Therapeutic impact of sphingosine 1-phosphate receptor signaling in multiple sclerosis

Mini-Reviews in Medicinal Chemistry

Volumn 16, Issue 7, 2016, Pages 547-554

  Candido, Kristina ^a   Soufi, Henry ^a   Bandyopadhyay, Mausumi ^b,c  

^a SAINT JAMES SCHOOL OF MEDICINE   (Anguilla)

^b MEDICAL UNIVERSITY OF SOUTH CAROLINA   (United States)

^c Trident Technical College   (United States)

Author keywords

Fingolimod; Multiple sclerosis; Oligodendrocyte; Sphingosine1 phosphate receptor; T cell

Indexed keywords

ALEMTUZUMAB; FINGOLIMOD; GLATIRAMER; HYDROXYMETHYLGLUTARYL COENZYME A REDUCTASE INHIBITOR; INTERFERON BETA SERINE; NATALIZUMAB; RITUXIMAB; SPHINGOSINE 1 PHOSPHATE RECEPTOR;

ARTICLE; BLOOD BRAIN BARRIER; DEMYELINATION; GLIOSIS; HUMAN; MULTIPLE SCLEROSIS; NONHUMAN; OLIGODENDROGLIA; PHOSPHORYLATION; REMYELINIZATION; SIGNAL TRANSDUCTION; STEM CELL; AGONISTS; ANIMAL; DRUG EFFECTS; METABOLISM;

ANIMALS; FINGOLIMOD HYDROCHLORIDE; HUMANS; MULTIPLE SCLEROSIS; RECEPTORS, LYSOSPHINGOLIPID; SIGNAL TRANSDUCTION;

EID: 84961572507     PISSN: 13895575     EISSN: 18755607     Source Type: Journal    
DOI: 10.2174/1389557515666150709122517     Document Type: Article

References (101)

