Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

ACC 2024 Congress

Catch up on all the top stories and latest evidence in cardiology research with our ACC 2024 Congress hub page.
ADVANCED SEARCH
Log in
Top
Journal of Neuroinflammation
Published in: Journal of Neuroinflammation 1/2016

Open Access 01-12-2016 | Research

Siponimod (BAF312) prevents synaptic neurodegeneration in experimental multiple sclerosis

Authors: Antonietta Gentile, Alessandra Musella, Silvia Bullitta, Diego Fresegna, Francesca De Vito, Roberta Fantozzi, Eleonora Piras, Francesca Gargano, Giovanna Borsellino, Luca Battistini, Anna Schubart, Georgia Mandolesi, Diego Centonze

Published in: Journal of Neuroinflammation | Issue 1/2016

Login to get access

Abstract

Background

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.

Methods

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.

Results

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.

Conclusions

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.
Literature
1.
Lublin FD, Reingold SC, Cohen JA, Cutter GR, Sørensen PS, Thompson AJ, et al. Defining the clinical course of multiple sclerosis: the 2013 revisions. Neurology. 2014;83:278–86.CrossRefPubMedPubMedCentral
2.
Calabrese M, Magliozzi R, Ciccarelli O, Geurts JJ, Reynolds R, Martin R. Exploring the origins of grey matter damage in multiple sclerosis. Nat Rev Neurosci. 2015;16:147–58.CrossRefPubMed
3.
Salvetti M, Landsman D, Schwarz-Lam P, Comi G, Thompson AJ, Fox RJ. Progressive MS: from pathophysiology to drug discovery. Mult Scler. 2015;21:1376–84.CrossRefPubMed
4.
Fyfe I. In the news: ocrelizumab excites ECTRIMS. Nat Rev Neurol. 2015;11:667.
5.
Ciccarelli O, Barkhof F, Bodini B, De Stefano N, Golay X, Nicolay K, et al. Pathogenesis of multiple sclerosis: insights from molecular and metabolic imaging. Lancet Neurol. 2014;13:807–22.CrossRefPubMed
6.
Rossi S, Muzio L, De Chiara V, Grasselli G, Musella A, Musumeci G, et al. Impaired striatal GABA transmission in experimental autoimmune encephalomyelitis. Brain Behav Immun. 2011;25:947–56.CrossRefPubMed
7.
Mandolesi G, Grasselli G, Musella A, Gentile A, Musumeci G, Sepman H, et al. GABAergic signaling and connectivity on Purkinje cells are impaired in experimental autoimmune encephalomyelitis. Neurobiol Dis. 2012;46:414–24.CrossRefPubMed
8.
Mandolesi G, Musella A, Gentile A, Grasselli G, Haji N, Sepman H, et al. Interleukin-1β alters glutamate transmission at purkinje cell synapses in a mouse model of multiple sclerosis. J Neurosci. 2013;33:12105–21.CrossRefPubMed
9.
Nisticò R, Mango D, Mandolesi G, Piccinin S, Berretta N, Pignatelli M, et al. Inflammation subverts hippocampal synaptic plasticity in experimental multiple sclerosis. PLoS One. 2013;8:e54666.CrossRefPubMedPubMedCentral
10.
Mori F, Nisticò R, Mandolesi G, Piccinin S, Mango D, Kusayanagi H, et al. Interleukin-1β promotes long-term potentiation in patients with multiple sclerosis. Neuromolecular Med. 2014;16:38–51.CrossRefPubMed
11.
Mandolesi G, Gentile A, Musella A, Fresegna D, De Vito F, Bullitta S, et al. Synaptopathy connects inflammation and neurodegeneration in multiple sclerosis. Nat Rev Neurol. 2015;11:711–24.CrossRefPubMed
12.
13.
