Effects of Siponimod (BAF312) on Inflammation-Driven Synaptopathy in Experimental Multiple Sclerosis (P5.311)

• DOI: 10.1212/wnl.86.16_supplement.p5.311
• Publication Date: 2023-12-07T09:29:56Z
• Authors: Antonietta Gentile; Alessandra Musella; Silvia Bullitta; Diego Fresegna; Francesca De Vito; Eleonora Piras; Francesca Gargano; Giovanna Borsellino; Luca Battistini; Georgia Mandolesi; Anna Schubart; Diego Centonze

Objective: to investigate whether siponimod, in addition its peripheral immune-modulation, might exert direct neuroprotective effects. Background: data from Multiple Sclerosis (MS) patients and the MS animal model, experimental autoimmune encephalomyelitis (EAE), highlighted an inflammation-dependent synaptopathy affecting brain. In EAE, this characterized by imbalance between glutamatergic GABAergic transmission, has been shown be a potential therapeutic target. Siponimod, selective sphingosine 1-phosphate1,5 receptor modulator able reduce lymphocyte egress lymph nodes thus block their migration brain, is currently under clinical investigation secondary progressive (SPMS). Methods: minipumps allowing continuous intracerebroventricular (icv) infusion of siponimod or vehicle for four weeks were implanted into C57BL/6 mice, one week before EAE induction. Striatal electrophysiology, immunohistochemistry, western blot, q-PCR counts blood performed acute-phase mice. The immune-modulatory effect on microglia was assessed measuring IL6 RANTES Luminex medium BV2 cells activated with TNF-α pretreated siponimod. Results: administration 0.45 μg/day induced significant beneficial scores without reduction count. frequencies spontaneous inhibitory post-synaptic currents (sIPSCs), selectively reduced striatum, normalized siponimod-treated Conversely, EAE-related alterations transmission not corrected We observed attenuation astrogliosis microgliosis quantitative qualitative analysis GFAP IBA1 markers, together infiltration striatum siponimod-EAE vitro, release cells. Conclusions: our results show that preventive ameliorates score, rescues striatal defects, reduces inflammatory response possibly lowering mediators microglia. Study supported Novartis