1. Goodin, D. S. The epidemiology of multiple sclerosis: insights to disease pathogenesis. Handbook Clin. Neurol., 2014, 122, 231-66.
2. Cross, A. H.; Cross, K. A.; Piccio, L., Update on multiple sclerosis, its diagnosis and treatments. Clin. Chem. Lab. Med., 2012, 50(7), 1203-10.
3. Rodriguez, M., Multiple sclerosis: basic concepts and hypothesis. Mayo. Clin. Proc., 1989, 64(5), 570-6.
4. McCombe, P. A.; Greer, J. M.; Mackay, I. R., Sexual dimorphism in autoimmune disease. Curr. Mol. Med., 2009, 9(9), 1058-79.
5. Spence, R. D.; Voskuhl, R. R., Neuroprotective effects of estrogens and androgens in CNS inflammation and neurodegeneration. Front. Neuroendocrinol., 2013, 33(1), 105-15.
6. Pugliatti, M.; Eskic, D.; Mikolcic, T.; Pitschnau-Michel, D.; Myhr, K. M.; Sastre-Garriga, J.; Otero, S.; Wieczynska, L.; Torje, C.; Holloway, E.; Rienhoff, O.; Friede, T.; Buckow, K.; Ellenberger, D.; Hillert, J.; Glaser, A.; Flachenecker, P.; Fuge, J.; Schyns- Liharska, T.; Kasilingam, E.; Moretti, A.; Thalheim, C., Assess, compare and enhance the status of Persons with Multiple Sclerosis(MS) in Europe: a European Register for MS. Acta Neurol. Scand. Suppl., 2012, 195, 24-30.
7. Pugliatti, M.; Rosati, G.; Carton, H.; Riise, T.; Drulovic, J.; Vecsei, L.; Milanov, I., The epidemiology of multiple sclerosis in Europe. Eur. J. Neurol., 2006, 13(7), 700-22.
8. Pandit, L.; Shetty, R.; Misri, Z.; Bhat, S.; Amin, H.; Pai, V.; Rao, R., Optic neuritis: experience from a south Indian demyelinating disease registry. Neurol. India, 2012, 60(5), 470-5.
9. Segal, B. M., Stage-specific immune dysregulation in multiple sclerosis. J. Interferon. Cytokin. Res., 2014, 34(8), 633-40.
10. Bodhankar, S.; Vandenbark, A. A.; Offner, H., Oestrogen treatment of experimental autoimmune encephalomyelitis requires 17betaoestradiol- receptor-positive B cells that up-regulate PD-1 on CD4+ Foxp3+ regulatory T cells. Immunology, 2012, 137(4), 282-93.
11. Morales, L. B.; Loo, K. K.; Liu, H. B.; Peterson, C.; Tiwari- Woodruff, S.; Voskuhl, R. R., Treatment with an estrogen receptor alpha ligand is neuroprotective in experimental autoimmune encephalomyelitis. J. Neurosci., 2006, 26(25), 6823-33.
12. O'Connor, R. A.; Cambrook, H.; Huettner, K.; Anderton, S. M., Tbet is essential for Th1-mediated, but not Th17-mediated, CNS autoimmune disease. Eur. J. Immunol., 2013, 43(11), 2818-23.
13. Grifka-Walk, H. M.; Lalor, S. J.; Segal, B. M., Highly polarized Th17 cells induce EAE via a T-bet independent mechanism. Eur. J. Immunol., 2013 43(11), 2824-31.
14. Lee, Y.; Awasthi, A.; Yosef, N.; Quintana, F. J.; Xiao, S.; Peters, A.; Wu, C.; Kleinewietfeld, M.; Kunder, S.; Hafler, D. A.; Sobel, R.A.; Regev, A.; Kuchroo, V.K., Induction and molecular signature of pathogenic TH17 cells. 2012, Nat. Immunol., 13(10), 991-9.
15. Criste, G.; Trapp, B.; Dutta, R., Axonal loss in multiple sclerosis: causes and mechanisms. Handbook Clin. Neurol., 2014, 122, 101-13.
16. Calabrese, M.; Agosta, F.; Rinaldi, F.; Mattisi, I.; Grossi, P.; Favaretto, A.; Atzori, M.; Bernardi, V.; Barachino, L.; Rinaldi, L.; Perini, P.; Gallo, P.; Filippi, M., Cortical lesions and atrophy associated with cognitive impairment in relapsing-remitting multiple sclerosis. Arch. Neurol., 2009, 66(9), 1144-50.
17. Rocca, M. A.; Mesaros, S.; Preziosa, P.; Pagani, E.; Stosic-Opincal, T.; Dujmovic-Basuroski, I.; Drulovic, J.; Filippi, M., Wallerian and trans-synaptic degeneration contribute to optic radiation damage in multiple sclerosis: a diffusion tensor MRI study. Mult. Scler., 2013, 19(12), 1610-7.
