1932

Abstract

Fingolimod (FTY720, Gilenya) was the first US Food and Drug Administration–approved oral therapy for relapsing forms of multiple sclerosis (MS). Research on modified fungal metabolites converged with basic science studies that had identified lysophospholipid (LP) sphingosine 1-phosphate (S1P) receptors, providing mechanistic insights on fingolimod while validating LP receptors as drug targets. Mechanism of action (MOA) studies identified receptor-mediated processes involving the immune system and the central nervous system (CNS). These dual actions represent a more general theme for S1P and likely other LP receptor modulators. Fingolimod's direct CNS activities likely contribute to its efficacy in MS, with particular relevance to treating progressive disease stages and forms that involve neurodegeneration. The evolving understanding of fingolimod's MOA has provided strategies for developing next-generation compounds with superior attributes, suggesting new ways to target S1P as well as other LP receptor modulators for novel therapeutics in the CNS and other organ systems.

Loading

Article metrics loading...

/content/journals/10.1146/annurev-pharmtox-010818-021358
2019-01-06
2024-04-21
Loading full text...

Full text loading...

/deliver/fulltext/pharmtox/59/1/annurev-pharmtox-010818-021358.html?itemId=/content/journals/10.1146/annurev-pharmtox-010818-021358&mimeType=html&fmt=ahah

Literature Cited

  1. 1.  Kappos L, Antel J, Comi G, Montalban X, O'Connor P et al. 2006. Oral fingolimod (FTY720) for relapsing multiple sclerosis. N. Engl. J. Med. 355:1124–40
    [Google Scholar]
  2. 2.  Calabresi PA, Radue EW, Goodin D, Jeffery D, Rammohan KW et al. 2014. Safety and efficacy of fingolimod in patients with relapsing-remitting multiple sclerosis (FREEDOMS II): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Neurol 13:545–56
    [Google Scholar]
  3. 3.  Kappos L, O'Connor P, Radue EW, Polman C, Hohlfeld R et al. 2015. Long-term effects of fingolimod in multiple sclerosis: the randomized FREEDOMS extension trial. Neurology 84:1582–91
    [Google Scholar]
  4. 4.  Khatri B, Barkhof F, Comi G, Hartung HP, Kappos L et al. 2011. Comparison of fingolimod with interferon beta-1a in relapsing-remitting multiple sclerosis: a randomised extension of the TRANSFORMS study. Lancet Neurol 10:520–29
    [Google Scholar]
  5. 5.  Cohen JA, Barkhof F, Comi G, Hartung HP, Khatri BO et al. 2010. Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis. N. Engl. J. Med. 362:402–15
    [Google Scholar]
  6. 6.  Kappos L, Radue EW, O'Connor P, Polman C, Hohlfeld R et al. 2010. A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. N. Engl. J. Med. 362:387–401
    [Google Scholar]
  7. 7.  Cohen JA, Chun J 2011. Mechanisms of fingolimod's efficacy and adverse effects in multiple sclerosis. Ann. Neurol. 69:759–77
    [Google Scholar]
  8. 8.  Chun J, Hartung HP 2010. Mechanism of action of oral fingolimod (FTY720) in multiple sclerosis. Clin. Neuropharmacol. 33:91–101
    [Google Scholar]
  9. 9.  Kihara Y, Maceyka M, Spiegel S, Chun J 2014. Lysophospholipid receptor nomenclature review: IUPHAR Review 8. Br. J. Pharmacol. 171:3575–94
    [Google Scholar]
  10. 10.  Kihara Y, Mizuno H, Chun J 2015. Lysophospholipid receptors in drug discovery. Exp. Cell Res. 333:171–77
    [Google Scholar]
  11. 11.  Napoli KL 2000. The FTY720 story. Ther. Drug Monit. 22:47–51
    [Google Scholar]
  12. 12.  Kobayakawa T, Chiba K 2000. [Immunosuppressive agent FTY720]. Tanpakushitsu Kakusan Koso 45:1188–92 (In Japanese)
    [Google Scholar]
  13. 13.  Brinkmann V, Billich A, Baumruker T, Heining P, Schmouder R et al. 2010. Fingolimod (FTY720): discovery and development of an oral drug to treat multiple sclerosis. Nat. Rev. Drug Discov. 9:883–97
    [Google Scholar]
  14. 14.  Chun J, Brinkmann V 2011. A mechanistically novel, first oral therapy for multiple sclerosis: the development of fingolimod (FTY720, Gilenya). Discov. Med. 12:213–28
    [Google Scholar]
  15. 15.  Baecher-Allan C, Kaskow BJ, Weiner HL 2018. Multiple sclerosis: mechanisms and immunotherapy. Neuron 97:742–68
    [Google Scholar]
  16. 16.  Tur C, Moccia M, Barkhof F, Chataway J, Sastre-Garriga J et al. 2018. Assessing treatment outcomes in multiple sclerosis trials and in the clinical setting. Nat. Rev. Neurol. 14:75–93
    [Google Scholar]
  17. 17.  Matthews PM 2015. Decade in review—multiple sclerosis: new drugs and personalized medicine for multiple sclerosis. Nat. Rev. Neurol. 11:614–16
    [Google Scholar]
  18. 18.  Choi JW, Herr DR, Noguchi K, Yung YC, Lee CW et al. 2010. LPA receptors: subtypes and biological actions. Annu. Rev. Pharmacol. Toxicol. 50:157–86
