Mechanisms of fingolimod's efficacy and adverse effects in multiple sclerosis

Annals of Neurology

Volumn 69, Issue 5, 2011, Pages 759-777

  Cohen, Jeffrey A ^a   Chun, Jerold ^b  

^a LERNER RESEARCH INSTITUTE   (United States)

^b SCRIPPS RESEARCH INSTITUTE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

FINGOLIMOD; SPHINGOSINE 1 PHOSPHATE RECEPTOR;

ALLERGIC ENCEPHALOMYELITIS; ARTICLE; ASTROCYTE; BACKACHE; BRADYCARDIA; BRAIN SIZE; CIRCULATION; COUGHING; DIARRHEA; DISEASE COURSE; DRUG ABSORPTION; DRUG ACTIVITY; DRUG EFFICACY; DRUG INHIBITION; DRUG SAFETY; DRUG TOLERABILITY; DRUG WITHDRAWAL; DYSPNEA; HEADACHE; HUMAN; IMMUNE SYSTEM; INFECTION; INFLUENZA; LOWER RESPIRATORY TRACT INFECTION; LYMPH NODE; LYMPHOCYTE COUNT; MULTIPLE SCLEROSIS; NEUROPROTECTION; NONHUMAN; NUCLEAR MAGNETIC RESONANCE IMAGING; OLIGODENDROGLIA; PRIORITY JOURNAL; PROTEIN EXPRESSION; RECURRENT DISEASE; RETINA MACULA EDEMA; SIDE EFFECT; TREATMENT FAILURE;

ANIMALS; CENTRAL NERVOUS SYSTEM; CLINICAL TRIALS AS TOPIC; DISEASE MODELS, ANIMAL; DRUG-INDUCED LIVER INJURY; HEART DISEASES; HUMANS; IMMUNOSUPPRESSIVE AGENTS; INFECTION; LIVER DISEASES; LYMPHOCYTES; LYSOPHOSPHOLIPIDS; MULTIPLE SCLEROSIS; PROPYLENE GLYCOLS; RECEPTORS, LYSOSPHINGOLIPID; RESPIRATION DISORDERS; SPHINGOSINE;

EID: 79955455801     PISSN: 03645134     EISSN: 15318249     Source Type: Journal    
DOI: 10.1002/ana.22426     Document Type: Article

References (148)

1. Frohman EM, Racke MK, Raine CS,. Multiple sclerosis-the plaque and its pathogenesis. N Engl J Med 2006; 354: 942-955.
2. Chang A, Tourtellotte WW, Rudick RA, Trapp BD,. Premyelinating oligodendrocytes in chronic lesions of multiple sclerosis. N Engl J Med 2002; 346: 165-173. (Pubitemid 34438882)
3. Patrikios P, Stadelmann C, Kutzelnigg A, et al. Remyelination is extensive in a subset of multiple sclerosis patients. Brain 2006; 129: 3165-3172. (Pubitemid 44871433)
4. Stangel M,. Neuroprotection and neuroregeneration in multiple sclerosis. J Neurol 2008; 255 (suppl 6): 77-81.
5. Westermann J, Pabst R,. Distribution of lymphocyte subsets and natural killer cells in the human body. Clin Invest 1992; 70: 539-544.
6. Sallusto F, Geginat J, Lanzavecchia A,. Central memory and effector memory T cell subsets: function, generation, and maintenance. Annu Rev Immunol 2004; 22: 745-763. (Pubitemid 38680440)
7. Massberg S, Von Andrian UH,. Fingolimod and sphingosine-1-phosphate- modifiers of lymphocyte migration. N Engl J Med 2006; 355: 1088-1091.