18. Hanson, M.A.; Roth, C.B.; Jo, E.; Griffith, M.T.; Scott, F.L.; Reinhart, G.; Desale, H.; Clemons, B.; Cahalan, S. M.; Schuerer, S. C.; Sanna, M. G.; Han, G. W.; Kuhn, P.; Rosen, H.; Stevens, R. C., Crystal structure of a lipid G protein-coupled receptor. Science, 2012, 335(6070), 851-5.
19. Parrill, A. L.; Lima, S.; Spiegel, S., Structure of the first sphingosine 1-phosphate receptor. Sci. Signal., 2012, 5(225), p e23.
20. Hanson, M. A.; Peach, R., Structural biology of the S1P1 receptor. Curr. Top. Microbiol. Immunol., 2014, 378, 23-53.
21. Jaillard, C.; Harrison, S.; Stankoff, B.; Aigrot, M. S.; Calver, A. R.; Duddy, G.; Walsh, F. S.; Pangalos, M. N.; Arimura, N.; Kaibuchi, K.; Zalc, B.; Lubetzki, C., Edg8/S1P5: an oligodendroglial receptor with dual function on process retraction and cell survival. J. Neurosci., 2005, 25(6), 1459-69.
22. An, S.; Zheng, Y.; Bleu, T., Sphingosine 1-phosphate-induced cell proliferation, survival, and related signaling events mediated by G protein-coupled receptors Edg3 and Edg5. J. Biol. Chem., 2000, 275(1), 288-96.
23. Windh, R. T.; Lee, M. J.; Hla, T.; An, S.; Barr, A. J.; Manning, D. R., Differential coupling of the sphingosine 1-phosphate receptors Edg-1, Edg-3, and H218/Edg-5 to the G(i), G(q), and G(12) families of heterotrimeric G proteins. J. Biol. Chem., 1999, 274(39), 27351-8.
24. Siehler, S.; Wang, Y.; Fan, X.; Windh, R. T.; Manning, D. R., Sphingosine 1-phosphate activates nuclear factor-kappa B through Edg receptors. Activation through Edg-3 and Edg-5, but not Edg-1, in human embryonic kidney 293 cells. J. Biol. Chem., 2001, 276(52), 48733-9.
25. Baumruker, T.; Billich, A.; Brinkmann, V., FTY720, an immunomodulatory sphingolipid mimetic: translation of a novel mechanism into clinical benefit in multiple sclerosis. Exp. Opin. Invest. Drugs, 2007, 16(3), 283-9.
26. Bigaud, M.; Guerini, D.; Billich, A.; Bassilana, F.; Brinkmann, V., Second generation S1P pathway modulators: research strategies and clinical developments. Biochim. Biophys. Acta, 2014, 1841(5), 745-58.
27. Hla, T.; Brinkmann, V., Sphingosine 1-phosphate(S1P): Physiology and the effects of S1P receptor modulation. Neurology, 2011, 76(8 Suppl 3), S3-8.
28. Inagaki, Y.; Pham, T. T.; Fujiwara, Y.; Kohno, T.; Osborne, D. A.; Igarashi, Y.; Tigyi, G.; Parrill, A. L., Sphingosine 1-phosphate analog recognition and selectivity at S1P4 within the endothelial differentiation gene family of receptors. Biochem. J., 2005, 389(Pt 1), 187-95.
29. Brinkmann, V., FTY720(fingolimod) in Multiple Sclerosis: therapeutic effects in the immune and the central nervous system. Br. J. Pharmacol., 2009, 158(5), 1173-82.
30. Garris, C. S.; Wu, L.; Acharya, S.; Arac, A.; Blaho, V. A.; Huang, Y.; Moon, B. S.; Axtell, R. C.; Ho, P. P.; Steinberg, G. K.; Lewis, D. B.; Sobel, R. A.; Han, D. K.; Steinman, L.; Snyder, M. P.; Hla, T.; Han, M. H., Defective sphingosine 1-phosphate receptor 1(S1P1) phosphorylation exacerbates TH17-mediated autoimmune neuroinflammation. Nat. Immunol., 2014, 14(11), 1166-72.
31. Kono, M.; Tucker, A. E.; Tran, J.; Bergner, J. B.; Turner, E. M.; Proia, R. L., Sphingosine-1-phosphate receptor 1 reporter mice reveal receptor activation sites in vivo. J. Clin. Invest., 2014, 124(5), 2076-86.
