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Gentile, Antonietta, Musella, Alessandra, Bullitta, Silvia, Fresegna, Diego, De Vito, Francesca, Piras, Eleanora, Gargano, Francesca, Borsellino, Giovanna, Battistini, Luca, Schubart Wellensiek, Anna, Mandolesi, Georgia and Centonze, Diego (2016) EFFECTS OF SIPONIMOD (BAF312) ON SYNAPTIC NEURODEGENERATIVE DAMAGE IN EXPERIMENTAL MULTIPLE SCLEROSIS. J Neuroinflammation, 13 (1). p. 207. ISSN 1742-2094


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 CNS of mice with chronic progressive EAE. Minipumps allowing continuous intracerebroventricular (icv) infusion of siponimod for four weeks were implanted into C57BL/6 mice subjected to MOG35-55-induced EAE. Electrophysiology, immunohistochemistry, western blot, q-PCR 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.
Siponimod administration (0.45 g/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.
Altogether, our results show that siponimod has direct 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.

Item Type: Article
Date Deposited: 01 Sep 2016 00:45
Last Modified: 01 Sep 2016 00:45


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