Siponimod (BAF312) Activates Nrf2 While Hampering NFκB in Human Astrocytes, and Protects From Astrocyte-Induced Neurodegeneration
Open accessAbstract
Multiple sclerosis (MS) is an inflammatory neurodegenerative disease of the central nervous system (CNS) with heterogeneous pathophysiology. In its progressive course oligodendrocyte and neuroaxonal damage is sustained by compartmentalized inflammation due to glial dysregulation. Siponimod (BAF312), a modulator of two sphingosine-1-phosphate (S1P) receptors (S1P1 and S1P5) is the first oral treatment specifically approved for active secondary progressive MS. To address potential direct effects of BAF312 on glial function and glia-neuron interaction, we set up a series of in vitro functional assays with astrocytes generated from human fibroblasts. These cells displayed the typical morphology and markers of astroglia, and were susceptible to the action of inflammatory mediators and BAF312, because expressing receptors for IL1, IL17 and S1P (namely S1P1 and S1P3). Targeting of S1P signaling by BAF312 inhibited NFκB translocation evoked by inflammatory cytokines, indicating a direct anti-inflammatory activity of the drug on the human astrocyte. Further, while glia cells exposed to IL1 or IL17 downregulated protein expression of glutamate transporters, BAF312-treated astrocytes maintained high levels of GLAST and GLT1 regardless of the presence of inflammatory mediators. Interestingly, despite potential glial susceptibility to S1P signaling via S1P3, which is not targeted by BAF312, NFκB translocation and downregulation of glutamate transporters in response to S1P were inhibited at similar levels by BAF312 and FTY720, another S1P signaling modulator targeting also S1P3. Accordingly, specific inhibition of S1P1 via NIBR-0213 blocked S1P-evoked NFκB translocation, demonstrating that modulation of S1P1 is sufficient to dampen signaling via other S1P receptors. Considering that NFκB-dependent responses are regulated by Nrf2, we measured activation of this critical transcription factor for anti-oxidant reactions, and observed that BAF312 rapidly induced nuclear translocation of Nrf2, but this effect was attenuated in the presence of an inflammatory milieu. Finally, in vitro experiments with spinal neurons exposed to astrocyte-conditioned media showed that modulation of S1P or cytokine signaling in astrocytes via BAF312 prevented neurons from astrocyte-induced degeneration. Overall, these experiments on human astrocytes suggest that during neuroinflammation targeting of S1P1 via BAF312 may modulate key astrocyte functions and thereby attain neuroprotection indirectly.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
hiPSC-derived astrocytes are rapidly becoming commonplace in basic research and therapy development.
“are rapidly becoming commonplace in basic research11,82 and therapy development109”
From Reactive astrocyte nomenclature, definitions, and future directions (2021) · cites this paper as [109]
The Results section (“Generation and Characterization of Human iAstrocytes”; page unavailable) shows that the authors generated hiPSC-derived astrocytes as a research model, and the Methods show their use in testing siponimod. This provides an example relevant to basic research and therapy investigation, but the paper does not establish that such use is rapidly becoming commonplace. (LLM, conf=0.82)
Experimental — accuracy not yet measured
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
NF-κB signaling in inflammation
Liu, T., Zhang, L., Joo, D., & Sun, S.-C. (2017) · Signal Transduction and Targeted Therapy · doi:10.1038/sigtrans.2017.23 · Cited by 8,791 · see citing works
Compston, A., & Coles, A. J. (2008) · The Lancet · doi:10.1016/s0140-6736(08)61620-7 · Cited by 4,459 · see citing works
Astrocytes are active players in cerebral innate immunity
Farina, C., Aloisi, F., & Meinl, E. (2007) · Trends in Immunology · doi:10.1016/j.it.2007.01.005 · Cited by 1,304 · see citing works
Self-citationFingolimod (FTY720): discovery and development of an oral drug to treat multiple sclerosis