    [Google Scholar]
  19. 19.  Ishii I, Fukushima N, Ye X, Chun J 2004. Lysophospholipid receptors: signaling and biology. Annu. Rev. Biochem. 73:321–54
    [Google Scholar]
  20. 20.  Fukushima N, Ishii I, Contos JJ, Weiner JA, Chun J 2001. Lysophospholipid receptors. Annu. Rev. Pharmacol. Toxicol. 41:507–34
    [Google Scholar]
  21. 21.  Yung YC, Stoddard NC, Mirendil H, Chun J 2015. Lysophosphatidic acid signaling in the nervous system. Neuron 85:669–82
    [Google Scholar]
  22. 22.  Blaho VA, Hla T 2014. An update on the biology of sphingosine 1-phosphate receptors. J. Lipid Res. 55:1596–608
    [Google Scholar]
  23. 23.  Moolenaar WH, Perrakis A 2011. Insights into autotaxin: how to produce and present a lipid mediator. Nat. Rev. Mol. Cell Biol. 12:674–79
    [Google Scholar]
  24. 24.  Aikawa S, Hashimoto T, Kano K, Aoki J 2015. Lysophosphatidic acid as a lipid mediator with multiple biological actions. J. Biochem. 157:81–89
    [Google Scholar]
  25. 25.  Yung YC, Stoddard NC, Chun J 2014. LPA receptor signaling: pharmacology, physiology, and pathophysiology. J. Lipid Res. 55:1192–214
    [Google Scholar]
  26. 26.  Stoddard NC, Chun J 2015. Promising pharmacological directions in the world of lysophosphatidic acid signaling. Biomol. Ther. 23:1–11
    [Google Scholar]
  27. 27.  Gobley T 1845. Sur l'existence des acides oléique, margarique et phosphoglycérique dans le jaune d'oeuf. Premier Mémoire: Sur la composition chimique du jaune d'oeuf. C. R. Hebd. Acad. Sci. 21:766
    [Google Scholar]
  28. 28.  Gobley T 1874. Sur la lécithine et la cérébrine. J. Pharm. Chim. 19:4346–54
    [Google Scholar]
  29. 29.  Kyes P 1903. Ueber die Isolierung von Schlangengift-Lecithiden. Berliner klin. Wochenschr. 40:956–84
    [Google Scholar]
  30. 30.  King EJ, Dolan M 1933. The enzymic hydrolysis of phosphatides: lysolecithin. Biochem. J. 27:403–9
    [Google Scholar]
  31. 31.  Thudichum J 1884. A Treatise on the Chemical Constitution of the Brain London: Tindall & Cox
  32. 32.  Stoffel W, Assmann G, Binczek E 1970. Metabolism of sphingosine bases, XIII. Enzymatic synthesis of 1-phosphate esters of 4t-sphingenine (sphingosine), sphinganine (dihydrosphingosine), 4-hydroxysphinganine (phytosphingosine) and 3-dehydrosphinganine by erythrocytes. Hoppe Seylers Z. Physiol. Chem. 351:635–42
    [Google Scholar]
  33. 33.  Stoffel W, Sticht G, Le Kim D 1969. Metabolism of sphingosine bases. X. Degradation of (1-14C)dihydrosphingosine (sphinganine), (1-14C)2-amino-1,3-dihydroxyheptane and (1-14C)dihydrosphingosine phosphate in rat liver. Hoppe Seylers Z. Physiol. Chem. 350:63–68
    [Google Scholar]
  34. 34.  Sen S, Smeby RR, Bumpus FM 1968. Antihypertensive effect of an isolated phospholipid. Am. J. Physiol. 214:337–41
    [Google Scholar]
  35. 35.  Vogt W 1963. Pharmacologically active acidic phospholipids and glycolipids. Biochem. Pharmacol. 12:415–20
    [Google Scholar]
  36. 36.  Kirschner H, Vogt W 1961. [Pharmacologically active lipidsoluble acids in brain extracts: isolation of lysophosphatidic acid and ganglioside]. Biochem. Pharmacol. 8:224–34 (In German)
    [Google Scholar]
  37. 37.  Christiansen K, Carlsen J 1983. Reconstitution of a protein into lipid vesicles using natural detergents. Biochim. Biophys. Acta 735:225–33
    [Google Scholar]
  38. 38.  Lapetina EG, Billah MM, Cuatrecasas P 1981. Lysophosphatidic acid potentiates the thrombin-induced production of arachidonate metabolites in platelets. J. Biol. Chem. 256:11984–87
    [Google Scholar]
  39. 39.  Olivera A, Spiegel S 1993. Sphingosine-1-phosphate as second messenger in cell proliferation induced by PDGF and FCS mitogens. Nature 365:557–60
    [Google Scholar]
  40. 40.  McIntyre TM, Pontsler AV, Silva AR, St Hilaire A, Xu Y et al. 2003. Identification of an intracellular receptor for lysophosphatidic acid (LPA): LPA is a transcellular PPARγ agonist. PNAS 100:131–36
    [Google Scholar]
  41. 41.  Rai V, Toure F, Chitayat S, Pei R, Song F et al. 2012. Lysophosphatidic acid targets vascular and oncogenic pathways via RAGE signaling. J. Exp. Med. 209:2339–50
    [Google Scholar]
  42. 42.  van Koppen C, Meyer zu Heringdorf M, Laser KT, Zhang C, Jakobs KH et al. 1996. Activation of a high affinity Gi protein-coupled plasma membrane receptor by sphingosine-1-phosphate. J. Biol. Chem. 271:2082–87
    [Google Scholar]
  43. 43.  van Corven EJ, Groenink A, Jalink K, Eichholtz T, Moolenaar WH 1989. Lysophosphatidate-induced cell proliferation: identification and dissection of signaling pathways mediated by G proteins. Cell 59:45–54
    [Google Scholar]