32. Sic, H.; Kraus, H.; Madl, J.; Flittner, K. A.; von Munchow, A. L.; Pieper, K.; Rizzi, M.; Kienzler, A. K.; Ayata, K.; Rauer, S.; Kleuser, B.; Salzer, U.; Burger, M.; Zirlik, K.; Lougaris, V.; Plebani, A.; Romer, W.; Loeffler, C.; Scaramuzza, S.; Villa, A.; Noguchi, E.; Grimbacher, B.; Eibel, H., Sphingosine-1-phosphate receptors control B-cell migration through signaling components associated with primary immunodeficiencies, chronic lymphocytic leukemia, and multiple sclerosis. J. Aller. Clin. Immunol., 2014, 134(2), 420-8.
33. Kimura, A.; Ohmori, T.; Ohkawa, R.; Madoiwa, S.; Mimuro, J.; Murakami, T.; Kobayashi, E.; Hoshino, Y.; Yatomi, Y.; Sakata, Y., Essential roles of sphingosine 1-phosphate/S1P1 receptor axis in the migration of neural stem cells toward a site of spinal cord injury. Stem. Cells, 2007, 25(1), 115-24.
34. Chi, H., Sphingosine-1-phosphate and immune regulation: trafficking and beyond. Trends Pharmacol. Sci., 2011, 32(1), 16-24.
35. Pappu, R.; Schwab, S. R.; Cornelissen, I.; Pereira, J. P.; Regard, J. B.; Xu, Y.; Camerer, E.; Zheng, Y. W.; Huang, Y.; Cyster, J. G.; Coughlin, S. R., Promotion of lymphocyte egress into blood and lymph by distinct sources of sphingosine-1-phosphate. Science, 2007, 316(5822), 295-8.
36. Spiegel, S.; Milstien, S., The outs and the ins of sphingosine-1- phosphate in immunity. Nat. Rev. Immunol., 2011, 11(6), 403-15.
37. Venkataraman, K.; Thangada, S.; Michaud, J.; Oo, M. L.; Ai, Y.; Lee, Y. M.; Wu, M.; Parikh, N. S.; Khan, F.; Proia, R. L.; Hla, T., Extracellular export of sphingosine kinase-1a contributes to the vascular S1P gradient. Biochem. J., 2006, 397(3), 461-71.
38. Garris, C. S.; Blaho, V. A.; Hla, T.; Han, M. H., Sphingosine-1- phosphate receptor 1 signalling in T cells: trafficking and beyond. Immunology, 2014, 142(3), 347-53.
39. Wu, C.; Leong, S. Y.; Moore, C. S.; Cui, Q. L.; Gris, P.; Bernier, L. P.; Johnson, T. A.; Seguela, P.; Kennedy, T. E.; Bar-Or, A.; Antel, J. P., Dual effects of daily FTY720 on human astrocytes in vitro: relevance for neuroinflammation. J. Neuroinflam., 2013, 10, 41. 10:41. doi: 10.1186/1742-2094-10-41.
40. Choi, J. W.; Gardell, S. E.; Herr, D. R.; Rivera, R.; Lee, C. W.; Noguchi, K.; Teo, S. T.; Yung, Y. C.; Lu, M.; Kennedy, G.; Chun, J., FTY720(fingolimod) efficacy in an animal model of multiple sclerosis requires astrocyte sphingosine 1-phosphate receptor 1(S1P1) modulation. Proc. Natl. Acad. Sci. U.S.A., 2011, 108(2), 751-6.
41. Brana, C.; Frossard, M. J.; Pescini Gobert, R.; Martinier, N.; Boschert, U.; Seabrook, T. J., Immunohistochemical detection of sphingosine-1-phosphate receptor 1 and 5 in human multiple sclerosis lesions. Neuropathol. Appl. Neurobiol., 2014, 40(5), 564-78.
42. 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(1-2), 9-18.
43. Cohen, J. A.; Chun, J., Mechanisms of fingolimod's efficacy and adverse effects in multiple sclerosis. Ann. Neurol., 2011, 69(5), 759-77.
44. Schiffmann, S.; Ferreiros, N.; Birod, K.; Eberle, M.; Schreiber, Y.; Pfeilschifter, W.; Ziemann, U.; Pierre, S.; Scholich, K.; Grosch, S.; Geisslinger, G., Ceramide synthase 6 plays a critical role in the development of experimental autoimmune encephalomyelitis. J. Immunol., 2012, 188(11), 5723-33.
45. Eberle, M.; Ebel, P.; Wegner, M. S.; Mannich, J.; Tafferner, N.; Ferreiros, N.; Birod, K.; Schreiber, Y.; Krishnamoorthy, G.; Willecke, K.; Geisslinger, G.; Grosch, S.; Schiffmann, S., Regulation of ceramide synthase 6 in a spontaneous experimental autoimmune encephalomyelitis model is sex dependent. Biochem. Pharmacol., 2014, pii: S0006-2952(14)00489-4. doi: 10.1016/j.bcp.2014.08.016.