Brinkmann, V., Billich, A., Baumruker, T., Heining, P., Schmouder, R., Francis, G., Aradhye, S., & Burtin, P. (2010) · Nature Reviews Drug Discovery · doi:10.1038/nrd3248 · Cited by 1,273 · see citing works
Progressive multiple sclerosis: pathology and pathogenesis
Lassmann, H., van Horssen, J., & Mahad, D. (2012) · Nature Reviews Neurology · doi:10.1038/nrneurol.2012.168 · Cited by 1,033 · see citing works
Lassmann, H. (2016) · Elsevier eBooks · doi:10.1016/b978-0-12-801914-6.00001-5 · Cited by 952 · see citing works
Kappos, L., Bar-Or, A., Cree, B. A. C., Fox, R. J., Giovannoni, G., Gold, R., Vermersch, P., Arnold, D. L., Arnould, S., Scherz, T., et al. (2018) · The Lancet · doi:10.1016/s0140-6736(18)30475-6 · Cited by 942 · see citing works
Self-citationThe outs and the ins of sphingosine-1-phosphate in immunity
Spiegel, S., & Milstien, S. (2011) · Nature Reviews Immunology · doi:10.1038/nri2974 · Cited by 810 · see citing works
Mahmoud, S., Gharagozloo, M., Simard, C., & Gris, D. (2019) · Cells · doi:10.3390/cells8020184 · Cited by 698 · see citing works
Sofroniew, M. V. (2015) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a020420 · Cited by 695 · see citing works
Pathogenic Mechanisms Associated With Different Clinical Courses of Multiple Sclerosis
Lassmann, H. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2018.03116 · Cited by 678 · see citing works
Brambilla, R., Bracchi-Ricard, V. C., Hu, W.-H., Frydel, B. R., Bramwell, A., Karmally, S., Green, E. J., & Bethea, J. R. (2005) · The Journal of Experimental Medicine · doi:10.1084/jem.20041918 · Cited by 589 · see citing works
Choi, J. W., Gardell, S. E., Herr, D. R., Rivera, R. R., Lee, C., Noguchi, K., Teo, S. T., Yung, Y. C., Lu, M., Kennedy, G., et al. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1014154108 · Cited by 582 · see citing works
LUBLIN, F. D., Miller, D. H., Freedman, M. S., Cree, B., Wolinsky, J. S., Weiner, H. L., Lubetzki, C., Hartung, H., Montalbán, X., Uitdehaag, B. M. J., et al. (2016) · The Lancet · doi:10.1016/s0140-6736(15)01314-8 · Cited by 449 · see citing works
Reinhardt, P., Glatza, M., Hemmer, K., Tsytsyura, Y., Thiel, C. S., Höing, S., Moritz, S., Parga, J. A., Wagner, L., Bruder, J. M., et al. (2013) · PLoS ONE · doi:10.1371/journal.pone.0059252 · Cited by 443 · see citing works
Persistent signaling induced by FTY720-phosphate is mediated by internalized S1P1 receptors
Müllershausen, F., Zécri, F. J., Cetin, C., Billich, A., Guerini, D., & Seuwen, K. (2009) · Nature Chemical Biology · doi:10.1038/nchembio.173 · Cited by 370 · see citing works
Meyer, K., Ferraiuolo, L., Miranda, C. J., Likhite, S., McElroy, S., Renusch, S., Ditsworth, D., Lagier-Tourenne, C., Smith, R. A., Ravits, J., et al. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1314085111 · Cited by 345 · see citing works
Foster, C. A., Howard, L. M., Schweitzer, A., Persohn, E., HIESTAND, P. C., Balatoni, B., Reuschel, R., Beerli, C., Schwartz, M., & Billich, A. (2007) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.107.127183 · Cited by 321 · see citing works
Blood sphingolipidomics in healthy humans: impact of sample collection methodology
Hammad, S. M., Pierce, J. S., Soodavar, F., Smith, K. J., Gadban, M. M. A., Rembiesa, B. M., Klein, R. L., Hannun, Y. A., Bielawski, J., & Bielawska, A. E. (2010) · Journal of Lipid Research · doi:10.1194/jlr.d008532 · Cited by 315 · see citing works
Groves, A., Kihara, Y., & Chun, J. J. M. (2013) · Journal of the Neurological Sciences · doi:10.1016/j.jns.2013.02.011 · Cited by 314 · see citing works
Gergely, P. A., Nuesslein‐Hildesheim, B., Guerini, D., Brinkmann, V., Traebert, M., Bruns, C., Pan, S., Gray, N. S., Hinterding, K., Cooke, N., et al. (2012) · British Journal of Pharmacology · doi:10.1111/j.1476-5381.2012.02061.x · Cited by 305 · see citing works
The Nrf2–ARE cytoprotective pathway in astrocytes
Vargas, M. R., & Johnson, J. A. (2009) · Expert Reviews in Molecular Medicine · doi:10.1017/s1462399409001094 · Cited by 289 · see citing works