  44. 44.  Hecht JH, Weiner JA, Post SR, Chun J 1996. Ventricular zone gene-1 (vzg-1) encodes a lysophosphatidic acid receptor expressed in neurogenic regions of the developing cerebral cortex. J. Cell Biol. 135:1071–83
    [Google Scholar]
  45. 45.  Fukushima N, Kimura Y, Chun J 1998. A single receptor encoded by vzg-1/lpA1/edg-2 couples to G proteins and mediates multiple cellular responses to lysophosphatidic acid. PNAS 95:6151–56
    [Google Scholar]
  46. 46.  Contos JJ, Fukushima N, Weiner JA, Kaushal D, Chun J 2000. Requirement for the lpA1 lysophosphatidic acid receptor gene in normal suckling behavior. PNAS 97:13384–89
    [Google Scholar]
  47. 47.  Chun J, Hla T, Lynch KR, Spiegel S, Moolenaar WH 2010. International union of basic and clinical pharmacology. LXXVIII. Lysophospholipid receptor nomenclature. Pharmacol. Rev. 62:579–87
    [Google Scholar]
  48. 48.  Hla T, Maciag T 1990. An abundant transcript induced in differentiating human endothelial cells encodes a polypeptide with structural similarities to G-protein-coupled receptors. J. Biol. Chem. 265:9308–13
    [Google Scholar]
  49. 49.  Bandoh K, Aoki J, Hosono H, Kobayashi S, Kobayashi T et al. 1999. Molecular cloning and characterization of a novel human G-protein-coupled receptor, EDG7, for lysophosphatidic acid. J. Biol. Chem. 274:27776–85
    [Google Scholar]
  50. 50.  An S, Bleu T, Hallmark OG, Goetzl EJ 1998. Characterization of a novel subtype of human G protein-coupled receptor for lysophosphatidic acid. J. Biol. Chem. 273:7906–10
    [Google Scholar]
  51. 51.  An S, Bleu T, Huang W, Hallmark OG, Coughlin SR, Goetzl EJ 1997. Identification of cDNAs encoding two G protein-coupled receptors for lysosphingolipids. FEBS Lett 417:279–82
    [Google Scholar]
  52. 52.  Lee MJ, Van Brocklyn JR, Thangada S, Liu CH, Hand AR et al. 1998. Sphingosine-1-phosphate as a ligand for the G protein-coupled receptor EDG-1. Science 279:1552–55
    [Google Scholar]
  53. 53.  Hooks SB, Ragan SP, Hopper DW, Honemann CW, Durieux ME et al. 1998. Characterization of a receptor subtype-selective lysophosphatidic acid mimetic. Mol. Pharmacol. 53:188–94
    [Google Scholar]
  54. 54.  Moolenaar WH, Kranenburg O, Postma FR, Zondag GC 1997. Lysophosphatidic acid: G-protein signalling and cellular responses. Curr. Opin. Cell Biol. 9:168–73
    [Google Scholar]
  55. 55.  Lee MJ, Thangada S, Liu CH, Thompson BD, Hla T 1998. Lysophosphatidic acid stimulates the G-protein-coupled receptor EDG-1 as a low affinity agonist. J. Biol. Chem. 273:22105–12
    [Google Scholar]
  56. 56.  Witte ON, Kabarowski JH, Xu Y, Le LQ, Zhu K 2005. Retraction. Science 307:206
    [Google Scholar]
  57. 57.  Kabarowski JH, Zhu K, Le LQ, Witte ON, Xu Y 2001. Lysophosphatidylcholine as a ligand for the immunoregulatory receptor G2A. Science 293:702–5
    [Google Scholar]
  58. 58.  Xu Y, Zhu K, Hong G, Wu W, Baudhuin LM et al. 2000. Sphingosylphosphorylcholine is a ligand for ovarian cancer G-protein-coupled receptor 1. Nat. Cell Biol. 2:261–67
    [Google Scholar]
  59. 59.  Guo Z, Liliom K, Fischer DJ, Bathurst IC, Tomei LD et al. 1996. Molecular cloning of a high-affinity receptor for the growth factor-like lipid mediator lysophosphatidic acid from Xenopus oocytes. PNAS 93:14367–72
    [Google Scholar]
  60. 60.  Im DS, Heise CE, Nguyen T, O'Dowd BF, Lynch KR 2001. Identification of a molecular target of psychosine and its role in globoid cell formation. J. Cell Biol. 153:429–34
    [Google Scholar]
  61. 61.  Lauckner JE, Jensen JB, Chen HY, Lu HC, Hille B, Mackie K 2008. GPR55 is a cannabinoid receptor that increases intracellular calcium and inhibits M current. PNAS 105:2699–704
    [Google Scholar]
  62. 62.  Liu Y, Wada R, Yamashita T, Mi Y, Deng CX et al. 2000. Edg-1, the G protein-coupled receptor for sphingosine-1-phosphate, is essential for vascular maturation. J. Clin. Investig. 106:951–61
    [Google Scholar]
  63. 63.  Inoue A, Ishiguro J, Kitamura H, Arima N, Okutani M et al. 2012. TGFα shedding assay: an accurate and versatile method for detecting GPCR activation. Nat. Methods 9:1021–29
    [Google Scholar]
  64. 64.  Choi JW, Chun J 2013. Lysophospholipids and their receptors in the central nervous system. Biochim. Biophys. Acta 1831:20–32
    [Google Scholar]
  65. 65.  Kotsikorou E, Lynch DL, Abood ME, Reggio PH 2011. Lipid bilayer molecular dynamics study of lipid-derived agonists of the putative cannabinoid receptor, GPR55. Chem. Phys. Lipids 164:131–43
    [Google Scholar]
  66. 66.  Guy AT, Nagatsuka Y, Ooashi N, Inoue M, Nakata A et al. 2015. Glycerophospholipid regulation of modality-specific sensory axon guidance in the spinal cord. Science 349:974–77