8. Spiegel S, Milstien S,. Sphingosine-1-phosphate: an enigmatic signalling lipid. Nat Rev Mol Cell Biol 2003; 4: 397-407. (Pubitemid 36565571)
9. Le Stunff HL, Milstien S, Spiegel S,. Generation and metabolism of bioactive sphingosine-1-phosphate. J Cell Biochem 2004; 92: 882-899. (Pubitemid 44264239)
10. Edsall LC, Spiegel S,. Enzymatic measurement of sphingosine 1-phosphate. Anal Biochem 1999; 272: 80-86. (Pubitemid 29343385)
11. Fukushima N, Ishii I, Contos JJA, et al. Lysophospholipid receptors. Annu Rev Pharmacol Toxicol 2001; 41: 507-534. (Pubitemid 32385897)
12. Hla T,. Signaling and biological actions of sphingosine-1-phosphate. Pharmacol Res 2003; 47: 401-407.
13. Ishii I, Fukushima N, Ye X, Chun J,. Lysophospholipid receptors: signaling and biology. Annu Rev Biochem 2004; 73: 321-354. (Pubitemid 39050372)
14. Chun J, Hla T, Lynch KR, et al. International union of basic and clinical pharmacology. LXXVIII. Lysophospholipid receptor nomenclature. Pharmacol Rev 2010; 2010: 579-587.
15. Graeler M, Goetzl EJ,. Activation-regulated expression and chemotactic function of sphingosine 1-phosphate receptors in mouse splenic T cells. FASEB J 2002; 16: 1874-1878. (Pubitemid 35462606)
16. Graler MH, Goetzl EJ,. The immunosuppressant FTY720 down-regulates sphingosine 1-phosphate G-protein-coupled receptors. FASEB J 2004; 18: 551-553.
17. Lo CG, Xu Y, Proia RL, Cyster JG,. Cyclical modulation of sphingosine-1-phosphate receptor 1 surface expression during lymphocyte recirculation and relationship to lymphoid organ transit. J Exp Med 2005; 201: 291-301. (Pubitemid 40189438)
18. Schwab SR, Pereira JP, Matloubian M, et al. Lymphocyte sequestration through S1P lyase inhibition and disruption of S1P gradients. Science 2005; 309: 1735-1739. (Pubitemid 41285945)
19. Im D-S,. Linking Chinese medicine and G-protein-coupled receptors. Trends Pharmacol Sci 2003; 24: 2-4. (Pubitemid 36009281)
20. Kovarik JM, Schmouder R, Barilla D, et al. Single-dose FTY720 pharmacokinetics, food effect, and pharmacological responses in healthy subjects. Br J Clin Pharmacol 2004; 57: 586-591. (Pubitemid 38582178)
21. Kovarik JM, Hartmann S, Bartlett M, et al. Oral-intravenous crossover study of fingolimod pharmacokinetics, lymphocyte responses and cardiac effects. Biopharm Drug Dispos 2007; 28: 97-104. (Pubitemid 46455770)
22. Budde K, Schmouder R, Nashan B, et al. Pharmacodynamics of single doses of the novel immunosuppressant FTY720 in stable renal transplant patients. Am J Transplant 2003; 3: 846-854. (Pubitemid 36827906)
23. Kahan BD, Karlix JL, Ferguson RM, et al. Pharmacodynamics, pharmacokinetics, and safety of multiple doses of FTY720 in stable renal transplant patients: a multicenter, randomized, placebo-controlled, phase I study. Transplantation 2003; 76: 1079-1084. (Pubitemid 37280837)
24. Kovarik JM, Schmouder R, Barilla D, et al. Multiple-dose FTY720: tolerability, pharmacokinetics, and lymphocyte responses in healthy subjects. J Clin Pharmacol 2004; 44: 532-537. (Pubitemid 38509722)
25. Skerjanec A, Tedesco H, Neumayer HH, et al. FTY720, a novel immunomodulator in de novo kidney transplant patients: pharmacokinetics and exposure-response relationship. J Clin Pharmacol 2005; 45: 1268-1278. (Pubitemid 41513050)
26. Meno-Tetang GML, Li H, Mis S, et al. Physiologically based pharmacokinetic modeling of FTY720 (2-amino-2[2-(-4-octylphenyl)ethyl]propane-1, 3-diol hydrochloride) in rats after oral and intravenous doses. Drug Metab Dispos 2006; 34: 1480-1487. (Pubitemid 44285388)