Cutter NC, Scott DD, Johnson JC, Whiteneck G. Gabapentin effect on spasticity in multiple sclerosis: a placebo-controlled, randomized trial. Arch Phys Med Rehabil. 2000;81:164–9.CrossRefPubMed
14.
Pitt D, Werner P, Raine CS. Glutamate excitotoxicity in a model of multiple sclerosis. Nat Med. 2000;6:67–70.CrossRefPubMed
15.
Centonze D, Muzio L, Rossi S, Cavasinni F, De Chiara V, Bergami A, et al. Inflammation triggers synaptic alteration and degeneration in experimental autoimmune encephalomyelitis. J Neurosci. 2009;29:3442–52.CrossRefPubMed
16.
Bhat R, Axtell R, Mitra A, Miranda M, Lock C, Tsien RW, et al. Inhibitory role for GABA in autoimmune inflammation. Proc Natl Acad Sci U S A. 2010;107:2580–5.CrossRefPubMedPubMedCentral
17.
18.
Selmaj K, Li DK, Hartung HP, Hemmer B, Kappos L, Freedman MS, et al. Siponimod for patients with relapsing-remitting multiple sclerosis (BOLD): an adaptive, dose-ranging, randomised, phase 2 study. Lancet Neurol. 2013;12:756–67.CrossRefPubMed
19.
Gergely P, Nuesslein-Hildesheim B, Guerini D, Brinkmann V, Traebert M, Bruns C, et al. The selective sphingosine 1-phosphate receptor modulator BAF312 redirects lymphocyte distribution and hasspecies-specific effects on heart rate. Br J Pharmacol. 2012;167:1035–47.CrossRefPubMedPubMedCentral
20.
Shakeri-Nejad K, Aslanis V, Veldandi UK, Mooney L, Pezous N, Brendani B, et al. Effects of therapeutic and supratherapeutic doses of siponimod (BAF312) on cardiac repolarization in healthy subjects. Clin Ther. 2015;37:2489–505. e2.CrossRefPubMed
21.
Groves A, Kihara Y, Chun J. Fingolimod: direct CNS effects of sphingosine 1-phosphate (S1P) receptor modulation and implications in multiple sclerosis therapy. J Neurol Sci. 2013;328:9–18.CrossRefPubMedPubMedCentral
22.
Gentile A, Fresegna D, Federici M, Musella A, Rizzo FR, Sepman H, et al. Dopaminergic dysfunction is associated with IL-1β-dependent mood alterations in experimental autoimmune encephalomyelitis. Neurobiol Dis. 2015;74:347–58.CrossRefPubMed
23.
24.
Muzio L, Martino G, Furlan R. Multifaceted aspects of inflammation in multiple sclerosis: the role of microglia. J Neuroimmunol. 2007;191:39–44.CrossRefPubMed
25.
Ajami B, Bennett JL, Krieger C, McNagny KM, Rossi FM. Infiltrating monocytes trigger EAE progression, but do not contribute to the resident microglia pool. Nat Neurosci. 2011;14:1142–9.CrossRefPubMed
26.
Moreno M, Bannerman P, Ma J, Guo F, Miers L, Soulika AM, et al. Conditional ablation of astroglial CCL2 suppresses CNS accumulation of M1 macrophages and preserves axons in mice with MOG peptide EAE. J Neurosci. 2014;34:8175–85.CrossRefPubMedPubMedCentral
27.
Grasselli G, Rossi S, Musella A, Gentile A, Loizzo S, Muzio L, et al. Abnormal NMDA receptor function exacerbates experimental autoimmune encephalomyelitis. Br J Pharmacol. 2013;168:502–17.CrossRefPubMed
28.
Eugster HP, Frei K, Kopf M, Lassmann H, Fontana A. IL-6-deficient mice resist myelin oligodendrocyte glycoprotein-induced autoimmune encephalomyelitis. Eur J Immunol. 1998;28:2178–87.CrossRefPubMed
29.
Sørensen TL, Tani M, Jensen J, Pierce V, Lucchinetti C, Folcik VA, et al. Expression of specific chemokines and chemokine receptors in the central nervous system of multiple sclerosis patients. J Clin Invest. 1999;103:807–15.CrossRefPubMedPubMedCentral