    [Google Scholar]
  67. 67.  Contos JJ, Ishii I, Fukushima N, Kingsbury MA, Ye X et al. 2002. Characterization of lpa2 (Edg4) and lpa1/lpa2 (Edg2/Edg4) lysophosphatidic acid receptor knockout mice: signaling deficits without obvious phenotypic abnormality attributable to lpa2. Mol. . Cell Biol 22:6921–29
    [Google Scholar]
  68. 68.  Ye X, Hama K, Contos JJ, Anliker B, Inoue A et al. 2005. LPA3-mediated lysophosphatidic acid signalling in embryo implantation and spacing. Nature 435:104–8
    [Google Scholar]
  69. 69.  Lin ME, Rivera RR, Chun J 2012. Targeted deletion of LPA5 identifies novel roles for lysophosphatidic acid signaling in development of neuropathic pain. J. Biol. Chem. 287:17608–17
    [Google Scholar]
  70. 70.  Sumida H, Noguchi K, Kihara Y, Abe M, Yanagida K et al. 2010. LPA4 regulates blood and lymphatic vessel formation during mouse embryogenesis. Blood 116:5060–70
    [Google Scholar]
  71. 71.  Ishii I, Friedman B, Ye X, Kawamura S, McGiffert C et al. 2001. Selective loss of sphingosine 1-phosphate signaling with no obvious phenotypic abnormality in mice lacking its G protein-coupled receptor, LPB3/EDG-3. J. Biol. Chem. 276:33697–704
    [Google Scholar]
  72. 72.  Ishii I, Ye X, Friedman B, Kawamura S, Contos JJ et al. 2002. Marked perinatal lethality and cellular signaling deficits in mice null for the two sphingosine 1-phosphate (S1P) receptors, S1P2/LPB2/EDG-5 and S1P3/LPB3/EDG-3. J. Biol. Chem. 277:25152–59
    [Google Scholar]
  73. 73.  Jenne CN, Enders A, Rivera R, Watson SR, Bankovich AJ et al. 2009. T-bet-dependent S1P5 expression in NK cells promotes egress from lymph nodes and bone marrow. J. Exp. Med. 206:2469–81
    [Google Scholar]
  74. 74.  Hata E, Sasaki N, Takeda A, Tohya K, Umemoto E et al. 2016. Lysophosphatidic acid receptors LPA4 and LPA6 differentially promote lymphocyte transmigration across high endothelial venules in lymph nodes. Int. Immunol. 28:283–92
    [Google Scholar]
  75. 75.  Choi JW, Gardell SE, Herr DR, Rivera R, Lee CW et al. 2011. FTY720 (fingolimod) efficacy in an animal model of multiple sclerosis requires astrocyte sphingosine 1-phosphate receptor 1 (S1P1) modulation. PNAS 108:751–56
    [Google Scholar]
  76. 76.  Kono M, Mi Y, Liu Y, Sasaki T, Allende ML et al. 2004. The sphingosine-1-phosphate receptors S1P1, S1P2, and S1P3 function coordinately during embryonic angiogenesis. J. Biol. Chem. 279:29367–73
    [Google Scholar]
  77. 77.  Allende ML, Bektas M, Lee BG, Bonifacino E, Kang J et al. 2011. Sphingosine-1-phosphate lyase deficiency produces a pro-inflammatory response while impairing neutrophil trafficking. J. Biol. Chem. 286:7348–58
    [Google Scholar]
  78. 78.  Chun J, Hla T, Moolenaar W, Spiegel S, eds. 2014. Lysophospholipid Receptors: Signaling and Biochemistry Hoboken, NJ: Wiley
  79. 79.  Hanson MA, Roth CB, Jo E, Griffith MT, Scott FL et al. 2012. Crystal structure of a lipid G protein-coupled receptor. Science 335:851–55
    [Google Scholar]
  80. 80.  Chrencik JE, Roth CB, Terakado M, Kurata H, Omi R et al. 2015. Crystal structure of antagonist bound human lysophosphatidic acid receptor 1. Cell 161:1633–43
    [Google Scholar]
  81. 81.  Taniguchi R, Inoue A, Sayama M, Uwamizu A, Yamashita K et al. 2017. Structural insights into ligand recognition by the lysophosphatidic acid receptor LPA6. Nature 548:356–60
    [Google Scholar]
  82. 82.  Nishimasu H, Okudaira S, Hama K, Mihara E, Dohmae N et al. 2011. Crystal structure of autotaxin and insight into GPCR activation by lipid mediators. Nat. Struct. Mol. Biol. 18:205–12
    [Google Scholar]
  83. 83.  Blaho VA, Galvani S, Engelbrecht E, Liu C, Swendeman SL et al. 2015. HDL-bound sphingosine-1-phosphate restrains lymphopoiesis and neuroinflammation. Nature 523:342–46
    [Google Scholar]
  84. 84.  Brinkmann V, Davis MD, Heise CE, Albert R, Cottens S et al. 2002. The immune modulator FTY720 targets sphingosine 1-phosphate receptors. J. Biol. Chem. 277:21453–57
    [Google Scholar]
  85. 85.  Mandala S, Hajdu R, Bergstrom J, Quackenbush E, Xie J et al. 2002. Alteration of lymphocyte trafficking by sphingosine-1-phosphate receptor agonists. Science 296:346–49
    [Google Scholar]
  86. 86.  Adachi K, Kohara T, Nakao N, Arita M, Chiba K et al. 1995. Design, synthesis, and structure-activity relationships of 2-substituted-2-amino-1,3-propanediols: discovery of a novel immunosuppressant, FTY720. Bioorg. Med. Chem. Lett. 5:853–56
    [Google Scholar]
  87. 87.  Fujita T, Yoneta M, Hirose R, Sasaki S, Inoue K et al. 1995. Simple compounds, 2-alkyl-2-amino-1,3-propanediols have potent immunosuppressive activity. Bioorg. Med. Chem. Lett. 5:847–52
