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

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.

• Authors: Alessandra Musella, Antonietta Gentile, Livia Guadalupi, Francesca Romana Rizzo, Francesca De Vito, Diego Fresegna, Antonio Bruno, Ettore Dolcetti, Valentina Vanni, Laura Vitiello, Silvia Bullitta, Krizia Sanna, Silvia Caioli, Sara Balletta, Monica Nencini, Fabio Buttari, Mario Stampanoni Bassi, Diego Centonze, Georgia Mandolesi
• Journal: Cells (Cells) Vol. 9 Issue 5 (05 22 2020) ISSN: 2073-4409 [Electronic] Switzerland
• PMID: 32455907 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• AUY 954
• Anti-Inflammatory Agents
• Glutamates
• Indans
• Interleukin-1beta
• Oxadiazoles
• RNA, Messenger
• Sphingosine-1-Phosphate Receptors
• Thiophenes
• beta-Alanine
• ozanimod

Topics

• Animals
• Anti-Inflammatory Agents (pharmacology)
• Cell Line
• Central Nervous System (pathology)
• Disease Models, Animal
• Encephalomyelitis, Autoimmune, Experimental (immunology, pathology, physiopathology)
• Female
• Glutamates (metabolism)
• Indans (pharmacology)
• Interleukin-1beta (metabolism)
• Mice, Inbred C57BL
• Microglia (drug effects, metabolism)
• Multiple Sclerosis (immunology, pathology)
• Neostriatum (drug effects, pathology, physiopathology)
• Oxadiazoles (pharmacology)
• RNA, Messenger (genetics, metabolism)
• Sphingosine-1-Phosphate Receptors (agonists, metabolism)
• Synapses (drug effects, pathology)
• Synaptic Transmission (drug effects)
• T-Lymphocytes (immunology)
• Thiophenes (pharmacology)
• beta-Alanine (analogs & derivatives, pharmacology)