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A Clonal NG2-Glia Cell Response in a Mouse Model of Multiple Sclerosis
Open AccessArticle

Central Modulation of Selective Sphingosine-1-Phosphate Receptor 1 Ameliorates Experimental Multiple Sclerosis

1
Department of Human Sciences and Quality of Life Promotion, University of Rome San Raffaele, 00166 Rome, Italy
2
IRCCS San Raffaele Pisana, 00166 Rome, Italy
3
Department of Systems Medicine, University of Rome Tor Vergata, 00133 Rome, Italy
4
Unit of Neurology, IRCCS Neuromed, 86077 Pozzilli (IS), Italy
*
Author to whom correspondence should be addressed.
These authors contributed equally.
Cells 2020, 9(5), 1290; https://doi.org/10.3390/cells9051290
Received: 20 April 2020 / Revised: 14 May 2020 / Accepted: 18 May 2020 / Published: 22 May 2020
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. View Full-Text
Keywords: sphingosine-1-phosphate receptors; glutamate synaptic dysfunction; microglia; T lymphocytes; experimental autoimmune encephalomyelitis (EAE); pro-inflammatory cytokines; neuroinflammation; ozanimod; AUY954; A971432; S1P1; S1P5 sphingosine-1-phosphate receptors; glutamate synaptic dysfunction; microglia; T lymphocytes; experimental autoimmune encephalomyelitis (EAE); pro-inflammatory cytokines; neuroinflammation; ozanimod; AUY954; A971432; S1P1; S1P5
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Musella, A.; Gentile, A.; Guadalupi, L.; Rizzo, F.R.; De Vito, F.; Fresegna, D.; Bruno, A.; Dolcetti, E.; Vanni, V.; Vitiello, L.; Bullitta, S.; Sanna, K.; Caioli, S.; Balletta, S.; Nencini, M.; Buttari, F.; Stampanoni Bassi, M.; Centonze, D.; Mandolesi, G. Central Modulation of Selective Sphingosine-1-Phosphate Receptor 1 Ameliorates Experimental Multiple Sclerosis. Cells 2020, 9, 1290.

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