    [Google Scholar]
  88. 88.  Kiuchi M, Adachi K, Kohara T, Teshima K, Masubuchi Y et al. 1998. Synthesis and biological evaluation of 2,2-disubstituted 2-aminoethanols: analogues of FTY720. Bioorg. Med. Chem. Lett. 8:101–6
    [Google Scholar]
  89. 89.  Miyake Y, Kozutsumi Y, Nakamura S, Fujita T, Kawasaki T 1995. Serine palmitoyltransferase is the primary target of a sphingosine-like immunosuppressant, ISP-1/myriocin. Biochem. Biophys. Res. Commun. 211:396–403
    [Google Scholar]
  90. 90.  Fujita T, Inoue K, Yamamoto S, Ikumoto T, Sasaki S et al. 1994. Fungal metabolites. Part 11. A potent immunosuppressive activity found in Isaria sinclairii metabolite. J. Antibiot. 47:208–15
    [Google Scholar]
  91. 91.  Fujita T, Inoue K, Yamamoto S, Ikumoto T, Sasaki S et al. 1994. Fungal metabolites. Part 12. Potent immunosuppressant, 14-deoxomyriocin, (2S,3R,4R)-(E)-2-amino-3,4-dihydroxy-2-hydroxymethyleicos-6-enoic acid and structure-activity relationships of myriocin derivatives. J. Antibiot. 47:216–24
    [Google Scholar]
  92. 92.  Fujita T, Hirose R, Yoneta M, Sasaki S, Inoue K et al. 1996. Potent immunosuppressants, 2-alkyl-2-aminopropane-1,3-diols. J. Med. Chem. 39:4451–59
    [Google Scholar]
  93. 93.  Kluepfel D, Bagli J, Baker H, Charest MP, Kudelski A 1972. Myriocin, a new antifungal antibiotic from Myriococcum albomyces. J. Antibiot. 25:109–15
    [Google Scholar]
  94. 94.  Craveri R, Manachini PL, Aragozzini F 1972. Thermozymocidin new antifungal antibiotic from a thermophilic eumycete. Experientia 28:867–68
    [Google Scholar]
  95. 95.  Chiba K, Hoshino Y, Suzuki C, Masubuchi Y, Yanagawa Y et al. 1996. FTY720, a novel immunosuppressant possessing unique mechanisms. I. Prolongation of skin allograft survival and synergistic effect in combination with cyclosporine in rats. Transplant. Proc. 28:1056–59
    [Google Scholar]
  96. 96.  Enosawa S, Suzuki S, Kakefuda T, Li XK, Amemiya H 1996. Induction of selective cell death targeting on mature T-lymphocytes in rats by a novel immunosuppressant, FTY720. Immunopharmacology 34:171–79
    [Google Scholar]
  97. 97.  Suzuki S, Li XK, Enosawa S, Shinomiya T 1996. A new immunosuppressant, FTY720, induces bcl-2-associated apoptotic cell death in human lymphocytes. Immunology 89:518–23
    [Google Scholar]
  98. 98.  Nagahara Y, Enosawa S, Ikekita M, Suzuki S, Shinomiya T 2000. Evidence that FTY720 induces T cell apoptosis in vivo. Immunopharmacology 48:75–85
    [Google Scholar]
  99. 99.  Mitsusada M, Suzuki S, Kobayashi E, Enosawa S, Kakefuda T, Miyata M 1997. Prevention of graft rejection and graft-versus-host reaction by a novel immunosuppressant, FTY720, in rat small bowel transplantation. Transpl. Int. 10:343–49
    [Google Scholar]
  100. 100.  Sharma KG, Radha R, Pao A, Amet N, Baden L et al. 2010. Mycophenolic acid and intravenous immunoglobulin exert an additive effect on cell proliferation and apoptosis in the mixed lymphocyte reaction. Transpl. Immunol. 23:117–20
    [Google Scholar]
  101. 101.  O'Flaherty E, Wong WK, Pettit SJ, Seymour K, Ali S, Kirby JA 2000. Regulation of T-cell apoptosis: a mixed lymphocyte reaction model. Immunology 100:289–99
    [Google Scholar]
  102. 102.  Suzuki S, Enosawa S, Kakefuda T, Shinomiya T, Amari M et al. 1996. A novel immunosuppressant, FTY720, with a unique mechanism of action, induces long-term graft acceptance in rat and dog allotransplantation. Transplantation 61:200–5
    [Google Scholar]
  103. 103.  Chiba K, Yanagawa Y, Masubuchi Y, Kataoka H, Kawaguchi T et al. 1998. FTY720, a novel immunosuppressant, induces sequestration of circulating mature lymphocytes by acceleration of lymphocyte homing in rats. I. FTY720 selectively decreases the number of circulating mature lymphocytes by acceleration of lymphocyte homing. J. Immunol. 160:5037–44
    [Google Scholar]
  104. 104.  Yanagawa Y, Masubuchi Y, Chiba K 1998. FTY720, a novel immunosuppressant, induces sequestration of circulating mature lymphocytes by acceleration of lymphocyte homing in rats, III. Increase in frequency of CD62L-positive T cells in Peyer's patches by FTY720-induced lymphocyte homing. Immunology 95:591–94
    [Google Scholar]
  105. 105.  Yuzawa K, Otsuka M, Taniguchi H, Takada Y, Sakurayama N et al. 1998. An effect of FTY720 on acute rejection in canine renal transplantation. Transplant. Proc. 30:1046
    [Google Scholar]
  106. 106.  Kawaguchi T, Hoshino Y, Rahman F, Amano Y, Higashi H et al. 1996. FTY720, a novel immunosuppressant possessing unique mechanisms. III. Synergistic prolongation of canine renal allograft survival in combination with cyclosporine A. Transplant. Proc. 28:1062–63