27. Foster CA, Howard LM, Schweitzer A, et al. 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 2007; 323: 469-475.
28. Brinkmann V, Davis MD, Heise CE, et al. The immune modulator FTY720 targets sphingosine 1-phosphate receptors. J Biol Chem 2002; 277: 21453-21457. (Pubitemid 34952287)
29. Mandala S, Hajdu R, Bergstrom J, et al. Alteration of lymphocyte trafficking by sphingosine-1-phosphate receptor agonists. Science 2002; 296: 346-349. (Pubitemid 34303689)
30. Billich A, Bonrnancin F, Devay P, et al. Phosphorylation of the immunomodulatory drug FTY720 by sphingosine kinases. J Biol Chem 2003; 278: 47408-47415. (Pubitemid 37523181)
31. Paugh SW, Payne SG, Barbour SE, et al. The immunosuppressant FTY720 is phosphorylated by sphingosine kinase type 2. FEBS Lett 2003; 554: 189-193. (Pubitemid 37324838)
32. Allende ML, Sasaki T, Kawai H, et al. Mice deficient in sphingosine kinase 1 are rendered lymphopenic by FTY720. J Biol Chem 2004; 279: 52487-52492. (Pubitemid 39656625)
33. Kharel Y, Lee S, Snyder AH, et al. Sphingosine kinase 2 is required for modulation of lymphocyte traffic by FTY720. J Biol Chem 2005; 280: 36865-36872. (Pubitemid 41587768)
34. Zemann B, Kinzel B, Muller M, et al. Sphingosine kinase type 2 is essential for lymphopenia induced by the immunomodulatory drug FTY720. Blood 2006; 107: 1454-1458. (Pubitemid 43242381)
35. Oo ML, Thangada S, Wu M-T, et al. Immunosuppressive and anti-angiogenic sphingosine 1-phosphate receptor-1 agonists induce ubiquitinylation and proteosomal degradation of the receptor. J Biol Chem 2007; 282: 9082-9089. (Pubitemid 47093504)
36. Mullershausen F, Zecri F, Cetin C, et al. Persistent signaling induced by FTY720-phosphate is mediated by internalized S1P1 receptors. Nat Chem Biol 2009; 5: 428-434.
37. Matloubian M, Lo CG, Cinamon G, et al. Lymphocyte egress from thymus and peripheral lymphoid organs is dependent on S1P receptor 1. Nature 2004; 427: 355-360. (Pubitemid 38133663)
38. Sanna MG, Liao J, Jo E, et al. Sphingosine 1-phosphate (S1P) receptor subtypes S1P1 and S1P3, respectively, regulate lymphocyte recirculation and heart rate. J Biol Chem 2004; 279: 13839-13848. (Pubitemid 38468916)
39. Kappos L, Antel J, Comi G, et al. Oral fingolimod (FTY720) for relapsing multiple sclerosis. N Engl J Med 2006; 355: 1124-1140. (Pubitemid 44394919)
40. Kappos L, Radue E-W, O'Connor P, et al. A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. N Eng J Med 2010; 362: 387-401.
41. Cohen JA, Barkhof F, Comi G, et al. Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis. N Eng J Med 2010; 362: 402-415.
42. Montalban X, O'Connor P, Antel J, et al. Oral fingolimod (FTY720) shows sustained low rates of clinical and MRI disease activity in patients with relapsing multiple sclerosis: four-year results from a phase II extension (P06.128) [abstract]. Neurology 2009; 72 (suppl 3): A313.
43. Rudick RA, Fisher E, Lee J-C, et al. Use of the brain parenchymal fraction to measure whole brain atrophy in relapsing-remitting MS. Neurology 1999; 53: 1698-1704. (Pubitemid 29530342)
44. Hardmeier M, Wagenpfeil S, Freitag P, et al. Rate of brain atrophy in relapsing MS decreases during treatment with IFNb-1a. Neurology 2005; 64: 236-240.
45. Miller DH, Soon D, Fernando KT, et al. MRI outcomes in a placebo-controlled trial of natalizumab in relapsing MS. Neurology 2007; 68: 1390-1401. (Pubitemid 46659091)
46. Tedesco-Silva H, Mourad G, Kahan BD, et al. FTY720, a novel immunomodulator: efficacy and safety results from the first phase 2A study in de novo renal transplantation. Transplantation 2005; 79: 1553-1560. (Pubitemid 40847587)
47. Salvadori M, Budde K, Charpentier B, et al. FTY720 versus MMP with cyclosporine in de novo renal tansplantation: a 1-year, randomized controlled trial in Europe and Australasia. Am J Transplant 2006; 6: 2912-2921.
