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

引用

Neural Regeneration Research 2019年第11期14卷 1950-1960页

作者： Petra Hundehege Manuela Cerina Susann Eichler Christian Thomas Alexander M. Herrmann kerstin goel Thomas Müntefering Juncal Fernandez-Orth Stefanie Bock Venu Narayanan Thomas Budde Erwin-Josef Speckmann Heinz Wiendl Anna Schubart Tobias Ruck Sven G. Meuth Department of Neurology with Institute of Translational Neurology Westfalische Wilhelms-UniversitatMunsterGermany Institute of Physiology I Westfalische Wilhelms-UniversitatMunsterGermany Novartis Institutes of Biomedical Research BaselSwitzerland

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.

关键词： multiple sclerosis focal experimental autoimmune encephalomyelitis cortical grey matter white matter BAF312 neuroaxonal damage neuroprotection

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