BACKGROUND: Data from multiple sclerosis (MS) and the MS rodent model, 
experimental autoimmune encephalomyelitis (EAE), highlighted an 
inflammation-dependent synaptopathy at the basis of the neurodegenerative damage 
causing irreversible disability in these disorders. This synaptopathy is 
characterized by an imbalance between glutamatergic and GABAergic transmission 
and has been proposed to be a potential therapeutic target. Siponimod (BAF312), 
a selective sphingosine 1-phosphate1,5 receptor modulator, is currently under 
investigation in a clinical trial in secondary progressive MS patients. We 
investigated whether siponimod, in addition to its peripheral immune modulation, 
may exert direct neuroprotective effects in the central nervous system (CNS) of 
mice with chronic progressive EAE.
METHODS: Minipumps allowing continuous intracerebroventricular (icv) infusion of 
siponimod for 4 weeks were implanted into C57BL/6 mice subjected to 
MOG35-55-induced EAE. Electrophysiology, immunohistochemistry, western blot, 
qPCR experiments, and peripheral lymphocyte counts were performed. In addition, 
the effect of siponimod on activated microglia was assessed in vitro to confirm 
the direct effect of the drug on CNS-resident immune cells.
RESULTS: Siponimod administration (0.45 μg/day) induced a significant beneficial 
effect on EAE clinical scores with minimal effect on peripheral lymphocyte 
counts. Siponimod rescued defective GABAergic transmission in the striatum of 
EAE, without correcting the EAE-induced alterations of glutamatergic 
transmission. We observed a significant attenuation of astrogliosis and 
microgliosis together with reduced lymphocyte infiltration in the striatum of 
EAE mice treated with siponimod. Interestingly, siponimod reduced the release of 
IL-6 and RANTES from activated microglial cells in vitro, which might explain 
the reduced lymphocyte infiltration. Furthermore, the loss of 
parvalbumin-positive (PV+) GABAergic interneurons typical of EAE brains was 
rescued by siponimod treatment, providing a plausible explanation of the 
selective effects of this drug on inhibitory synaptic transmission.
CONCLUSIONS: Altogether, our results show that siponimod has neuroprotective 
effects in the CNS of EAE mice, which are likely independent of its peripheral 
immune effect, suggesting that this drug could be effective in limiting 
neurodegenerative pathological processes in MS.