48. Tedesco-Silva H, Pescovitz MD, Cibrik D, et al. Randomized controlled trial of FTY720 versus MMF in de novo renal transplantation. Transplantation 2006; 82: 1689-1697. (Pubitemid 46035653)
49. Park SI, Felipe CR, Machado PG, et al. Pharmacokinetic/pharmacodynamic relationships of FTY720 in kidney transplant recipients. Braz J Med Biol Res 2005; 38: 683-694. (Pubitemid 40867507)
50. Francis G, Kappos L, O'Connor P, et al. Lymphocytes and fingolimod-temporal pattern and relationship with infections (P442). Mult Scler 2010; 16 (suppl 10): S146-S147.
51. Johnson TA, Shames I, Keezer M, et al. Reconstitution of circulating lymphocyte counts in FTY720-treated MS patients. Clin Immunol 2010; 137: 15-20.
52. Bohler T, Waiser J, Schuetz M, et al. FTY720 exerts differential effects on CD4+ and CD8+ T-lymphocyte subpopulations expressing chemokine and adhesion receptors. Nephrol Dial Transplant 2004; 19: 702-713. (Pubitemid 38263133)
53. Yanagawa Y, Masubuchi Y, Chiba K,. 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 1998; 95: 591-594. (Pubitemid 28559152)
54. Hofmann M, Brinkmann V, Zerwes H-G,. FTY720 preferentially depletes naive T cells from peripheral and lymphoid organs. Int Immunopharmacol 2006; 6: 1902-1910. (Pubitemid 44855701)
55. Mehling M, Lindberg R, Raulf F, et al. Th17 central memory T cells are reduced by FTY720 in patients with multiple sclerosis. Neurology 2010; 75: 403-410.
56. Axtell RC, de Jong BA, Boniface K, et al. T helper type 1 and 17 cells determine efficacy of interferon-b in multiple sclerosis and experimental encephalomyelitis. Nat Med 2010; 16: 406-413.
57. Mehling M, Brinkmann V, Antel J, et al. FTY720 therapy exerts differential effects on T cell subsets in multiple sclerosis. Neurology 2008; 71: 1261-1267.
58. Brinkmann V,. FTY720 (fingolimod) in multiple sclerosis: therapeutic effects in the immune and the central nervous system. Br J Pharmacol 2009; 158: 1173-1182.
59. Kabashima K, Haynes NM, Xu Y, et al. Plasma cell S1P1 expression determines secondary lymphoid organ retention versus bone marrow tropism. J Exp Med 2006; 203: 2683-2690. (Pubitemid 44833344)
60. Chiba K, Yanagawa Y, Masubuchi Y, et al. 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 1998; 160: 5037-5044. (Pubitemid 28215340)
61. Brinkmann V, Chen S, Feng L, et al. FTY720 alters lymphocyte homing and protects allografts without inducing general immunosuppression. Transplant Proc 2001; 33: 530-531. (Pubitemid 32237498)
62. Xie JH, Nomura N, Koprak SL, et al. Sphoingosine-1-phosphate receptor agonism impairs the efficiency of the local immune response by altering trafficking of naive and antigen-activated CD4+ T cells. J Immunol 2003; 170: 3662-3670. (Pubitemid 36359236)
63. Mizugishi K, Yamashita T, Olivera A, et al. Essential role for sphingosine kinases in neural and vascular development. Mol Cell Biol 2005; 25: 11113-11121. (Pubitemid 41747151)
64. Wu Y-P, Mizugishi K, Bektas M, et al. Sphingosine kinase 1/S1P receptor signaling axis controls glial proliferation in mice with Sandhoff disease. Hum Mol Genet 2008; 17: 2257-2264.
65. Kimura A, Ohmori T, Ohkawa R, et al. 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: 115-124. (Pubitemid 46052981)
66. Anelli V, Bassi R, Tettamanti G, et al. Extracellular release of newly synthesized sphingosine-1-phosphate by cerebellar granule cells and astrocytes. J Neurochem 2005; 92: 1204-1215. (Pubitemid 40344310)
67. Rius RA, Edsall LC, Spiegel S,. Activation of sphingosine kinase in pheochromocytoma PC12 neuronal cells in response to trophic factors. FEBS Lett 1997; 417: 173-176. (Pubitemid 27491727)
68. Riboni L, Viani P, Bassi R, et al. Cultured granule cells and astrocytes from cerebellum differ in metabolizing sphingosine. J Neurochem 2000; 75: 503-510. (Pubitemid 30485431)
69. Bassi R, Anelli V, Giussani P, et al. Sphingosine-1-phosphate is released by cerebellar astrocytes in response to bFGF and induces astrocyte proliferation through G1-protein-coupled receptors. Glia 2006; 53: 621-630.
