The next-generation sphingosine-1 receptor modulator BAF312 (siponimod) improves cortical network functionality in focal autoimmune encephalomyelitis

Abstract

Autoimmune diseases of the central nervous system (CNS) like multiple sclerosis (MS) are characterized by inflammation and demyelinated lesions in white and grey matter regions. While inflammation is present at all stages of MS, it is more pronounced in the relapsing forms of the disease, whereas progressive MS (PMS) shows significant neuroaxonal damage and grey and white matter atrophy. Hence, disease-modifying treatments beneficial in patients with relapsing MS have limited success in PMS. BAF312 (siponimod) is a novel sphingosine-1-phosphate receptor modulator shown to delay progression in PMS. Besides reducing inflammation by sequestering lymphocytes in lymphoid tissues, BAF312 crosses the blood-brain barrier and binds its receptors on neurons, astrocytes and oligodendrocytes. To evaluate potential direct neuroprotective effects, BAF312 was systemically or locally administered in the CNS of experimental autoimmune encephalomyelitis mice with distinct grey- and white-matter lesions (focal experimental autoimmune encephalomyelitis using an osmotic mini-pump). Ex-vivo flow cytometry revealed that systemic but not local BAF312 administration lowered immune cell infiltration in animals with both grey and white matter lesions. Ex-vivo voltage-sensitive dye imaging of acute brain slices revealed an altered spatio-temporal pattern of activation in the lesioned cortex compared to controls in response to electrical stimulation of incoming white-matter fiber tracts. Here, BAF312 administration showed partial restore of cortical neuronal circuit function. The data suggest that BAF312 exerts a neuroprotective effect after crossing the blood-brain barrier independently of peripheral effects on immune cells. Experiments were carried out in accordance with German and EU animal protection law and approved by local authorities (Landesamt für Natur, Umwelt und Verbraucherschutz Nordrhein-Westfalen; 87-51.04.2010.A331) on December 28, 2010.

Does Siponimod Exert Direct Effects in the Central Nervous System?

“…The observed anti-inflammatory potency of siponimod in EAE has since been reproduced by others [118]. In a recent study, the authors showed that the adoptive transfer of proteolipid protein-primed Th17 cells into SJL/J recipient mice induces subpial demyelination, microgliosis, and destruction of the glial limitans superficialis and that this inflammatory cortical demyelination is improved by siponimod treatment [119].…”

“…Additionally, using an organotypic slice culture model, it was shown that siponimod attenuates lysophosphatidylcholine-induced demyelination. At a more functional level, it has been shown that siponimod can improve cortical network functionality in acute brain slices isolated from EAE mice [118]. Since peripheral immune cells (especially lymphocytes) do not play a role in organotypic slice culture models, this experimental setup has shown convincingly that siponimod can have beneficial effects in the context of MS by directly modulating the brain cell function.…”

Sphingosine-1-Phosphate Receptor Modulators and Oligodendroglial Cells: Beyond Immunomodulation

“…However, some evidence suggests its direct involvement in the control of CNS activities. In a modified EAE model with cytokines-mediated induction of cortical grey matter and subcortical white matter lesions, systemic, but not intracerebral administration of siponimod (3 mg/kg) ameliorated the clinical symptoms of EAE mice [ 146 ]. Similarly, in the EAE mouse model, continuous intracerebroventricular infusion of siponimod (0.45 μg/day) exerted a positive effect on the imbalanced synaptic transmission that occurs during the disease.…”

Sphingosine‐1‐phosphate (S1P) receptors: Promising drug targets for treating bone‐related diseases

“…It has been noted that ponesimod acts as the potential treatment for MS and other immune‐mediated diseases, so that the treatment for bone‐related diseases through immunoregulatory mechanism is also a potential choice 87 . BAF312 (siponimod), a dual agonist at S1PR1 and S1PR5, which is currently undergoing clinical trials for the treatment of secondary progressive multiple sclerosis (MS) 88 . Besides reducing inflammation by sequestering lymphocytes in lymphoid tissues, BAF312 could also cross the blood‐brain barrier and binds its receptors on many kinds of cells 88 .…”

“…BAF312 (siponimod), a dual agonist at S1PR1 and S1PR5, which is currently undergoing clinical trials for the treatment of secondary progressive multiple sclerosis (MS) 88 . Besides reducing inflammation by sequestering lymphocytes in lymphoid tissues, BAF312 could also cross the blood‐brain barrier and binds its receptors on many kinds of cells 88 . Similarly, ozanimod (RPC1063) is a specific and potent small molecule modulator of the S1PR1 and S1PR5, which has shown therapeutic effect on relapsing MS and ulcerative colitis 89 .…”