University Hospital Düsseldorf
Neurology

Author Of 1 Presentation

Experimental Models Poster Presentation

P0991 - Protective and Remyelinating Potential of Siponimod in a Xenopus Model of Demyelination and a Mouse Model of Experimental Autoimmune Encephalomyelitis (ID 1320)

Abstract

Background

Siponimod, a potent and highly selective sphingosine 1-phosphate receptor modulator, has recently been approved for treatment of relapsing forms of MS and active SPMS.

Objectives

To assess remyelination and neuroprotective potential of siponimod in a Xenopus remyelination and a mouse optic neuritis (EAEON) model using histological analysis and longitudinal visual system readouts.

Methods

We used a conditional demyelination transgenic Xenopus laevis model (MBP-GFP-NTR), in which oligodendrocyte apoptosis can be induced by metronidazole (MTZ) treatment. After MTZ withdrawal, remyelination was assessed with or without siponimod (0.1nM-1µM). In a pharmacokinetics study, brain siponimod levels were analysed. EAEON was induced in female C57BL/6J mice immunized with myelin oligodendrocyte glycoprotein 35-55 (MOG35-55) and continuously fed with vehicle- or siponimod-loaded pellets at 10 or 30 mg/kg of food, either prophylactically or therapeutically, over 90 days. Sections of the optic nerve (Xenopus and mouse) were used to detect de- and remyelination, as well as inflammatory infiltrates. In mice, thickness of retinal layers and visual function were assessed by optical coherence tomography and optokinetic response, respectively. Circulating lymphocytes (flow-cytometry) and siponimod blood and brain levels were analysed at the end of the experiment.

Results

Treatment of demyelinated tadpoles with siponimod (1nM in swimming water) improved remyelination by a factor of 2.3±0.2 fold in comparison to control. The dose-response of siponimod efficiency to accelerate remyelination showed a bell-shaped curve with a maximum remyelination effect at concentrations ranging between 70-80 nM in tissues. In the EAEON mouse model, prophylactic siponimod treatments with 10 or 30 mg/kg attenuated the EAEON clinical scores by about 80% and 95%, respectively, and reduced the retinal neurodegeneration and the loss of visual function. Interestingly, therapeutic treatment starting at day 14 of EAEON had no impact on optic nerve immune cell infiltrates but resulted in increased myelin levels and protection of inner retinal layers also in a bell-shaped dose-response curve with significant protective effects only at the lower dose.

Conclusions

Our data suggest that while siponimod strongly impacts immune cells at higher concentrations (classical dose-response), its effects on remyelination and neuroaxonal survival are dose-dependent following the dynamics of a bell-shaped dose-response curve in both animal models.

Collapse