70. Choi JW, Gardell SE, Herr DR, et al. FTY720 (fingolimod) efficacy in an animal model of multiple sclerosis requires astrocyte sphingosine 1-phosphate receptor (S1P1) modulation. Proc Natl Acad Sci U S A 2011; 108: 751-756.
71. Williams AC, Piaton G, Lubetzki C,. Astrocytes-friends or foes in multiple sclerosis? Glia 2007; 55: 1300-1312.
72. Nair A, Frederick TJ, Miller SD,. Astrocytes in multiple sclerosis: a product of their environment. Cell Mol Life Sci 2008; 65: 2702-2720.
73. Pebay A, Toutant M, Premont J, et al. Antiproliferative properties of sphingosine-1-phosphate in human hepatic myofibroblasts. Eur J Neurosci 2001; 13: 2067-2076. (Pubitemid 32578792)
74. Malchinkhuu E, Sato K, Muraki T, et al. Assessment of the role of sphingosine 1-phosphate and its receptors in high-density lipoprotein-induced stimulation of astroglial function. Biochem J 2003; 370: 817-827. (Pubitemid 36399073)
75. Sorensen SD, Nicole O, Peavy RD, et al. Common signaling pathways link activation of murine PAR-1, LPA, and S1P receptors to proliferation of astrocytes. Mol Pharmacol 2003; 64: 1199-1209. (Pubitemid 37310753)
76. Rao TS, Lariosa-Willingham KD, Lin F-F, Palfreyman EL,. Pharmacological characterization of lysophospholipid receptor signal transduction pathways in rat cerebrocortical astrocytes. Brain Res 2003; 990: 182-194. (Pubitemid 37244074)
77. Rao TS, Lariosa-Willingham KD, Lin F-F, et al. Growth factor pre-treatment differentially regulates phosphoinositide turnover downstream of lysophospholipid receptor and metabotropic glutamate receptors in cultured rat cerebrocortical astrocytes. Int J Dev Neurosci 2004; 22: 131-135. (Pubitemid 38597128)
78. Mullershausen F, Craveiro LM, Shin Y, et al. Phosphorylated FTY702 promotes astrocyte migration through sphingosine-1-phosphate receptors. J Neurochem 2007; 102: 1151-1161. (Pubitemid 47174238)
79. van Doorn R, van Horssen J, Verziji D, et al. Sphingosine 1-phosphate receptors 1 and 3 are upregulated in multiple sclerosis lesions (P662). Mult Scler 2010; 16 (suppl 10): S228.
80. Sato K, Ishikawa K, Ui M, Okajima F,. Sphingosine 1-phosphate induces expression of early growth response-1 and fibroblast growth factor-2 through mechanism involving extracellular signal-regulated kinase in astroglial cells. Mol Brain Res 1999; 74: 182-189. (Pubitemid 30038192)
81. Riboni L, Viani P, Bassi R, et al. Basic fibroblast growth factor-induced proliferation of primary astrocytes. J Biol Chem 2001; 276: 12797-12804.