    [Google Scholar]
  107. 107.  Suzuki S, Kakefuda T, Amemiya H, Chiba K, Hoshino Y et al. 1998. An immunosuppressive regimen using FTY720 combined with cyclosporin in canine kidney transplantation. Transpl. Int. 11:95–101
    [Google Scholar]
  108. 108.  Yuzawa K, Otsuka M, Taniguchi H, Takada Y, Sakurayama N et al. 1999. Rescue effect of FTY720 on acute renal rejection in dogs. Transplant. Proc. 31:872
    [Google Scholar]
  109. 109.  Budde K, Schutz M, Glander P, Peters H, Waiser J et al. 2006. FTY720 (fingolimod) in renal transplantation. Clin. Transplant. 20:Suppl. 1717–24
    [Google Scholar]
  110. 110.  Tedesco-Silva H, Szakaly P, Shoker A, Sommerer C, Yoshimura N et al. 2007. FTY720 versus mycophenolate mofetil in de novo renal transplantation: six-month results of a double-blind study. Transplantation 84:885–92
    [Google Scholar]
  111. 111.  Tedesco-Silva H, Pescovitz MD, Cibrik D, Rees MA, Mulgaonkar S et al. 2006. Randomized controlled trial of FTY720 versus MMF in de novo renal transplantation. Transplantation 82:1689–97
    [Google Scholar]
  112. 112.  Suzuki S, Li XK, Shinomiya T, Enosawa S, Kakefuda T et al. 1996. Induction of lymphocyte apoptosis and prolongation of allograft survival by FTY720. Transplant. Proc. 28:2049–50
    [Google Scholar]
  113. 113.  Chiba K, Yanagawa Y, Kataoka H, Kawaguchi T, Ohtsuki M, Hoshino Y 1999. FTY720, a novel immunosuppressant, induces sequestration of circulating lymphocytes by acceleration of lymphocyte homing. Transplant. Proc. 31:1230–33
    [Google Scholar]
  114. 114.  Chun J 1999. Lysophospholipid receptors: implications for neural signaling. Crit. Rev. Neurobiol. 13:151–68
    [Google Scholar]
  115. 115.  Chun J, Contos JJ, Munroe D 1999. A growing family of receptor genes for lysophosphatidic acid (LPA) and other lysophospholipids (LPs). Cell Biochem. Biophys. 30:213–42
    [Google Scholar]
  116. 116.  Chun J, Weiner JA, Fukushima N, Contos JJ, Zhang G et al. 2000. Neurobiology of receptor-mediated lysophospholipid signaling. From the first lysophospholipid receptor to roles in nervous system function and development. Ann. N.Y. Acad. Sci. 905:110–17
    [Google Scholar]
  117. 117.  Ye X, Fukushima N, Kingsbury MA, Chun J 2002. Lysophosphatidic acid in neural signaling. Neuroreport 13:2169–75
    [Google Scholar]
  118. 118.  Mullershausen F, Craveiro LM, Shin Y, Cortes-Cros M, Bassilana F et al. 2007. Phosphorylated FTY720 promotes astrocyte migration through sphingosine-1-phosphate receptors. J. Neurochem. 102:1151–61
    [Google Scholar]
  119. 119.  McGiffert C, Contos JJ, Friedman B, Chun J 2002. Embryonic brain expression analysis of lysophospholipid receptor genes suggests roles for s1p1 in neurogenesis and s1p1–3 in angiogenesis. FEBS Lett 531:103–8
    [Google Scholar]
  120. 120.  Dubin AE, Bahnson T, Weiner JA, Fukushima N, Chun J 1999. Lysophosphatidic acid stimulates neurotransmitter-like conductance changes that precede GABA and l-glutamate in early, presumptive cortical neuroblasts. J. Neurosci. 19:1371–81
    [Google Scholar]
  121. 121.  Weiner JA, Hecht JH, Chun J 1998. Lysophosphatidic acid receptor gene vzg-1/lpA1/edg-2 is expressed by mature oligodendrocytes during myelination in the postnatal murine brain. J. Comp. Neurol. 398:587–98
    [Google Scholar]
  122. 122.  Weiner JA, Chun J 1999. Schwann cell survival mediated by the signaling phospholipid lysophosphatidic acid. PNAS 96:5233–38
    [Google Scholar]
  123. 123.  Weiner JA, Fukushima N, Contos JJ, Scherer SS, Chun J 2001. Regulation of Schwann cell morphology and adhesion by receptor-mediated lysophosphatidic acid signaling. J. Neurosci. 21:7069–78
    [Google Scholar]
  124. 124.  Moller T, Contos JJ, Musante DB, Chun J, Ransom BR 2001. Expression and function of lysophosphatidic acid receptors in cultured rodent microglial cells. J. Biol. Chem. 276:25946–52
    [Google Scholar]
  125. 125.  Fujino M, Funeshima N, Kitazawa Y, Kimura H, Amemiya H et al. 2003. Amelioration of experimental autoimmune encephalomyelitis in Lewis rats by FTY720 treatment. J. Pharmacol. Exp. Ther. 305:70–77
    [Google Scholar]
  126. 126.  Bernard CC, Leydon J, Mackay IR 1976. T cell necessity in the pathogenesis of experimental autoimmune encephalomyelitis in mice. Eur. J. Immunol. 6:655–60
    [Google Scholar]
  127. 127.  Ortiz-Ortiz L, Nakamura RM, Weigle WO 1976. T cell requirement for experimental allergic encephalomyelitis induction in the rat. J. Immunol. 117:576–79
    [Google Scholar]