30.
Baranzini SE, Elfstrom C, Chang SY, Butunoi C, Murray R, Higuchi R, et al. Transcriptional analysis of multiple sclerosis brain lesions reveals a complex pattern of cytokine expression. J Immunol. 2000;165:6576–82.CrossRefPubMed
31.
dos Santos AC, Barsante MM, Arantes RM, Bernard CC, Teixeira MM, et al. CCL2 and CCL5 mediate leukocyte adhesion in experimental autoimmune encephalomyelitis—an intravital microscopic study. J Neuroimmunol. 2005;162:122–9.CrossRefPubMed
32.
Furlan R, Rovaris M, Martinelli Boneschi F, Khademi M, Bergami A, et al. Immunological patterns identifying disease course and evolution in multiple sclerosis patients. J Neuroimmunol. 2005;165:192–200.CrossRefPubMed
33.
Kawaguchi Y, Wilson CJ, Augood SJ, Emson PC. Striatal interneurones: chemical, physiological and morphological characterization. Trends Neurosci. 1995;18:527–35.CrossRefPubMed
34.
Gustafson N, Gireesh-Dharmaraj E, Czubayko U, Blackwell KT, Plenz D. A comparative voltage and current-clamp analysis of feedback and feedforward synaptic transmission in the striatal microcircuit in vitro. J Neurophysiol. 2006;95:737–52.CrossRefPubMed
35.
De Stefano N, Matthews PM, Filippi M, Agosta F, De Luca M, et al. Evidence of early cortical atrophy in MS: relevance to white matter changes and disability. Neurology. 2003;60:1157–62.CrossRefPubMed
36.
Roosendaal SD, Bendfeldt K, Vrenken H, Polman CH, Borgwardt S, et al. Grey matter volume in a large cohort of MS patients: relation to MRI parameters and disability. Mult Scler. 2011;17:1098–106.CrossRefPubMed
37.
38.
Colombo E, Di Dario M, Capitolo E, Chaabane L, Newcombe J, Martino G, et al. Fingolimod may support neuroprotection via blockade of astrocyte nitric oxide. Ann Neurol. 2014;76:325–37.CrossRefPubMed
39.
Haji N, Mandolesi G, Gentile A, Sacchetti L, Fresegna D, Rossi S, et al. TNF-α-mediated anxiety in a mouse model of multiple sclerosis. Exp Neurol. 2012;237:296–303.CrossRefPubMed
40.
Gentile A, De Vito F, Fresegna D, Musella A, Buttari F, Bullitta S, et al. Exploring the role of microglia in mood disorders associated with experimental multiple sclerosis. Front Cell Neurosci. 2015;9:243.CrossRefPubMedPubMedCentral
41.
Uzawa A, Mori M, Uchida T, Masuda H, Ohtani R, Kuwabara S. Increased levels of CSF CD59 in neuromyelitis optica and multiple sclerosis. Clin Chim Acta. 2016;453:131–3.CrossRefPubMed
42.
Maimone D, Guazzi GC, Annunziata P. IL-6 detection in multiple sclerosis brain. J Neurol Sci. 1997;146(1):59–65.CrossRefPubMed
43.
Szczuciński A, Losy J. CCL5, CXCL10 and CXCL11 chemokines in patients with active and stable relapsing-remitting multiple sclerosis. Neuroimmunomodulation. 2011;18(1):67–72.CrossRefPubMed
44.
Mori F, Nisticò R, Nicoletti CG, Zagaglia S, Mandolesi G, Piccinin S et al. RANTES correlates with inflammatory activity and synaptic excitability in multiple sclerosis. Mult Scler. 2016. doi:10.1177/ 1352458515621796.
45.
Rossi S, Lo Giudice T, De Chiara V, Musella A, Studer V, Motta C, et al. Oral fingolimod rescues the functional deficits of synapses in experimental autoimmune encephalomyelitis. Br J Pharmacol. 2012;165:861–9.CrossRefPubMedPubMedCentral
46.