46. Vidaurre, O.G.; Haines, J.D.; Katz Sand, I.; Adula, K.P.; Huynh, J.L.; McGraw, C.A.; Zhang, F.; Varghese, M.; Sotirchos, E.; Bhargava, P.; Bandaru, V.V.; Pasinetti, G.; Zhang, W.; Inglese, M.; Calabresi, P. A.; Wu, G.; Miller, A. E.; Haughey, N. J.; Lublin, F. D.; Casaccia, P., Cerebrospinal fluid ceramides from patients with multiple sclerosis impair neuronal bioenergetics. Brain, 2014, 137(Pt 8), 2271-86.
47. Van Doorn, R.; Van Horssen, J.; Verzijl, D.; Witte, M.; Ronken, E.; Van Het Hof, B.; Lakeman, K.; Dijkstra, C. D.; Van Der Valk, P.; Reijerkerk, A.; Alewijnse, A. E.; Peters, S. L.; De Vries, H. E., Sphingosine 1-phosphate receptor 1 and 3 are upregulated in multiple sclerosis lesions. Glia, 2010, 58(12), 1465-76.
48. Coelho, R. P.; Saini, H. S.; Sato-Bigbee, C., Sphingosine-1- phosphate and oligodendrocytes: from cell development to the treatment of multiple sclerosis. Prostaglandins Other Lipid Mediat., 2010, 91(3-4), 139-44.
49. Colombo, E.; Dario, M. D.; Capitolo, E.; Chaabane, L.; Newcombe, J.; Martino, G.; Farina, C., Fingolimod may support neuroprotection via blockade of astrocyte nitric oxide. Ann. Neurol., 2014, Jul 4. doi: 10.1002/ana.24217.
50. Cahalan, S. M.; Gonzalez-Cabrera, P. J.; Nguyen, N.; Guerrero, M.; Cisar, E. A.; Leaf, N. B.; Brown, S. J.; Roberts, E.; Rosen, H., Sphingosine 1-phosphate receptor 1(S1P(1)) upregulation and amelioration of experimental autoimmune encephalomyelitis by an S1P(1) antagonist. Mol. Pharmacol., 2013, 83(2), 316-21.
51. Novgorodov, A. S.; El-Alwani, M.; Bielawski, J.; Obeid, L. M.; Gudz, T. I., Activation of sphingosine-1-phosphate receptor S1P5 inhibits oligodendrocyte progenitor migration. FASEB J., 2007, 21(7), 1503-14.
52. Miron, V. E.; Ludwin, S. K.; Darlington, P. J.; Jarjour, A. A.; Soliven, B.; Kennedy, T. E.; Antel, J. P., Fingolimod(FTY720) enhances remyelination following demyelination of organotypic cerebellar slices. Am. J. Pathol., 2010, 176(6), 2682-94.
53. Rao, T. S.; Lariosa-Willingham, K. D.; Lin, F. F.; Palfreyman, E. L.; Yu, N.; Chun, J.; Webb, M., Pharmacological characterization of lysophospholipid receptor signal transduction pathways in rat cerebrocortical astrocytes. Brain Res., 2003, 990(1-2), 182-94.
54. Rao, T. S.; Lariosa-Willingham, K. D.; Lin, F. F.; Yu, N.; Tham, C. S.; Chun, J.; Webb, M., Growth factor pre-treatment differentially regulates phosphoinositide turnover downstream of lysophospholipid receptor and metabotropic glutamate receptors in cultured rat cerebrocortical astrocytes. Intl. J. Dev. Neurosci., 2004, 22(3), 131-5.
55. Lee, C. W.; Choi, J. W.; Chun, J., Neurological S1P signaling as an emerging mechanism of action of oral FTY720(fingolimod) in multiple sclerosis. Arch. Pharm. Res., 2010, 33(10), 1567-74.
56. Jackson, S. J.; Giovannoni, G.; Baker, D., Fingolimod modulates microglial activation to augment markers of remyelination. J. Neuroinflam., 2011, 8, 76. doi: 10.1186/1742-2094-8-76.
57. Hu, Y.; Lee, X.; Ji, B.; Guckian, K.; Apicco, D.; Pepinsky, R. B.; Miller, R. H.; Mi, S., Sphingosine 1-phosphate receptor modulator fingolimod(FTY720) does not promote remyelination in vivo. Mol. Cell Neurosci., 2011, 48(1), 72-81.
58. Soliven, B.; Miron, V.; Chun, J., The neurobiology of sphingosine 1-phosphate signaling and sphingosine 1-phosphate receptor modulators. Neurology, 2011, 76(8 Suppl 3), S9-14.
59. Miron, V. E.; Jung, C. G.; Kim, H. J.; Kennedy, T. E.; Soliven, B.; Antel, J. P., FTY720 modulates human oligodendrocyte progenitor process extension and survival. Ann. Neurol., 2008, 63(1), 61-71.