  128. 128.  Yanagawa Y, Hoshino Y, Kataoka H, Kawaguchi T, Ohtsuki M et al. 1999. FTY720, a novel immunosuppressant, prolongs rat skin allograft survival by decreasing T-cell infiltration into grafts. Transplant. Proc. 31:1227–79
    [Google Scholar]
  129. 129.  Webb M, Tham CS, Lin FF, Lariosa-Willingham K, Yu N et al. 2004. Sphingosine 1-phosphate receptor agonists attenuate relapsing-remitting experimental autoimmune encephalitis in SJL mice. J. Neuroimmunol. 153:108–21
    [Google Scholar]
  130. 130.  Mehling M, Brinkmann V, Antel J, Bar-Or A, Goebels N et al. 2008. FTY720 therapy exerts differential effects on T cell subsets in multiple sclerosis. Neurology 71:1261–67
    [Google Scholar]
  131. 131.  Noguchi K, Chun J 2011. Roles for lysophospholipid S1P receptors in multiple sclerosis. Crit. Rev. Biochem. Mol. Biol. 46:2–10
    [Google Scholar]
  132. 132.  Cyster JG, Schwab SR 2012. Sphingosine-1-phosphate and lymphocyte egress from lymphoid organs. Annu. Rev. Immunol. 30:69–94
    [Google Scholar]
  133. 133.  Brinkmann V 2009. FTY720 (fingolimod) in multiple sclerosis: therapeutic effects in the immune and the central nervous system. Br. J. Pharmacol. 158:1173–82
    [Google Scholar]
  134. 134.  Nakamura M, Matsuoka T, Chihara N, Miyake S, Sato W et al. 2014. Differential effects of fingolimod on B-cell populations in multiple sclerosis. Mult. Scler. 20:1371–80
    [Google Scholar]
  135. 135.  Khanna N, Elzi L, Mueller NJ, Garzoni C, Cavassini M et al. 2009. Incidence and outcome of progressive multifocal leukoencephalopathy over 20 years of the Swiss HIV Cohort Study. Clin. Infect. Dis. 48:1459–66
    [Google Scholar]
  136. 136.  Berger JR 2017. Classifying PML risk with disease modifying therapies. Mult. Scler. Relat. Disord. 12:59–63
    [Google Scholar]
  137. 137.  Redelman-Sidi G, Michielin O, Cervera C, Ribi C, Aguado JM et al. 2018. ESCMID Study Group for Infections in Compromised Hosts (ESGICH) consensus document on the safety of targeted and biological therapies: an infectious diseases perspective-immune checkpoint inhibitors, cell adhesion inhibitors, sphingosine 1-phosphate receptor modulators and proteasome inhibitors. Clin. Microbiol. Infect. 24:Suppl. 2S95–107
    [Google Scholar]
  138. 138.  Grebenciucova E, Pruitt A 2017. Infections in patients receiving multiple sclerosis disease-modifying therapies. Curr. Neurol. Neurosci. Rep. 17:88
    [Google Scholar]
  139. 139. Novartis. 2017. Novartis multiple sclerosis therapy fingolimod granted FDA Breakthrough Therapy designation for pediatric MS Press Release, Dec. 18. https://www.pharma.us.novartis.com/news/media-releases/novartis-multiple-sclerosis-therapy-fingolimod-granted-fda-breakthrough-therapy
  140. 140. Novartis. 2017. Novartis pivotal data show children and adolescents with relapsing MS had an 82% lower relapse rate with fingolimod vs. interferon beta-1a Press Release, Oct. 28. https://www.pharma.us.novartis.com/news/media-releases/novartis-pivotal-data-show-children-and-adolescents-relapsing-ms-had-82-lower
  141. 141.  Matloubian M, Lo CG, Cinamon G, Lesneski MJ, Xu Y et al. 2004. Lymphocyte egress from thymus and peripheral lymphoid organs is dependent on S1P receptor 1. Nature 427:355–60
    [Google Scholar]
  142. 142.  Pappu R, Schwab SR, Cornelissen I, Pereira JP, Regard JB et al. 2007. Promotion of lymphocyte egress into blood and lymph by distinct sources of sphingosine-1-phosphate. Science 316:295–98
    [Google Scholar]
  143. 143.  Kovarik JM, Schmouder R, Barilla D, Riviere GJ, Wang Y, Hunt T 2004. Multiple-dose FTY720: tolerability, pharmacokinetics, and lymphocyte responses in healthy subjects. J. Clin. Pharmacol. 44:532–37
    [Google Scholar]
  144. 144.  Foster CA, Howard LM, Schweitzer A, Persohn E, Hiestand PC et al. 2007. Brain penetration of the oral immunomodulatory drug FTY720 and its phosphorylation in the central nervous system during experimental autoimmune encephalomyelitis: consequences for mode of action in multiple sclerosis. J. Pharmacol. Exp. Ther. 323:469–75
    [Google Scholar]
  145. 145.  Groves A, Kihara Y, Chun J 2013. Fingolimod: direct CNS effects of sphingosine 1-phosphate (S1P) receptor modulation and implications in multiple sclerosis therapy. J. Neurol. Sci. 328:9–18
    [Google Scholar]
  146. 146.  Soliven B, Miron V, Chun J 2011. The neurobiology of sphingosine 1-phosphate signaling and sphingosine 1-phosphate receptor modulators. Neurology 76:S9–14
    [Google Scholar]
  147. 147.  Miron VE, Schubart A, Antel JP 2008. Central nervous system-directed effects of FTY720 (fingolimod). J. Neurol. Sci. 274:13–17
    [Google Scholar]
