The Sphingosine 1-phosphate (S1P) Receptor Modulator, Siponimod Decreases Oligodendrocyte Cell Death and Axon Demyelination in a Mouse Model of Multiple Sclerosis (I10.011)

OBJECTIVE: The aim of this study was to assess the therapeutic effects of Siponimod is a sphingosine 1-phosphate (S1P) receptor modulator, Siponimod to inhibit axonal demyelination and degeneration in the cuprizone mouse model of multiple sclerosis (MS). BACKGROUND: Siponimod is selective for S1P1 and S1P5 receptors. S1P1 receptors are essential for lymphocyte egress from lymph nodes. In addition, Siponimod crosses the blood brain barrier, likely modulates S1P receptors on cells within the CNS, such as astrocytes, microglia, or oligodendrocytes. Because the experimental autoimmune encephalomyelitis-EAE mouse models of MS has simultaneous remyelination, demyelination and inflammation, it is extremely difficult to dissect out the potential action of Siponimod on the individual components. Here, we assessed the effect of Siponimod on demyelination and remyelination using the toxic demyelination cuprizone diet+rapamycin model. DESIGN/METHODS: Age and sex matched C57BL/6 mice were gavaged daily with Siponimod (0.11mg/kg/mouse/day) or vehicle either during predominantly demyelinating (4.5week cuprizone+rapamycin) or remyelinating periods ([4.5week cuprizone+rapamycin]+[3weeks normal diet]). Electrophysiology conduction recordings immunohistochemistry and electron microscopy of the corpus callosum were performed. RESULTS: Siponimod-treated demyelinating groups showed a significant 25[percnt] to 40[percnt] decrease in the loss of myelin proteins, mature oligodendrocytes and a decrease in axon damage versus vehicle-treated groups. No significant difference between treated and untreated remyelinating groups by immunohistochemistry but nearly 25[percnt] increased number of myelinated axons were observed by electron microscopy analysis. Electrophysiology analysis is underway to assess the functional consequences of Siponimod on callosal axons. A 40[percnt] decrease in microglia/ macrophages but a 25[percnt] increase in astrocyte numbers was observed in demyelinating and remyelinating Siponimod treated groups. CONCLUSIONS: Our results show that Siponimod significantly protects and potentially improves axon function during chronic demyelination periods. This could be of significant importance as Siponimod could protect axons during relapses and progressive demyelination in MS. A study supported by Novartis Pharmaceutical Industries. Disclosure: Dr. Tiwari-Woodruff has received research support from Novartis Pharmaceutical. Dr. Yamate-Morgan has nothing to disclose. Dr. Sekyi has nothing to disclose. Dr. Lauderdale has nothing to disclose. Dr. Hasselmann has nothing to disclose. Dr. Schubart has received research support from Novartis.