Brambilla, R., Persaud, T., Hu, X.-C., Karmally, S., Shestopalov, V., Dvoriantchikova, G., Ivanov, D., Nathanson, L., Barnum, S., & Bethea, J. (2009) · Journal of Immunology · doi:10.4049/jimmunol.0802954 · Cited by 285 · see citing works
Fingolimod phosphate promotes the neuroprotective effects of microglia
Noda, H., Takeuchi, H., Mizuno, T., & Suzumura, A. (2013) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2012.12.005 · Cited by 212 · see citing works
Vercellino, M., Merola, A., Piacentino, C., Votta, B., Capello, E., Mancardi, G. L., Mutani, R., Giordana, M. T., & Cavalla, P. (2007) · Journal of Neuropathology & Experimental Neurology · doi:10.1097/nen.0b013e31812571b0 · Cited by 190 · see citing works
Murphy‐Royal, C., Dupuis, J. P., Groc, L., & Oliet, S. H. R. (2017) · Journal of Neuroscience Research · doi:10.1002/jnr.24029 · Cited by 168 · see citing works
Differential effects of fingolimod (FTY720) on immune cells in the CSF and blood of patients with MS
Kowarik, M. C., Pellkofer, H., Cepok, S., Korn, T., Kümpfel, T., Buck, D., Hohlfeld, R., Berthele, A., & Hemmer, B. (2011) · Neurology · doi:10.1212/wnl.0b013e3182143564 · Cited by 159 · see citing works
Siponimod (BAF312) prevents synaptic neurodegeneration in experimental multiple sclerosis
Gentile, A., Musella, A., Bullitta, S., Fresegna, D., Vito, F. D., Fantozzi, R., Piras, E., Gargano, F., Borsellino, G., Battistini, L., et al. (2016) · Journal of Neuroinflammation · doi:10.1186/s12974-016-0686-4 · Cited by 159 · see citing works
Immunological Aspects of Approved MS Therapeutics
Rommer, P. S., Milo, R., Han, M. H., Satyanarayan, S., Sellner, J., Hauer, L., Illés, Z., Warnke, C., Laurent, S. A., Weber, M. S., et al. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.01564 · Cited by 157 · see citing works
Fingolimod may support neuroprotection via blockade of astrocyte nitric oxide
Colombo, E., Dario, M. D., Capitolo, E., Chaabane, L., Newcombe, J., Martino, G., & Farina, C. (2014) · Annals of Neurology · doi:10.1002/ana.24217 · Cited by 150 · see citing works
Self-citationColombo, E., Cordiglieri, C., Melli, G., Newcombe, J., Krumbholz, M., Parada, L. F., Medico, E., Hohlfeld, R., Meinl, E., & Farina, C. (2012) · Journal of Experimental Medicine · doi:10.1084/jem.20110698 · Cited by 146 · see citing works
Self-citationAltered expression of glutamate transporters in experimental autoimmune encephalomyelitis
Ohgoh, M. (2002) · Journal of Neuroimmunology · doi:10.1016/s0165-5728(02)00029-2 · Cited by 143 · see citing works
Brambilla, R., Hurtado, A., Persaud, T., Esham, K., Pearse, D. D., Oudega, M., & Bethea, J. R. (2009) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2009.06190.x · Cited by 130 · see citing works
Mechanisms of glutamate toxicity in multiple sclerosis: biomarker and therapeutic opportunities
Macrez, R., Stys, P. K., Vivien, D., Lipton, S. A., & Docagne, F. (2016) · The Lancet Neurology · doi:10.1016/s1474-4422(16)30165-x · Cited by 130 · see citing works
A Potent and Selective S1P1 Antagonist with Efficacy in Experimental Autoimmune Encephalomyelitis
Quancard, J., Bollbuck, B., Janser, P., Angst, D., Berst, F., Buehlmayer, P., Streiff, M. B., Beerli, C., Brinkmann, V., Guerini, D., et al. (2012) · Chemistry & Biology · doi:10.1016/j.chembiol.2012.07.016 · Cited by 128 · see citing works
The dual S1PR1/S1PR5 drug BAF312 (Siponimod) attenuates demyelination in organotypic slice cultures
O’Sullivan, C., Schubart, A., Mir, A. K., & Dev, K. K. (2016) · Journal of Neuroinflammation · doi:10.1186/s12974-016-0494-x · Cited by 124 · see citing works
Reactive Oxygen Species from Human Astrocytes Induced Functional Impairment and Oxidative Damage
Sheng, W. S., Hu, S., Feng, A., & Rock, R. B. (2013) · Neurochemical Research · doi:10.1007/s11064-013-1123-z · Cited by 116 · see citing works
Soliven, B. C., Miron, V. E., & Chun, J. J. M. (2011) · Neurology · doi:10.1212/wnl.0b013e31820d9507 · Cited by 103 · see citing works
Fischer, I., Alliod, C., Martinier, N., Newcombe, J., Brana, C., & Pouly, S. (2011) · PLoS ONE · doi:10.1371/journal.pone.0023905 · Cited by 102 · see citing works
