelination markers, were significantly reduced. At the end of week seven, loss of myelin staining intensities was still pronounced, but anti-myelin basic protein (MBP) and myelin-associated glycoprotein (MAG) expression was significantly higher in Siponimod- versus vehicle-treated mice. Consistent with this finding, densities of OLIG2+ oligodendrocytes significantly recovered in Siponimod-treated but not in vehicle-treated mice. This enhanced recovery was paralleled by the trend of lower densities of Ki67+ proliferating oligodendrocyte progenitor cells. Our findings suggest that Siponimod has modest pro-regenerative capacities, partly explaining the amelioration of disease progression in secondary progressive MS patients.https://doi.org/10.1038/s41598-025-87825-8Multiple sclerosisCuprizoneSiponimodRemyelinationSphingosine-1-phosphate |
| spellingShingle | Johann Krüger Newshan Behrangi David Schliep Leo Heinig Elise Vankriekelsvenne Nicole Wigger Markus Kipp Siponimod supports remyelination in the non-supportive environment Scientific Reports Multiple sclerosis Cuprizone Siponimod Remyelination Sphingosine-1-phosphate |
| title | Siponimod supports remyelination in the non-supportive environment |
| title_full | Siponimod supports remyelination in the non-supportive environment |
| title_fullStr | Siponimod supports remyelination in the non-supportive environment |
| title_full_unstemmed | Siponimod supports remyelination in the non-supportive environment |
| title_short | Siponimod supports remyelination in the non-supportive environment |
| title_sort | siponimod supports remyelination in the non supportive environment |
| topic | Multiple sclerosis Cuprizone Siponimod Remyelination Sphingosine-1-phosphate |
| url | https://doi.org/10.1038/s41598-025-87825-8 |
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