82. Glickman M, Malek RL, Kwitek-Black AE, et al. Molecular cloning, tissue-specific expression, and chromosomal localization of a novel nerve growth factor-regulated G-protein-coupled receptor, nrg-1. Mol Cell Neurosci 1999; 14: 141-152. (Pubitemid 29444884)
83. Im D-S, Heise CE, Ancellin N, et al. Characterization of a novel sphingosine 1-phosphate receptor, Edg-8. J Biol Chem 2000; 275: 14281-14286. (Pubitemid 30339709)
84. Dev KK, Mullershausen F, Mattes H, et al. Brain sphingosine-1-phosphate receptors: implications for FTY720 in the treatment of multiple sclerosis. Pharmacol Ther 2008; 117: 77-93. (Pubitemid 350192672)
85. Terai K, Soga T, Takahashi M, et al. Edg-8 receptors are preferentially expressed in oligodendrocyte lineage cells of the rat CNS. Neuroscience 2003; 116: 1053-1062. (Pubitemid 36262963)
86. Jaillard C, Harrison S, Stankoff B, et al. Edg8/S1P5: an oligodendroglial receptor with dual function on process retraction and cell survival. J Neurosci 2005; 25: 1459-1469. (Pubitemid 40250722)
87. Yu N, Lariosa-Willingham KD, Lin F-F, et al. Characterization of the lysophosphatidic acid and sphingosine-1-phosphate-mediated signal transduction in rat cortical oligodendrocytes. Glia 2004; 45: 17-27. (Pubitemid 38076224)
88. Jung CG, Kim HJ, Miron VE, et al. Functional consequences of S1P receptor modulation in rat oligodendroglial lineage cells. Glia 2007; 55: 1656-1667. (Pubitemid 47612852)
89. Novgorodov AS, El-Alwani M, Bielawski J, et al. Activation of sphingosine-1-phosphate receptor S1P5 inhibits oligodendrocyte progenitor migration. FASEB J 2007; 21: 1503-1514. (Pubitemid 46684852)
90. Miron VE, Hall JA, Kennedy TE, et al. Cyclical and dose-dependent responses of adult human mature oligodendrocytes to fingolimod. Am J Pathol 2008; 173: 1143-1152.
91. Miron VE, Jung CG, Kim HJ, et al. FTY720 modulates human oligodendrocyte progenitor process extension and survival. Ann Neurol 2008; 63: 61-71. (Pubitemid 351240552)
92. Miron VE, Schubart A, Antel JP,. Central nervous system-directed effects of FTY720 (fingolimod). J Neurol Sci 2008; 274: 13-17.
93. Coelho RP, Payne SG, Bittman R, et al. The immunomodulator FTY720 has a direct cytoprotective effect in oligodendrocyte progenitors. J Pharmacol Exp Ther 2007; 323: 626-635. (Pubitemid 350005137)
94. Buccoliero R, Futerman AH,. The roles of ceramide and complex sphingolipids in neuronal function. Pharmacol Res 2003; 47: 409-419. (Pubitemid 36379203)
95. Harada J, Foley M, Moskowitz MA, Waeber C,. Sphingosine-1-phosphate induces proliferation and morphological changes of neural progenitor cells. J Neurochem 2004; 88: 1026-1039. (Pubitemid 38199325)
96. McGiffert C, Contos JJA, Friedman B, Chun J,. Embryonic brain expression analysis of lysophospholipid receptor genes suggest roles for s1p1 in neurogenesis and s1p1-3 in angiogenesis. FEBS Lett 2002; 531: 103-108. (Pubitemid 35232794)
97. Postma FR, Jalink K, Hengeveld T, Moolenaar WH,. Sphingosine-1-phosphate rapidly induces rho-dependent neurite retraction: action through a specific cell surface receptor. EMBO J 1996; 15: 2388-2395.
98. Sato K, Tomura H, Igarashi Y, et al. Exogenous sphingosine 1-phosphate induces neurite retraction possibly through a cell surface receptor in PC12 cells. Biochem Biophys Res Commun 1997; 240: 329-334.
99. Van Brocklyn JR, Tu Z, Edsall LC, et al. Sphingosine 1-phosphate-induced cell rounding and neurite retraction are mediated by the G protein-coupled receptor H218. J Biol Chem 1999; 274: 4626-4632.
100. Edsall LC, Pirianov GG, Spiegel S,. Involvement of sphingosine 1-phosphate in nerve growth factor-mediated neuronal survival and differentiation. J Neurosci 1997; 17: 6952-6960. (Pubitemid 27427874)
101. Culmsee C, Gerling N, Lehmann M, et al. Nerve growth factor survival signaling in cultured hippocampal neurons is mediated through TRKA and requires the common neurotrophin receptor P75. Neuroscience 2002; 115: 1089-1108. (Pubitemid 35351700)
102. Kajimoto T, Okada T, Yu H, et al. Involvement of sphingosine-1-phosphate in glutamate secretion in hippocampal neurons. Mol Cell Biol 2007; 27: 3429-3440. (Pubitemid 46685218)
103. Deogracias R, Klein C, Matsumoto T, et al. Expression of brain-derived neurotrophic factor is regulated by fingolimod (FTY720) in cultured neurons (P728). Mult Scler 2008; 14 (suppl 1): S243.