FTY720 attenuates excitotoxicity and neuroinflammation
Cipriani, R., Chara, J. C., Antigüedad, A. R., & Matute, C. (2015) · Journal of Neuroinflammation · doi:10.1186/s12974-015-0308-6 · Cited by 101 · see citing works
Draheim, T., Liessem, A., Scheld, M., Wilms, F., Weißflog, M., Denecke, B., Kensler, T. W., Zendedel, A., Beyer, C., Kipp, M., et al. (2016) · Glia · doi:10.1002/glia.23058 · Cited by 95 · see citing works
Wang, X., Deckert, M., Xuân, N. T., Nishanth, G., Just, S., Waisman, A., Naumann, M., & Schlüter, D. (2013) · Acta Neuropathologica · doi:10.1007/s00401-013-1183-9 · Cited by 87 · see citing works
Dual effects of daily FTY720 on human astrocytes in vitro: relevance for neuroinflammation
Wu, C., Leong, S. Y., Moore, C. S., Cui, Q., Gris, P., Bernier, L., Johnson, T., Séguéla, P., Kennedy, T. E., Bar‐Or, A., et al. (2013) · Journal of Neuroinflammation · doi:10.1186/1742-2094-10-41 · Cited by 51 · see citing works
Pathway specific modulation of S1P1 receptor signalling in rat and human astrocytes
Healy, L. M., Sheridan, G. K., Pritchard, A. J., Rutkowska, A., Müllershausen, F., & Dev, K. K. (2013) · British Journal of Pharmacology · doi:10.1111/bph.12207 · Cited by 47 · see citing works
Luessi, F., Kraus, S. H. P., Trinschek, B., Lerch, S., Ploen, R., Paterka, M., Roberg, T., Poisa-Beiro, L., Klotz, L., Wiendl, H., et al. (2015) · Multiple Sclerosis Journal · doi:10.1177/1352458515574895 · Cited by 40 · see citing works
Myeloid cells as target of fingolimod action in multiple sclerosis
Dario, M. D., Colombo, E., Govi, C., Feo, D. D., Messina, M., Romeo, M. A. L., Sangalli, F., Moiola, L., Rodegher, M., Martino, G., et al. (2015) · Neurology Neuroimmunology & Neuroinflammation · doi:10.1212/nxi.0000000000000157 · Cited by 31 · see citing works
Self-citationGajofatto, A. (2017) · Drug Design Development and Therapy · doi:10.2147/dddt.s122249 · Cited by 29 · see citing works
Fingolimod effects in neuroinflammation: Regulation of astroglial glutamate transporters?
Lee, D.-H., Seubert, S., Huhn, K., Brecht, L., Rötger, C., Waschbisch, A., Schlachetzki, J. C. M., Klausmeyer, A., Melms, A., Wiese, S., et al. (2017) · PLoS ONE · doi:10.1371/journal.pone.0171552 · Cited by 26 · see citing works
Pellegrini, S., Manenti, F., Chimienti, R., Nano, R., Ottoboni, L., Ruffini, F., Martino, G., Ravassard, P., Piemonti, L., & Sordi, V. (2018) · Cell Transplantation · doi:10.1177/0963689718798564 · Cited by 23 · see citing works
Self-citationSpada, A., Baronchelli, S., Ottoboni, L., Ruffini, F., Martino, G., Convertino, N., Ntai, A., Steiner, T., Biunno, I., & Blasio, A. D. (2016) · Journal of Histochemistry & Cytochemistry · doi:10.1369/0022155416673969 · Cited by 9 · see citing works
Self-citationDavid, O. J., Berwick, A., Pezous, N., Lang, M., Tiel‐Wilck, K., Ziemssen, T., Li, P., Hara, H., & Schmouder, R. (2017) · Clinical Pharmacology in Drug Development · doi:10.1002/cpdd.424 · Cited by 6 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Reactive astrocyte nomenclature, definitions, and future directions
Escartin, C., Galea, E., Lakatos, A., O’Callaghan, J. P., Petzold, G. C., Serrano-Pozo, A., Steinhäuser, C., Volterra, A., Carmignoto, G., Agarwal, A., et al. (2021) · Nature Neuroscience · doi:10.1038/s41593-020-00783-4 · Cited by 2,533 · see citing works
Self-citationProtective Functions of Reactive Astrocytes Following Central Nervous System Insult
Linnerbauer, M., & Rothhammer, V. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.573256 · Cited by 221 · see citing works
Traumatic Brain Injury: Mechanisms of Glial Response
Mira, R. G., Lira, M., & Cerpa, W. F. (2021) · Frontiers in Physiology · doi:10.3389/fphys.2021.740939 · Cited by 215 · see citing works
Immunological Aspects of Approved MS Therapeutics
Rommer, P. S., Milo, R., Han, M. H., Satyanarayan, S., Sellner, J., Hauer, L., Illés, Z., Warnke, C., Laurent, S. A., Weber, M. S., et al. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.01564 · Cited by 157 · see citing works