60. Chiba, K.; Kataoka, H.; Seki, N.; Shimano, K.; Koyama, M.; Fukunari, A.; Sugahara, K.; Sugita, T., Fingolimod(FTY720), sphingosine 1-phosphate receptor modulator, shows superior efficacy as compared with interferon-beta in mouse experimental autoimmune encephalomyelitis. Intl. Immunopharmacol., 2011, 11(3), 366-72.
61. Chun, J.; Hartung, H. P., Mechanism of action of oral fingolimod(FTY720) in multiple sclerosis. Clin. Neuropharmacol., 2010, 33(2), 91-101.
62. Mehling, M.; Lindberg, R.; Raulf, F.; Kuhle, J.; Hess, C.; Kappos, L.; Brinkmann, V., Th17 central memory T cells are reduced by FTY720 in patients with multiple sclerosis. Neurology, 2010, 75(5), 403-10.
63. Brinkmann, V., FTY720(fingolimod) in Multiple Sclerosis: therapeutic effects in the immune and the central nervous system. Br. J. Pharmacol., 2009, 158(5), 1173-82.
64. Garris, C. S.; Wu, L.; Acharya, S.; Arac, A.; Blaho, V. A.; Huang, Y.; Moon, B. S.; Axtell, R. C.; Ho, P. P.; Steinberg, G. K.; Lewis, D. B.; Sobel, R. A.; Han, D. K.; Steinman, L.; Snyder, M. P.; Hla, T.; Han, M. H., Defective sphingosine 1-phosphate receptor 1(S1P1) phosphorylation exacerbates TH17-mediated autoimmune neuroinflammation. Nat. Immunol., 2014, 14(11), 1166-72.
65. Kono, M.; Tucker, A. E.; Tran, J.; Bergner, J. B.; Turner, E. M.; Proia, R. L., Sphingosine-1-phosphate receptor 1 reporter mice reveal receptor activation sites in vivo. J. Clin. Invest., 2014, 124(5), 2076-86.
66. Sic, H.; Kraus, H.; Madl, J.; Flittner, K. A.; von Munchow, A. L.; Pieper, K.; Rizzi, M.; Kienzler, A. K.; Ayata, K.; Rauer, S.; Kleuser, B.; Salzer, U.; Burger, M.; Zirlik, K.; Lougaris, V.; Plebani, A.; Romer, W.; Loeffler, C.; Scaramuzza, S.; Villa, A.; Noguchi, E.; Grimbacher, B.; Eibel, H., Sphingosine-1-phosphate receptors control B-cell migration through signaling components associated with primary immunodeficiencies, chronic lymphocytic leukemia, and multiple sclerosis. J. Aller. Clin. Immunol., 2014, 134(2), 420-8.
67. Kimura, A.; Ohmori, T.; Ohkawa, R.; Madoiwa, S.; Mimuro, J.; Murakami, T.; Kobayashi, E.; Hoshino, Y.; Yatomi, Y.; Sakata, Y., Essential roles of sphingosine 1-phosphate/S1P1 receptor axis in the migration of neural stem cells toward a site of spinal cord injury. Stem. Cells, 2007, 25(1), 115-24.
68. Chi, H., Sphingosine-1-phosphate and immune regulation: trafficking and beyond. Trends Pharmacol. Sci., 2011, 32(1), 16-24.
69. Pappu, R.; Schwab, S. R.; Cornelissen, I.; Pereira, J. P.; Regard, J. B.; Xu, Y.; Camerer, E.; Zheng, Y. W.; Huang, Y.; Cyster, J. G.; Coughlin, S. R., Promotion of lymphocyte egress into blood and lymph by distinct sources of sphingosine-1-phosphate. Science, 2007, 316(5822), 295-8.
70. Spiegel, S.; Milstien, S., The outs and the ins of sphingosine-1- phosphate in immunity. Nat. Rev. Immunol., 2011, 11(6), 403-15.
71. Venkataraman, K.; Thangada, S.; Michaud, J.; Oo, M. L.; Ai, Y.; Lee, Y. M.; Wu, M.; Parikh, N. S.; Khan, F.; Proia, R. L.; Hla, T., Extracellular export of sphingosine kinase-1a contributes to the vascular S1P gradient. Biochem. J., 2006, 397(3), 461-71.
72. Garris, C. S.; Blaho, V. A.; Hla, T.; Han, M. H., Sphingosine-1- phosphate receptor 1 signalling in T cells: trafficking and beyond. Immunology, 2014, 142(3), 347-53.
73. Wu, C.; Leong, S. Y.; Moore, C. S.; Cui, Q. L.; Gris, P.; Bernier, L. P.; Johnson, T. A.; Seguela, P.; Kennedy, T. E.; Bar-Or, A.; Antel, J. P., Dual effects of daily FTY720 on human astrocytes in vitro: relevance for neuroinflammation. J. Neuroinflam., 2013, 10, 41. 10:41. doi: 10.1186/1742-2094-10-41.
