Siponimod (BAF312) prevents synaptic neurodegeneration in experimental multiple sclerosis

Abstract

BackgroundData 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.MethodsMinipumps 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.ResultsSiponimod 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.ConclusionsAltogether, 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.

Species differences in immune‐mediated CNS tissue injury and repair: A (neuro)inflammatory topic

“…While effective for treatment of RRMS, fingolimod failed to reach a positive endpoint in the treatment of primary progressive MS (Lublin et al, ). The S1PR modulator siponimod also did reach its primary endpoint in a study of secondary progressive MS patients (Gentile et al, ; Kappos et al, ; Miron, Hall, Kennedy, Soliven, & Antel, ). Whether the disparate results reflect clinical variables (patient population, study design) or can be linked to effects on glial cells remain to be defined.…”

“…While effective for treatment of RRMS, fingolimod failed to reach a positive endpoint in the treatment of primary progressive MS (Lublin et al, 2016). The S1PR modulator siponimod also did reach its primary endpoint in a study of secondary progressive MS patients (Gentile et al, 2016;Kappos et al, 2018;Miron, Hall, Kennedy, Soliven, & Antel, 2008).…”

Siponimod enriches regulatory T and B lymphocytes in secondary progressive multiple sclerosis

“…Immunoprofiling of the lymphoid tissue and CNS will ultimately be needed to fully understand how siponimod slows disease progression in SPMS. Furthermore, CNS neurons and glia express S1PRs, S1P modulators are neuroprotective in various preclinical models (39,40), and siponimod is CNS penetrant (41). Although clear evidence for neuroprotective activity within MS patients has not yet been established, it was proposed that an S1PR-mediated reduction in glial activation may synergize with the peripheral immune modulation to prevent disease-associated inflammatory activity in the CNS (42).…”

New possibilities for the therapy of secondary progressive multiple sclerosis

“…В то же время сипонимод проникает через ГЭБ и модулирует активность астроглии и олигодендроглии через SIP-рецепторы 1-го типа на астроцитах и SIP-рецепторы 5-го типа на олигодендроцитах [19]. Установлено, что такая модуляция способна оказывать нейропротективное действие в животных моделях РС [20]. Период полувыведения сипонимода гораздо короче, чем у финголимода (30 и 200 ч соответственно), поэтому его эффекты, в том числе побочные, после отмены заканчиваются раньше, что, несомненно, имеет позитивное значение при выборе ПИТРС.…”