Gao, J., Ma, C., Xia, D., Chen, N., Zhang, J., Xu, F., Li, F., He, Y., & Gong, Q. (2022) · British Journal of Pharmacology · doi:10.1111/bph.15961 · Cited by 134 · see citing works
FGF21 attenuates neurodegeneration through modulating neuroinflammation and oxidant-stress
Kang, K., Xu, P., Wang, M., Chunyu, J., Sun, X., Ren, G., Xiao, W. L., & Li, D. (2020) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2020.110439 · Cited by 117 · see citing works
snRNA-seq stratifies multiple sclerosis patients into distinct white matter glial responses
Macnair, W., Calini, D., Agirre, E., Bryois, J., Jäkel, S., Smith, R. S., Kukanja, P., Stokar-Regenscheit, N., Ott, V., Foo, L. C., et al. (2025) · Neuron · doi:10.1016/j.neuron.2024.11.016 · Cited by 88 · see citing works
Upadhayay, S., & Mehan, S. (2021) · Brain Disorders · doi:10.1016/j.dscb.2021.100019 · Cited by 71 · see citing works
Central nervous system demyelinating diseases: glial cells at the hub of pathology
Coutinho-Costa, V. G., Araújo, S., Alves-Leon, S., & Gomes, F. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1135540 · Cited by 67 · see citing works
Dumitrescu, L., Papathanasiou, A. I., Coclitu, C., Garjani, A., Evangelou, N., Constantinescu, C. S., Popescu, B. O., & Tănăsescu, R. (2023) · Expert Opinion on Pharmacotherapy · doi:10.1080/14656566.2023.2178898 · Cited by 59 · see citing works
Zhang, H., Zhang, X., Chai, Y., Wang, Y., Zhang, J., & Chen, X. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1584577 · Cited by 59 · see citing works
NRF2 as a therapeutic opportunity to impact in the molecular roadmap of ALS
Jiménez-Villegas, J., Ferraiuolo, L., Mead, R. J., Shaw, P. J., Cuadrado, A., & Rojo, A. I. (2021) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2021.07.022 · Cited by 44 · see citing works
Microglia: The Missing Link to Decipher and Therapeutically Control MS Progression?
Geladaris, A., Häusler, D., & Weber, M. S. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22073461 · Cited by 43 · see citing works
The Two Sides of Siponimod: Evidence for Brain and Immune Mechanisms in Multiple Sclerosis
COHAN, S. L., Benedict, R. H. B., Cree, B., DeLuca, J., Hua, L. H., & Chun, J. J. M. (2022) · CNS Drugs · doi:10.1007/s40263-022-00927-z · Cited by 42 · see citing works
Sphingosine-1-Phosphate Receptor Modulators and Oligodendroglial Cells: Beyond Immunomodulation
Roggeri, A., Schepers, M., Tiane, A., Rombaut, B., van Veggel, L., Hellings, N., Prickaerts, J., Pittaluga, A., & Vanmierlo, T. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21207537 · Cited by 40 · see citing works
Neurodegenerative Diseases: Unraveling the Heterogeneity of Astrocytes
Santiago-Balmaseda, A., Aguirre-Orozco, A., Valenzuela-Arzeta, I. E., Villegas-Rojas, M. M., Pérez‐Segura, I., Jiménez-Barrios, N., Hurtado-Robles, E., Rodríguez-Hernández, L. D., Rivera-German, E. R., Guerra‐Crespo, M., et al. (2024) · Cells · doi:10.3390/cells13110921 · Cited by 43 · see citing works
Sukocheva, O. A., Неганова, М. Е., Aleksandrova, Y. R., Burcher, J. T., Chugunova, E., Fan, R., Tse, E., Sethi, G., Bishayee, A., & Liu, J. (2024) · Cell Communication and Signaling · doi:10.1186/s12964-024-01626-6 · Cited by 40 · see citing works
Challenges and Opportunities of Targeting Astrocytes to Halt Neurodegenerative Disorders
Valori, C. F., Possenti, A., Brambilla, L., & Rossi, D. (2021) · Cells · doi:10.3390/cells10082019 · Cited by 37 · see citing works
Chatzikonstantinou, S., Poulidou, V., Arnaoutoglou, M., Kazis, D. A., Heliopoulos, I., Grigoriadis, N., & Boziki, M. K. (2021) · Cells · doi:10.3390/cells10113217 · Cited by 35 · see citing works
Toward identifying key mechanisms of progression in multiple sclerosis
Husseini, L., Geladaris, A., & Weber, M. S. (2023) · Trends in Neurosciences · doi:10.1016/j.tins.2023.11.005 · Cited by 35 · see citing works
Tonev, D. G., & Momchilova, A. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms242417223 · Cited by 34 · see citing works
Gaire, B. P., & Choi, J.-W. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22157864 · Cited by 33 · see citing works
Does Siponimod Exert Direct Effects in the Central Nervous System?