74. Choi, J. W.; Gardell, S. E.; Herr, D. R.; Rivera, R.; Lee, C. W.; Noguchi, K.; Teo, S. T.; Yung, Y. C.; Lu, M.; Kennedy, G.; Chun, J., FTY720(fingolimod) efficacy in an animal model of multiple sclerosis requires astrocyte sphingosine 1-phosphate receptor 1(S1P1) modulation. Proc. Natl. Acad. Sci. U.S.A., 2011, 108(2), 751-6.
75. Brana, C.; Frossard, M. J.; Pescini Gobert, R.; Martinier, N.; Boschert, U.; Seabrook, T. J., Immunohistochemical detection of sphingosine-1-phosphate receptor 1 and 5 in human multiple sclerosis lesions. Neuropathol. Appl. Neurobiol., 2014, 40(5), 564-78.
76. 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(1-2), 9-18.
77. Cohen, J. A.; Chun, J., Mechanisms of fingolimod's efficacy and adverse effects in multiple sclerosis. Ann. Neurol., 2011, 69(5), 759-77.
78. Schiffmann, S.; Ferreiros, N.; Birod, K.; Eberle, M.; Schreiber, Y.; Pfeilschifter, W.; Ziemann, U.; Pierre, S.; Scholich, K.; Grosch, S.; Geisslinger, G., Ceramide synthase 6 plays a critical role in the development of experimental autoimmune encephalomyelitis. J. Immunol., 2012, 188(11), 5723-33.
79. Eberle, M.; Ebel, P.; Wegner, M. S.; Mannich, J.; Tafferner, N.; Ferreiros, N.; Birod, K.; Schreiber, Y.; Krishnamoorthy, G.; Willecke, K.; Geisslinger, G.; Grosch, S.; Schiffmann, S., Regulation of ceramide synthase 6 in a spontaneous experimental autoimmune encephalomyelitis model is sex dependent. Biochem. Pharmacol., 2014, pii: S0006-2952(14)00489-4. doi: 10.1016/j.bcp.2014.08.016.
80. Vidaurre, O.G.; Haines, J.D.; Katz Sand, I.; Adula, K.P.; Huynh, J.L.; McGraw, C.A.; Zhang, F.; Varghese, M.; Sotirchos, E.; Bhargava, P.; Bandaru, V.V.; Pasinetti, G.; Zhang, W.; Inglese, M.; Calabresi, P. A.; Wu, G.; Miller, A. E.; Haughey, N. J.; Lublin, F. D.; Casaccia, P., Cerebrospinal fluid ceramides from patients with multiple sclerosis impair neuronal bioenergetics. Brain, 2014, 137(Pt 8), 2271-86.
81. Van Doorn, R.; Van Horssen, J.; Verzijl, D.; Witte, M.; Ronken, E.; Van Het Hof, B.; Lakeman, K.; Dijkstra, C. D.; Van Der Valk, P.; Reijerkerk, A.; Alewijnse, A. E.; Peters, S. L.; De Vries, H. E., Sphingosine 1-phosphate receptor 1 and 3 are upregulated in multiple sclerosis lesions. Glia, 2010, 58(12), 1465-76.
82. Coelho, R. P.; Saini, H. S.; Sato-Bigbee, C., Sphingosine-1- phosphate and oligodendrocytes: from cell development to the treatment of multiple sclerosis. Prostaglandins Other Lipid Mediat., 2010, 91(3-4), 139-44.
83. Colombo, E.; Dario, M. D.; Capitolo, E.; Chaabane, L.; Newcombe, J.; Martino, G.; Farina, C., Fingolimod may support neuroprotection via blockade of astrocyte nitric oxide. Ann. Neurol., 2014, Jul 4. doi: 10.1002/ana.24217.
84. Cahalan, S. M.; Gonzalez-Cabrera, P. J.; Nguyen, N.; Guerrero, M.; Cisar, E. A.; Leaf, N. B.; Brown, S. J.; Roberts, E.; Rosen, H., Sphingosine 1-phosphate receptor 1(S1P(1)) upregulation and amelioration of experimental autoimmune encephalomyelitis by an S1P(1) antagonist. Mol. Pharmacol., 2013, 83(2), 316-21.
85. Novgorodov, A. S.; El-Alwani, M.; Bielawski, J.; Obeid, L. M.; Gudz, T. I., Activation of sphingosine-1-phosphate receptor S1P5 inhibits oligodendrocyte progenitor migration. FASEB J., 2007, 21(7), 1503-14.
86. Miron, V. E.; Ludwin, S. K.; Darlington, P. J.; Jarjour, A. A.; Soliven, B.; Kennedy, T. E.; Antel, J. P., Fingolimod(FTY720) enhances remyelination following demyelination of organotypic cerebellar slices. Am. J. Pathol., 2010, 176(6), 2682-94.
