title: Siponimod (BAF312) prevents synaptic neurodegeneration in experimental multiple sclerosis.
abstract: Data from multiple sclerosis (MS) and the MS rodent model, experimental autoimmune encephalomyelitis (EAE), highlighted an inflammation-dependent synaptopathy at the basis of the neurodegenerative damage causing irreversible disability in these disorders. This synaptopathy is characterized by an imbalance between glutamatergic and GABAergic transmission and has been proposed to be a potential therapeutic target. Siponimod (BAF312), a selective sphingosine 1-phosphate1,5 receptor modulator, is currently under investigation in a clinical trial in secondary progressive MS patients. We investigated whether siponimod, in addition to its peripheral immune modulation, may exert direct neuroprotective effects in the central nervous system (CNS) of mice with chronic progressive EAE.
  
  
  
  Minipumps allowing continuous intracerebroventricular (icv) infusion of siponimod for 4 weeks were implanted into C57BL/6 mice subjected to MOG35-55-induced EAE. Electrophysiology, immunohistochemistry, western blot, qPCR experiments, and peripheral lymphocyte counts were performed. In addition, the effect of siponimod on activated microglia was assessed in vitro to confirm the direct effect of the drug on CNS-resident immune cells.
  
  
  
  Siponimod administration (0.45 μg/day) induced a significant beneficial effect on EAE clinical scores with minimal effect on peripheral lymphocyte counts. Siponimod rescued defective GABAergic transmission in the striatum of EAE, without correcting the EAE-induced alterations of glutamatergic transmission. We observed a significant attenuation of astrogliosis and microgliosis together with reduced lymphocyte infiltration in the striatum of EAE mice treated with siponimod. Interestingly, siponimod reduced the release of IL-6 and RANTES from activated microglial cells in vitro, which might explain the reduced lymphocyte infiltration. Furthermore, the loss of parvalbumin-positive (PV+) GABAergic interneurons typical of EAE brains was rescued by siponimod treatment, providing a plausible explanation of the selective effects of this drug on inhibitory synaptic transmission.
  
  
  
  Altogether, our results show that siponimod has neuroprotective effects in the CNS of EAE mice, which are likely independent of its peripheral immune effect, suggesting that this drug could be effective in limiting neurodegenerative pathological processes in MS.
authors: Laboratory of Neuroimmunology and Synaptic Transmission, IRCCS Fondazione Santa Lucia, Centro Europeo di Ricerca sul Cervello (CERC), 00143, Rome, Italy.|Multiple Sclerosis Research Unit, Department of Systems Medicine, Tor Vergata University, 00133, Rome, Italy.
authors: Antonietta
authors: A
authors: Gentile
authors: Laboratory of Neuroimmunology and Synaptic Transmission, IRCCS Fondazione Santa Lucia, Centro Europeo di Ricerca sul Cervello (CERC), 00143, Rome, Italy.
authors: Alessandra
authors: A
authors: Musella
authors: Laboratory of Neuroimmunology and Synaptic Transmission, IRCCS Fondazione Santa Lucia, Centro Europeo di Ricerca sul Cervello (CERC), 00143, Rome, Italy.
authors: Silvia
authors: S
authors: Bullitta
authors: Laboratory of Neuroimmunology and Synaptic Transmission, IRCCS Fondazione Santa Lucia, Centro Europeo di Ricerca sul Cervello (CERC), 00143, Rome, Italy.|Multiple Sclerosis Research Unit, Department of Systems Medicine, Tor Vergata University, 00133, Rome, Italy.
authors: Diego
authors: D
authors: Fresegna
authors: Laboratory of Neuroimmunology and Synaptic Transmission, IRCCS Fondazione Santa Lucia, Centro Europeo di Ricerca sul Cervello (CERC), 00143, Rome, Italy.|Multiple Sclerosis Research Unit, Department of Systems Medicine, Tor Vergata University, 00133, Rome, Italy.
authors: Francesca
authors: F
authors: De Vito
authors: Unit of Neurology and Neurorehabilitation, IRCCS Istituto Neurologico Mediterraneo (INM) Neuromed, 86077, Pozzilli, IS, Italy.
authors: Roberta
authors: R
authors: Fantozzi
authors: Neuroimmunology Unit, IRCCS Fondazione Santa Lucia-CERC, 00143, Rome, Italy.
authors: Eleonora
authors: E
authors: Piras
authors: Neuroimmunology Unit, IRCCS Fondazione Santa Lucia-CERC, 00143, Rome, Italy.
authors: Francesca
authors: F
authors: Gargano
authors: Neuroimmunology Unit, IRCCS Fondazione Santa Lucia-CERC, 00143, Rome, Italy.
authors: Giovanna
authors: G
authors: Borsellino
authors: Neuroimmunology Unit, IRCCS Fondazione Santa Lucia-CERC, 00143, Rome, Italy.
authors: Luca
authors: L
authors: Battistini
authors: Novartis Institutes of Biomedical Research, Basel, Switzerland.
authors: Anna
authors: A
authors: Schubart
authors: Laboratory of Neuroimmunology and Synaptic Transmission, IRCCS Fondazione Santa Lucia, Centro Europeo di Ricerca sul Cervello (CERC), 00143, Rome, Italy. g.mandolesi@hsantalucia.it.
authors: Georgia
authors: G
authors: Mandolesi
authors: Multiple Sclerosis Research Unit, Department of Systems Medicine, Tor Vergata University, 00133, Rome, Italy.|Unit of Neurology and Neurorehabilitation, IRCCS Istituto Neurologico Mediterraneo (INM) Neuromed, 86077, Pozzilli, IS, Italy.
authors: Diego
authors: D
authors: Centonze
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism; D001384:Azetidines / Q000494:pharmacology / Q000627:therapeutic use*; D001593:Benzyl Compounds / Q000494:pharmacology / Q000627:therapeutic use*; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism; D002461:Cell Line, Transformed; D002540:Cerebral Cortex / Q000166:cytology; D016207:Cytokines / Q000494:pharmacology; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000139:chemically induced / Q000150:complications*; D005620:Freund's Adjuvant / Q000276:immunology / Q000633:toxicity; D051379:Mice; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism; D063308:Myelin-Oligodendrocyte Glycoprotein / Q000276:immunology / Q000633:toxicity; D009410:Nerve Degeneration / Q000209:etiology / Q000473:pathology / Q000517:prevention & control; D009431:Neural Conduction / Q000187:drug effects / Q000502:physiology; D009457:Neuroglia / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000187:drug effects; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D010446:Peptide Fragments / Q000276:immunology / Q000633:toxicity; D013569:Synapses / Q000187:drug effects / Q000502:physiology*; D055366:Synaptic Potentials / Q000187:drug effects; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D066127:White Matter / Q000187:drug effects / Q000473:pathology
chemical_list: C491049:Aif1 protein, mouse; D015703:Antigens, CD; D001384:Azetidines; D001593:Benzyl Compounds; D002135:Calcium-Binding Proteins; D016207:Cytokines; D008840:Microfilament Proteins; D063308:Myelin-Oligodendrocyte Glycoprotein; D018696:Neuroprotective Agents; D010446:Peptide Fragments; C445081:myelin oligodendrocyte glycoprotein (35-55); D005620:Freund's Adjuvant; C578989:siponimod
keywords: Experimental autoimmune encephalomyelitis; GABA; Neurodegeneration; Parvalbumin neuron; Striatum; Synaptic transmission