Kipp, M. (2020) · Cells · doi:10.3390/cells9081771 · Cited by 30 · see citing works
Bigaud, M., Rudolph, B., Briard, E., Beerli, C., Hofmann, A., Hermes, E., Müllershausen, F., Schubart, A., & Gardin, A. (2021) · Multiple Sclerosis Journal - Experimental Translational and Clinical · doi:10.1177/20552173211049168 · Cited by 28 · see citing works
Basavarajappa, D. K., Gupta, V., Chitranshi, N., Wall, R. V., Rajput, R., Pushpitha, K., Sharma, S., Mirzaei, M., Klistorner, A. I., & Graham, S. L. (2022) · Neural Regeneration Research · doi:10.4103/1673-5374.344952 · Cited by 28 · see citing works
Siponimod ameliorates metabolic oligodendrocyte injury via the sphingosine-1 phosphate receptor 5
Behrangi, N., Heinig, L., Frintrop, L., Santrau, E., Kurth, J., Krause, B., Atanasova, D., Clarner, T., Fragoulis, A., Joksch, M., et al. (2022) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2204509119 · Cited by 27 · see citing works
Recent insights into astrocytes as therapeutic targets for demyelinating diseases
Gorter, R. P., & Baron, W. (2022) · Current Opinion in Pharmacology · doi:10.1016/j.coph.2022.102261 · Cited by 25 · see citing works
Kihara, Y., & Chun, J. J. M. (2023) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2023.108432 · Cited by 24 · see citing works
The function of astrocytes and their role in neurological diseases
Yuan, W., Huang, W., Jiang, Y., Xu, H., Duan, C., Chen, N., Liu, Y., & Fu, X. (2023) · European Journal of Neuroscience · doi:10.1111/ejn.16160 · Cited by 24 · see citing works
Dong, W., Li, Q., Lu, X., Lan, J., Qiu, Z., Wang, X., Wang, J., Zheng, X., Chen, S., Zhang, C., et al. (2024) · Experimental & Molecular Medicine · doi:10.1038/s12276-024-01203-4 · Cited by 21 · see citing works
Siponimod for multiple sclerosis
Cao, L., Li, M., Yao, L., Yan, P., Wang, X., Yang, Z. H., Lao, Y., Li, H., Yang, K., & Li, K. (2021) · Cochrane Database of Systematic Reviews · doi:10.1002/14651858.cd013647.pub2 · Cited by 21 · see citing works
Lessons from S1P receptor targeting in multiple sclerosis.
Colombo, E., & Farina, C. (2021) · Pharmacology and Therapeutics · doi:10.1016/j.pharmthera.2021.107971 · Cited by 21 · see citing works
Self-citationZhang, Z., Li, Y., Shi, J., Zhu, L., Dai, Y., Fu, P., Liu, S., Hong, M., Zhang, J., Wang, J., et al. (2022) · Aging and Disease · doi:10.14336/ad.2022.1102 · Cited by 20 · see citing works
Bioavailable central nervous system disease-modifying therapies for multiple sclerosis
Hartung, H., Cree, B., Barnett, M. H., Meuth, S. G., Bar‐Or, A., & Steinman, L. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1290666 · Cited by 19 · see citing works
Remyelination trial failures: Repercussions of ignoring neurorehabilitation and exercise in repair
Ploughman, M., Yong, V. W., Spermon, B., Goelz, S. E., & Giovannoni, G. (2022) · Multiple Sclerosis and Related Disorders · doi:10.1016/j.msard.2022.103539 · Cited by 19 · see citing works
Vališ, M., Achiron, A., Hartung, H. P., Mareš, J., Tichá, V., Štourač, P., Halúsková, S., Angelucci, F., & Pavelek, Z. (2023) · Drugs in R&D · doi:10.1007/s40268-023-00434-6 · Cited by 18 · see citing works
Mohammed, E. M. A. (2024) · Frontiers in Bioscience · doi:10.31083/j.fbl2911386 · Cited by 20 · see citing works
Microglia Contributes to BAF-312 Effects on Blood–Brain Barrier Stability
Spampinato, S. F., Costantino, G., Merlo, S., Canonico, P. L., & Sortino, M. A. (2022) · Biomolecules · doi:10.3390/biom12091174 · Cited by 18 · see citing works
Anti-inflammatory Effects of Siponimod in a Mouse Model of Excitotoxicity-Induced Retinal Injury
Basavarajappa, D. K., Gupta, V., Chitranshi, N., Viswanathan, D., Gupta, V., Wall, R. V., Palanivel, V., Mirzaei, M., You, Y., Klistorner, A. I., et al. (2023) · Molecular Neurobiology · doi:10.1007/s12035-023-03535-0 · Cited by 18 · see citing works