87. Rao, T. S.; Lariosa-Willingham, K. D.; Lin, F. F.; Palfreyman, E. L.; Yu, N.; Chun, J.; Webb, M., Pharmacological characterization of lysophospholipid receptor signal transduction pathways in rat cerebrocortical astrocytes. Brain Res., 2003, 990(1-2), 182-94.
88. Rao, T. S.; Lariosa-Willingham, K. D.; Lin, F. F.; Yu, N.; Tham, C. S.; Chun, J.; Webb, M., Growth factor pre-treatment differentially regulates phosphoinositide turnover downstream of lysophospholipid receptor and metabotropic glutamate receptors in cultured rat cerebrocortical astrocytes. Intl. J. Dev. Neurosci., 2004, 22(3), 131-5.
89. Lee, C. W.; Choi, J. W.; Chun, J., Neurological S1P signaling as an emerging mechanism of action of oral FTY720(fingolimod) in multiple sclerosis. Arch. Pharm. Res., 2010, 33(10), 1567-74.
90. Jackson, S. J.; Giovannoni, G.; Baker, D., Fingolimod modulates microglial activation to augment markers of remyelination. J. Neuroinflam., 2011, 8, 76. doi: 10.1186/1742-2094-8-76.
91. Hu, Y.; Lee, X.; Ji, B.; Guckian, K.; Apicco, D.; Pepinsky, R. B.; Miller, R. H.; Mi, S., Sphingosine 1-phosphate receptor modulator fingolimod(FTY720) does not promote remyelination in vivo. Mol. Cell Neurosci., 2011, 48(1), 72-81.
92. Soliven, B.; Miron, V.; Chun, J., The neurobiology of sphingosine 1-phosphate signaling and sphingosine 1-phosphate receptor modulators. Neurology, 2011, 76(8 Suppl 3), S9-14.
93. Miron, V. E.; Jung, C. G.; Kim, H. J.; Kennedy, T. E.; Soliven, B.; Antel, J. P., FTY720 modulates human oligodendrocyte progenitor process extension and survival. Ann. Neurol., 2008, 63(1), 61-71.
94. Chiba, K.; Kataoka, H.; Seki, N.; Shimano, K.; Koyama, M.; Fukunari, A.; Sugahara, K.; Sugita, T., Fingolimod(FTY720), sphingosine 1-phosphate receptor modulator, shows superior efficacy as compared with interferon-beta in mouse experimental autoimmune encephalomyelitis. Intl. Immunopharmacol., 2011, 11(3), 366-72.
95. Chun, J.; Hartung, H. P., Mechanism of action of oral fingolimod(FTY720) in multiple sclerosis. Clin. Neuropharmacol., 2010, 33(2), 91-101.
96. Mehling, M.; Lindberg, R.; Raulf, F.; Kuhle, J.; Hess, C.; Kappos, L.; Brinkmann, V., Th17 central memory T cells are reduced by FTY720 in patients with multiple sclerosis. Neurology, 2010, 75(5), 403-10.
97. Pritchard, A.J.; Mir, A.K.; Dev, K.K., Fingolimod attenuates splenocyte-induced demyelination in cerebellar slice cultures. PLoS One, 2014, 9(6), e99444.
98. Lu, L.; Barfejani, A. H.; Qin, T.; Dong, Q.; Ayata, C.; Waeber, C., Fingolimod exerts neuroprotective effects in a mouse model of intracerebral hemorrhage. Brain Res., 2014, 1555, 89-96.
99. Tolle, M.; Levkau, B.; Kleuser, B.; van der Giet, M., Sphingosine- 1-phosphate and FTY720 as anti-atherosclerotic lipid compounds. Eur. J. Clin. Invest., 2007, 37(3), 171-9.
100. Wang, G.; Kim, R.Y.; Imhof, I.; Honbo, N.; Luk, F.S.; Li, K.; Kumar, N.; Zhu, B.Q.; Eberle, D.; Ching, D.; Karliner, J.S.; Raffai, R.L., The immunosuppressant FTY720 prolongs survival in a mouse model of diet-induced coronary atherosclerosis and myocardial infarction. J. Cardiovasc. Pharmacol., 2014, 63(2), 132-43.
101. Hofmann, U.; Burkard, N.; Vogt, C.; Thoma, A.; Frantz, S.; Ertl, G.; Ritter, O.; Bonz, A., Protective effects of sphingosine-1- phosphate receptor agonist treatment after myocardial ischaemiareperfusion. Cardiovasc. Res., 2009, 83(2), 285-93.