104. Kataoka H, Sugahara K, Shimano K, et al. FTY720, sphingosine 1-phosphate receptor modulator, ameliorates experimental autoimmune encephalomyelitis by inhibition of T cell infiltration. Cell Mol Immunol 2005; 2: 439-448.
105. Balatoni B, Storch MK, Swoboda E-M, et al. FTY720 sustains and restores neuronal function in the DA rat model of MOG-induced experimental autoimmune encephalomyelitis. Brain Res Bull 2007; 74: 307-316. (Pubitemid 47368881)
106. Pryce G, Al-Izki S, Baker D, Giovannoni G,. Control of chronic relapsing progressive EAE with fingolimod (P01.092). Neurology 2008; 70 (suppl 1): A29.
107. Papadopoulos D, Rundle J, Patel R, et al. FTY720 ameliorates MOG-induced experimental autoimmune encephalomyelitis by suppressing both cellular and humoral immune responses. J Neurosci Res 2010; 88: 346-359.
108. Webb M, Tham C-S, Lin F-F, et al. Sphingosine 1-phosphate receptor agonists attenuate relapsing-remitting experimental autoimmune encephalitis in SJL mice. J Neuroimmunol 2004; 153: 108-121. (Pubitemid 38950933)
109. Schubart AS, Howard L, Seabrook T, et al. FTY720 suppresses ongoing EAE and promotes a remyelinating environment preventing axonal degeneration within the CNS (P06.166). Neurology 2008; 70 (suppl 1): A339.
110. Rossi S, De Chiara V, Motta C, et al. Fingolimod treatment prevents the clinical, synaptic and dendritic abnormalities of experimental autoimmune encephalomyelitis (P880). Mult Scler 2010; 16 (suppl 10): S309-S310.
111. Schubart A, Seabrook T, Rausch M, et al. CNS mediated effects of FTY720 (fingolimod) (P07.101). Neurology 2007; 68 (suppl 1): A315.
112. Anthony DC, Sibson NR, Leppert D, Piani Meier D,. Fingolimod (FTY720) therapy reduces demyelination and microglial activation in a focal delayed-type hypersensitivity model of multiple sclerosis during the remission phase (P814). Mult Scler 2010; 16 (suppl 10): S283-S284.
113. Zhang Z, Zhang Z, Fauser U, et al. FTY720 attenuates accumulation of EMAP-II+ and MHC-II+ monocytes in early lesions of rat traumatic brain injury. J Cell Mol Med 2007; 11: 307-314. (Pubitemid 46693329)
114. Zhang J, Zhang A, Sun Y, et al. Treatment with immunosuppressants FTY720 and tacrolimus promotes functional recovery after spinal cord injury in rats. Tohoku J Exp Med 2009; 219: 295-302.
115. Collins W, Cohen J, O'Connor P, et al. Long-term safety of oral fingolimod (FTY720) in relapsing multiple sclerosis: integrated analyses of phase 1 and 3 studies (P843). Mult Scler 2010; 16 (suppl 10): S295.
116. NDA 02257-FDA approved labeling text for Gilenya (fingolimod) capsules. September 21, 2010. Available at:. Accessed March 23, 2011.
117. Peters SLM, Alewijnse AE,. Sphingosine-1-phosphate signaling in the cardiovascular system. Curr Opin Pharmacol 2007; 7: 186-192. (Pubitemid 46404742)
118. Mazurais D, Roberts P, Gout B, et al. Cell type-specific localization of human cardiac S1P receptors. J Histochem Cytochem 2002; 50: 661-669. (Pubitemid 34437559)
119. Liliom K, Sun G, Bunemann M, et al. Sphingosylphosphocholine is a naturally occurring lipid mediator in blood plasma: a possible role in regulating cardiac function via sphingolipid receptors. Biochem J 2001; 355: 189-197. (Pubitemid 32304249)
120. Koyrakh L, Roman MI, Brinkmann V, Wickman K,. The heart rate decrease caused by acute FTY720 administration is mediated by the G protein-gated potassium channel IKACh. Am J Transplant 2005; 5: 529-536. (Pubitemid 40313344)
121. Forrest M, Sun S-Y, Hajdu R, et al. Immune cell regulation and cardiovascular effects of sphingosine 1-phosphate receptor agonists in rodents are mediated by distinct receptor subtypes. J Pharmacol Exp Ther 2004; 309: 758-768. (Pubitemid 38542632)
122. Gergely P, Wallstrom E, Nuesslein-Hildesheim B, et al. Phase I study with the selective S1P1/S1P5 receptor modulator BAF312 indicates that S1P1 rather than S1P3 mediates transient heart rate reduction in humans (P437). Mult Scler 2009; 15 (suppl 2): S125-S126.
