University medical center Göttingen
Neuropathology

Author Of 1 Presentation

Disease Modifying Therapies – Mechanism of Action Poster Presentation

P0394 - Siponimod treatment leads to a dose-dependent reduction of EAE severity associated with downregulation of microglial activity. (ID 1898)

Speakers
Presentation Number
P0394
Presentation Topic
Disease Modifying Therapies – Mechanism of Action

Abstract

Background

The sphingosine-1-phosphate (S1P) modulator siponimod has been approved for the treatment of active secondary progressive multiple sclerosis. While the reduction of relapse frequency represents a well established effect of S1P modulators in the treatment of multiple sclerosis, their impact on progressive disease is still controversial.

Objectives

The objective of this study was to elucidate effects of siponimod treatment on resident CNS cells in the context of glial cell-mediated neurodegenerative pathomechanisms in progressive multiple sclerosis. We focussed on the impact of siponimod treatment on functional microglial phenotypes.

Methods

Experimental autoimmune encephalomyelitis (EAE) was induced in wild type C57BL/6 mice aged 8-12 weeks with MOG35-55 peptide emulsified in CFA and the additional injection of pertussis toxin. Siponimod treatment was started 20 days post immunization, after mice had reached peak disease and was performed at least for 60 days. Siponimod was administered orally via food pellets containing 3 mg, 10 mg or 30 mg siponimod/kg, respectively. The clinical outcome of mice was measured by the EAE score and their performance in the elevated beam test. After 60 days of treatment, mice were sacrificed for FACS analysis of microglia isolated from brain and spinal cord using the Multi Tissue Dissociation Kit 1.

Results

Siponimod treatment induced a robust reduction of mean clinical scores of mice in all siponimod treatment groups compared to the vehicle group. Dose-dependent clinical differences in disease severity of siponimod-treated mice were observed in the elevated beam test, with mice treated with the highest siponimod dose performing better than mice treated with the low or intermediate siponimod dose. In siponimod-treated animals MHC class II expression of microglial cells was downregulated in a dose-dependent manner.

Conclusions

Therapeutic siponimod treatment started 20 days post immunization and continued over two months leads to a reduction of EAE severity in a dose-dependent manner that is associated with a downregulation of microglial MHC class II expression as a marker of microglial activity. It remains unclear whether the effect of siponimod on microglial activity is directly mediated by modulation of microglial S1P receptors.

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