Gentile A, Rossi S, Studer V, Motta C, De Chiara V, Musella A, et al. Glatiramer acetate protects against inflammatory synaptopathy in experimental autoimmune encephalomyelitis. J Neuroimmune Pharmacol. 2013;8:651–63.CrossRefPubMed
47.
Musella A, Mandolesi G, Gentile A, Rossi S, Studer V, Motta C, et al. Cladribine interferes with IL-1β synaptic effects in experimental multiple sclerosis. J Neuroimmunol. 2013;264:8–13.CrossRefPubMed
48.
Clements RJ, McDonough J, Freeman EJ. Distribution of parvalbumin and calretinin immunoreactive interneurons in motorcortex from multiple sclerosis post-mortem tissue. Exp Brain Res. 2008;187:459–65.CrossRefPubMed
49.
Ji MH, Qiu LL, Tang H, Ju LS, Sun XR, Zhang H, et al. Sepsis-induced selective parvalbumin interneuron phenotype loss and cognitive impairments may be mediated by NADPH oxidase 2 activation in mice. J Neuroinflammation. 2015;12:182.CrossRefPubMedPubMedCentral
50.
Czeh B, Simon M, van der Hart MG, Schmelting B, Hesselink MB, Fuchs E. Chronic stress decreases the number of parvalbumin-immunoreactive interneurons in the hippocampus: prevention by treatment with a substance P receptor (NK1) antagonist. Neuropsychopharmacology. 2005;30:67–79.CrossRefPubMed
51.
Allen SJ, Watson JJ, Shoemark DK, Barua NU, Patel NK. GDNF, NGF and BDNF as therapeutic options for neurodegeneration. Pharmacol Ther. 2013;138:155–75.CrossRefPubMed
52.
Cawley N, Solanky BS, Muhlert N, Tur C, Edden RA, Wheeler-Kingshott CA, et al. Reduced gamma-aminobutyric acid concentration is associated with physical disability in progressive multiple sclerosis. Brain. 2015;138:2584–95.CrossRefPubMed
53.
Haber SN. The place of dopamine in the cortico-basal ganglia circuit. Neuroscience. 2014;282C:248–57.CrossRef
54.
Tao G, Datta S, He R, Nelson F, Wolinsky JS, Narayana PA. Deep gray matter atrophy in multiple sclerosis: a tensor based morphometry. J Neurol Sci. 2009;282:39–46.CrossRefPubMedPubMedCentral
Metadata
Title
Siponimod (BAF312) prevents synaptic neurodegeneration in experimental multiple sclerosis
Authors
Antonietta Gentile
Alessandra Musella
Silvia Bullitta
Diego Fresegna
Francesca De Vito
Roberta Fantozzi
Eleonora Piras
Francesca Gargano
Giovanna Borsellino
Luca Battistini
Anna Schubart
Georgia Mandolesi
Diego Centonze
Publication date
01-12-2016
Publisher
BioMed Central
Published in
Journal of Neuroinflammation / Issue 1/2016
Electronic ISSN: 1742-2094
DOI
https://doi.org/10.1186/s12974-016-0686-4

Other articles of this Issue 1/2016

Journal of Neuroinflammation 1/2016 Go to the issue

Research

Resveratrol suppresses glial activation and alleviates trigeminal neuralgia via activation of AMPK

Research

In vitro evaluation of physiologically relevant concentrations of teriflunomide on activation and proliferation of primary rodent microglia

Research

Metabolic consequences of inflammatory disruption of the blood-brain barrier in an organ-on-chip model of the human neurovascular unit

Research

Hyperhomocysteinemia induced by excessive methionine intake promotes rupture of cerebral aneurysms in ovariectomized rats

Research

Cerebrospinal fluid cytokines in Lyme neuroborreliosis

Research

The anti-inflammatory Annexin A1 induces the clearance and degradation of the amyloid-β peptide