Siponimod supports remyelination in the non-supportive environment.

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