Spampinato, S. F., Merlo, S., Costantino, G., Sano, Y., Kanda, T., & Sortino, M. A. (2021) · Journal of Neuroimmune Pharmacology · doi:10.1007/s11481-021-10016-5 · Cited by 17 · see citing works
Colombo, E., Pascente, R., Triolo, D., Bassani, C., Angelis, A. D., Ruffini, F., Ottoboni, L., Comı, G., Martino, G., & Farina, C. (2020) · Molecules · doi:10.3390/molecules25225403 · Cited by 15 · see citing works
Self-citationSabsabi, S., Mikhael, E., Jalkh, G., Macaron, G., & Rensel, M. R. (2022) · Patient Preference and Adherence · doi:10.2147/ppa.s221882 · Cited by 14 · see citing works
Wang, J., Meng, X., Jialun, Y., Tang, Y., Zeng, F., Wang, Y., Chen, Z., Chen, D., Zou, R., & Liu, W. (2025) · Neurochemical Research · doi:10.1007/s11064-025-04350-w · Cited by 13 · see citing works
Evidence for TGF-β1/Nrf2 Signaling Crosstalk in a Cuprizone Model of Multiple Sclerosis
Guevara, C., Vicencio, S., Pizarro, I. S., Villavicencio-Tejo, F., Quintanilla, R. A., Astudillo, P., Ampuero, E., Varas, R., Orellana, J. A., & Ortíz, F. C. (2024) · Antioxidants · doi:10.3390/antiox13080914 · Cited by 12 · see citing works
Siponimod for multiple sclerosis
Cao, L., Lao, Y., Yao, L., Yan, P., Wang, X., Yang, Z. H., Li, M., Li, H., & Yang, K. (2020) · Cochrane Database of Systematic Reviews · doi:10.1002/14651858.cd013647 · Cited by 9 · see citing works
Drug library screen identifies inhibitors of toxic astrogliosis
Masvekar, R., Kosa, P. F., Barbour, C. R., Milstein, J. L., & Bielekova, B. (2020) · Multiple Sclerosis and Related Disorders · doi:10.1016/j.msard.2022.103499 · Cited by 9 · see citing works
The Relevance of Astrocytic Cell Culture Models for Neuroinflammation in Neurodegeneration Research
Preato, A. M., Pinheiro, E. D. S., Rosenstock, T. R., & Glezer, I. (2024) · Neuroglia · doi:10.3390/neuroglia5010003 · Cited by 8 · see citing works
Mishra, M. K., Wang, J., Mirzaei, R., Chan, R., Melo, H., Zhang, P., Ling, C., Bruccoleri, A. G., Tang, L., & Yong, V. W. (2022) · Cells · doi:10.3390/cells11030440 · Cited by 9 · see citing works
Efforts Towards Repurposing of Antioxidant Drugs and Active Compounds for Multiple Sclerosis Control
Theodosis‐Nobelos, P., & Rekka, E. A. (2022) · Neurochemical Research · doi:10.1007/s11064-022-03821-8 · Cited by 8 · see citing works
Anti-inflammatory effects of siponimod on astrocytes
Ogasawara, A., Takeuchi, H., Komiya, H., Ogawa, Y., Nishimura, K., Kubota, S., Hashiguchi, S., Takahashi, K., Kunii, M., Tanaka, K., et al. (2022) · Neuroscience Research · doi:10.1016/j.neures.2022.08.003 · Cited by 7 · see citing works
Oliveira, M. S., Reiche, L., Daniele, E., Kortebi, I., Faiz, M., & Küry, P. (2023) · Neural Regeneration Research · doi:10.4103/1673-5374.380879 · Cited by 6 · see citing works
Xie, Y., Yao, H., Peng, J.-F., Ni, D., Liu, W.-T., Li, C.-Q., & Yi, G. (2024) · Journal of drug targeting · doi:10.1080/1061186x.2024.2309577 · Cited by 5 · see citing works
Senzaki, K., Ochi, H., Ochi, M., Okada, Y., Miura, S., & Ohyagi, Y. (2021) · eNeurologicalSci · doi:10.1016/j.ensci.2021.100346 · Cited by 5 · see citing works
Weier, A., Enders, M., Kirchner, P., Ekici, A. B., Bigaud, M., Kapitza, C., Wörl, J., & Küerten, S. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms232214209 · Cited by 4 · see citing works
Interleukin-9 Regulates NF-kB-Mediated Activation of Astrocytes in Multiple Sclerosis Brain
Cinotti, M., Amadio, S., Tidei, D., Donninelli, G., Stacchiotti, C., Paolis, V. D., Colombo, E., Angelis, A. D., Ruffini, F., Martino, G., et al. (2026) · Neurology Neuroimmunology & Neuroinflammation · doi:10.1212/nxi.0000000000200537 · Cited by 2 · see citing works
Self-citationSphingosine‐1‐Phosphate Promotes FOS Activation in Osteosarcoma Under Tumor Acidosis
