Central Modulation of Selective Sphingosine-1-Phosphate Receptor 1 Ameliorates Experimental Multiple Sclerosis
Open Access
- 22 May 2020
- Vol. 9 (5), 1290
- https://doi.org/10.3390/cells9051290
Abstract
Future treatments of multiple sclerosis (MS), a chronic autoimmune neurodegenerative disease of the central nervous system (CNS), aim for simultaneous early targeting of peripheral immune function and neuroinflammation. Sphingosine-1-phosphate (S1P) receptor modulators are among the most promising drugs with both “immunological” and “non-immunological” actions. Selective S1P receptor modulators have been recently approved for MS and shown clinical efficacy in its mouse model, the experimental autoimmune encephalomyelitis (EAE). Here, we investigated the anti-inflammatory/neuroprotective effects of ozanimod (RPC1063), a S1P1/5 modulator recently approved in the United States for the treatment of MS, by performing ex vivo studies in EAE brain. Electrophysiological experiments, supported by molecular and immunofluorescence analysis, revealed that ozanimod was able to dampen the EAE glutamatergic synaptic alterations, through attenuation of local inflammatory response driven by activated microglia and infiltrating T cells, the main CNS-cellular players of EAE synaptopathy. Electrophysiological studies with selective S1P1 (AUY954) and S1P5 (A971432) agonists suggested that S1P1 modulation is the main driver of the anti-excitotoxic activity mediated by ozanimod. Accordingly, in vivo intra-cerebroventricular treatment of EAE mice with AUY954 ameliorated clinical disability. Altogether these results strengthened the relevance of S1P1 agonists as immunomodulatory and neuroprotective drugs for MS therapy.Keywords
Funding Information
- Fondazione Italiana Sclerosi Multipla (2018/B/2, 2019/S/1)
- Ministero della Salute (GR-2016-02361163, GR-2016-02362380, GR-2018-12366154, RF-2018-12366144)
This publication has 51 references indexed in Scilit:
- Multiple SclerosisThe New England Journal of Medicine, 2018
- Synaptopathy connects inflammation and neurodegeneration in multiple sclerosisNature Reviews Neurology, 2015
- Immunopathology of multiple sclerosisNature Reviews Immunology, 2015
- In vivo evidence of glutamate toxicity in multiple sclerosisAnnals of Neurology, 2014
- Interleukin-1 Alters Glutamate Transmission at Purkinje Cell Synapses in a Mouse Model of Multiple SclerosisJournal of Neuroscience, 2013
- GABAergic signaling and connectivity on Purkinje cells are impaired in experimental autoimmune encephalomyelitisNeurobiology of Disease, 2012
- Impaired striatal GABA transmission in experimental autoimmune encephalomyelitisBrain, Behavior, and Immunity, 2011
- Interleukin‐1β causes synaptic hyperexcitability in multiple sclerosisAnnals of Neurology, 2011
- The link between inflammation, synaptic transmission and neurodegeneration in multiple sclerosisCell Death & Differentiation, 2009
- The relation between inflammation and neurodegeneration in multiple sclerosis brainsBrain, 2009