  148. 148.  Hunter SF, Bowen JD, Reder AT 2016. The direct effects of fingolimod in the central nervous system: implications for relapsing multiple sclerosis. CNS Drugs 30:135–47
    [Google Scholar]
  149. 149.  Rothhammer V, Kenison JE, Tjon E, Takenaka MC, de Lima KA et al. 2017. Sphingosine 1-phosphate receptor modulation suppresses pathogenic astrocyte activation and chronic progressive CNS inflammation. PNAS 114:2012–17
    [Google Scholar]
  150. 150.  Dusaban SS, Chun J, Rosen H, Purcell NH, Brown JH 2017. Sphingosine 1-phosphate receptor 3 and RhoA signaling mediate inflammatory gene expression in astrocytes. J. Neuroinflammation 14:111
    [Google Scholar]
  151. 151.  Jung CG, Kim HJ, Miron VE, Cook S, Kennedy TE et al. 2007. Functional consequences of S1P receptor modulation in rat oligodendroglial lineage cells. Glia 55:1656–67
    [Google Scholar]
  152. 152.  Miron VE, Ludwin SK, Darlington PJ, Jarjour AA, Soliven B et al. 2010. Fingolimod (FTY720) enhances remyelination following demyelination of organotypic cerebellar slices. Am. J. Pathol. 176:2682–94
    [Google Scholar]
  153. 153.  Zhang Y, Li X, Ciric B, Ma CG, Gran B et al. 2017. Effect of fingolimod on neural stem cells: a novel mechanism and broadened application for neural repair. Mol. Ther. 25:401–15
    [Google Scholar]
  154. 154.  Li C, Li JN, Kays J, Guerrero M, Nicol GD 2015. Sphingosine 1-phosphate enhances the excitability of rat sensory neurons through activation of sphingosine 1-phosphate receptors 1 and/or 3. J. Neuroinflammation 12:70
    [Google Scholar]
  155. 155.  Di Menna L, Molinaro G, Di Nuzzo L, Riozzi B, Zappulla C et al. 2013. Fingolimod protects cultured cortical neurons against excitotoxic death. Pharmacol. Res. 67:1–9
    [Google Scholar]
  156. 156.  Durafourt BA, Lambert C, Johnson TA, Blain M, Bar-Or A, Antel JP 2011. Differential responses of human microglia and blood-derived myeloid cells to FTY720. J. Neuroimmunol. 230:10–16
    [Google Scholar]
  157. 157.  Noda H, Takeuchi H, Mizuno T, Suzumura A 2013. Fingolimod phosphate promotes the neuroprotective effects of microglia. J. Neuroimmunol. 256:13–18
    [Google Scholar]
  158. 158.  Cannon RE, Peart JC, Hawkins BT, Campos CR, Miller DS 2012. Targeting blood-brain barrier sphingolipid signaling reduces basal P-glycoprotein activity and improves drug delivery to the brain. PNAS 109:15930–35
    [Google Scholar]
  159. 159.  Cruz VT, Fonseca J 2014. Central effects of fingolimod. Rev. Neurol. 59:121–28
    [Google Scholar]
  160. 160.  Foster CA, Mechtcheriakova D, Storch MK, Balatoni B, Howard LM et al. 2009. FTY720 rescue therapy in the dark agouti rat model of experimental autoimmune encephalomyelitis: expression of central nervous system genes and reversal of blood-brain-barrier damage. Brain Pathol 19:254–66
    [Google Scholar]
  161. 161.  Vidal-Jordana A, Sastre-Garriga J, Perez-Miralles F, Tur C, Tintore M et al. 2013. Early brain pseudoatrophy while on natalizumab therapy is due to white matter volume changes. Mult. Scler. 19:1175–81
    [Google Scholar]
  162. 162.  Zivadinov R, Reder AT, Filippi M, Minagar A, Stuve O et al. 2008. Mechanisms of action of disease-modifying agents and brain volume changes in multiple sclerosis. Neurology 71:136–44
    [Google Scholar]
  163. 163.  Sormani MP, De Stefano N, Francis G, Sprenger T, Chin P et al. 2015. Fingolimod effect on brain volume loss independently contributes to its effect on disability. Mult. Scler. 21:916–24
    [Google Scholar]
  164. 164.  Kappos L, Bar-Or A, Cree B, Fox R, Giovannoni G et al. 2017. Efficacy of siponimod in secondary progressive multiple sclerosis: results of the phase 3 study (CT.002). Neurology 88:Suppl. 16CT.002
    [Google Scholar]
  165. 165.  De Stefano N, Silva DG, Barnett MH 2017. Effect of fingolimod on brain volume loss in patients with multiple sclerosis. CNS Drugs 31:289–305
    [Google Scholar]
  166. 166. US Food Drug Admin. 2018. Early Alzheimer's disease: developing drugs for treatment: guidance for industry Draft Guidance, US Food Drug Admin. Silver Spring, MD: https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM596728.pdf
  167. 167.  Takai Y, Misu T, Takahashi T, Nakashima I, Fujihara K 2013. [NMO spectrum disorders and anti AQP4 antibody]. Brain Nerve 65:333–43 (In Japanese)
    [Google Scholar]
  168. 168.  Fu Y, Zhang N, Ren L, Yan Y, Sun N et al. 2014. Impact of an immune modulator fingolimod on acute ischemic stroke. PNAS 111:18315–20
    [Google Scholar]
/content/journals/10.1146/annurev-pharmtox-010818-021358
Loading
/content/journals/10.1146/annurev-pharmtox-010818-021358
Loading

Data & Media loading...

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error