Bozzini, N., Cortini, M., Righi, A., Grigoriadis, A. E., Dack, M. R. G., Elizabeta, I., Torricelli, F., Manicardi, V., Baldini, N., & Avnet, S. (2026) · Acta Physiologica · doi:10.1111/apha.70214 · Cited by 2 · see citing works
Dolcetti, E., Annovazzi, P. O. L., Clerico, M., Cocco, E. E., Conte, A., Marfia, G. A., Salvetti, M., Tomassini, V., Clerici, V. T., Totaro, R., et al. (2024) · Current Neuropharmacology · doi:10.2174/011570159x326862240909105845 · Cited by 2 · see citing works
iAstrocytes do not restrain T cell proliferation in vitro
Colombo, E., Angelis, A. D., Bassani, C., Ruffini, F., Ottoboni, L., Garzetti, L., Finardi, A., Martino, G., Furlan, R., & Farina, C. (2023) · BMC Neuroscience · doi:10.1186/s12868-023-00806-3 · Cited by 1 · see citing works
Self-citationMcErlain, T., Glass, M. J., McCulla, E. C., Madden, C. A., Hillers‐Ziemer, L. E., Overdahl, K. E., Jarmusch, A. K., Kruhlak, M. J., Chesler, A. T., Yang, H. H., et al. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.02.15.638347 · Cited by 1 · see citing works
Казанчян, П. О., Попов, В. А., Сотников, П. Г., & Mb, B. (2005) · CyberLeninK (CyberLeninka)
Neuroinflammation in Multiple Sclerosis
Prasad, P., Roth, L., Ionescu, R.-B., Willis, C. M., Nicaise, A. M., Krzak, G., Peruzzotti‐Jametti, L., & Pluchino, S. (2022) · Elsevier eBooks · doi:10.1016/b978-0-12-821618-7.00267-4
The role of astrocyte in the circadian rhythm
Zhang, L. (2023) · Highlights in Science Engineering and Technology · doi:10.54097/hset.v54i.9781
Cao, G., Guo, J., Yang, K., Xu, R., Jin, X., Hou, L., Bian, P., Fu, W., Yang, S., Li, J., et al. (2023) · Research Square · doi:10.21203/rs.3.rs-3667838/v1
Vrînceanu, O., Maier, S., Manu, D. R., Bănescu, C. V., & Bălașa, R. (2026) · Cells · doi:10.3390/cells15161441
Dynamic contributions of astrocytes in Alzheimer’s disease
Guo, F., Li, T., & He, X. (2026) · Experimental Neurology · doi:10.1016/j.expneurol.2026.116032
- Authors
- Colombo, E., Bassani, C., De Angelis, A., Ruffini, F., Ottoboni, L., Comi, G., Martino, G., & Farina, C.
- Affiliations
- IRCCS Ospedale San Raffaele (IT)
- Corresponding author
- Farina, Cinthia
- Venue
- Frontiers in Immunology
- Publisher
- Frontiers Media SA
- Published
- 2020-04-08
- Volume
- 11
- Pages
- 635-635
- ISSN
- 1664-3224 (ISSN-L)
- PMC
- PMC7156595
- OpenAlex
- W3015602791
- Cited by
- 66
- References
- 51
- Citations by year
- 2026: 4 · 2025: 3 · 2024: 9 · 2023: 14 · 2022: 14 · 2021: 13 · 2020: 7 · 2019: 1
- FWCI
- 7.89
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Frontiers in Immunology (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Archivio Istituzionale della Ricerca (Universita Degli Studi Di Milano) (submittedVersion, other-oa)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Archivio Istituzionale della Ricerca - Università Vita-Salute San Raffaele (submittedVersion)
- Funders
- Fondazione Italiana Sclerosi Multipla (2016/R/14)
- Novartis Pharma
- Topics
- Health Sciences › Medicine › Pathology and Forensic Medicine › Multiple Sclerosis Research Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sphingolipid Metabolism and Signaling
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- siponimod, Nrf2, NF-κB, astrocytes, multiple sclerosis, sphingosine-1-phosphate receptor, S1PR1, S1PR3, fingolimod, glutamate transporters, GLAST, GLT-1, neuroinflammation, spinal cord neurons, oxidative stress, interleukin-1, IL-17, neuron-glia interactions, neuroprotection
- MeSH terms
- Sphingosine 1 Phosphate Receptor Modulators, Astrocytes, Azetidines, Benzyl Compounds, Cell Differentiation, Cells, Cultured, Fibroblasts, Humans, Multiple Sclerosis, Signal Transduction, Down-Regulation, NF-kappa B, Neurodegenerative Diseases, Excitatory Amino Acid Transporter 2, NF-E2-Related Factor 2, Disease Resistance
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