123. Schmouder R, Serra D, Wang Y, et al. FTY720: placebo-controlled study of the effect on cardiac rate and rhythm in healthy subjects. J Clin Pharmacol 2006; 46: 895-904. (Pubitemid 44050826)
124. DiMarco JP, O'Connor P, Cohen JA, et al. First-dose effect of fingolimod: pooled safety data from two phase 3 studies (TRANSFORMS and FREEDOMS) (P830). Mult Scler 2010; 16 (suppl 10): S290.
125. Liu Y, Wada R, Yamashita T, et al. Edg-1, the G protein-coupled receptor for sphingosine-1-phosphate, is essential for vascular maturation. J Clin Invest 2000; 106: 951-961.
126. Chae S-S, Proia RL, Hla T,. Constitutive expression of the S1P1 receptor in adult tissues. Prostaglandins Other Lipid Mediat 2004; 73: 141-150. (Pubitemid 38446477)
127. Singer II, Tian M, Wickham LA, et al. Sphingosine-1-phosphate agonists increase macrophage homing, lymphocyte contacts, and endothelial junctional complex formation in murine lymph nodes. J Immunol 2005; 175: 7151-7161. (Pubitemid 41713408)
128. Brinkmann V, Cyster JG, Hla T,. FTY720: sphingosine 1-phosphate receptor-1 in the control of lymphocyte egress and endothelial barrier function. Am J Transplant 2004; 4: 1019-1025. (Pubitemid 38868590)
129. McVerry BJ, Garcia GN,. Endothelial cell barrier regulation by sphingosine 1-phosphate. J Cell Biochem 2004; 92: 1075-1085. (Pubitemid 44264219)
130. Brinkmann V, Baumruker T,. Pulmonary and vascular pharmacology of sphingosine 1-phosphate. Curr Opin Pharmacol 2006; 6: 244-250. (Pubitemid 44274746)
131. Marsolais D, Rosen H,. Chemical modulators of sphingosine-1-phosphate receptors as barrier-oriented therapeutic molecules. Nat Rev Drug Discov 2009; 8: 297-307.
132. Salomone S, Yoshimura S-i, Reuter U, et al. S1P3 receptors mediate the potent constriction of cerebral arteries by sphingosine 1-phosphate. Eur J Pharmacol 2003; 469: 125-134. (Pubitemid 36629558)
133. Rosen H, Goetzl EJ,. Sphingosine 1-phosphate and its receptors: an autocrine and paracrine network. Nat Rev Immunol 2005; 5: 560-570. (Pubitemid 40961333)
134. Tolle M, Levkau B, Keul P, et al. Immunomodulator FTY720 induces eNOS-dependent arterial vasodilatation via the lysophospholipid receptor S1P3. Circ Res 2005; 96: 913-920. (Pubitemid 40604976)
135. Cohen JA,. Online supplement to: Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis. N Engl J Med 2010; 362: 402-415.
136. Pfaff M, Powaga N, Akinci S, et al. Activation of the SPHK/S1P signalling pathway is coupled to muscarinic receptor-mediated regulation of peripheral airways. Respir Res 2005; 6: 48.
137. Kume H, Takeda N, Oguma T, et al. Sphingosine 1-phosphate causes airway hyper-reactivity by rho-mediated myosin phosphatase inactivation. J Pharmacol Exp Ther 2007; 320: 766-773. (Pubitemid 46147958)
138. Roviezzo F, Di Lorenzo A, Bucci M, et al. Sphingosine-1-phosphate/ sphingosine kinase pathway is involved in mouse airway hyperresponsiveness. Am J Respir Cell Mol Biol 2007; 36: 757-762. (Pubitemid 46871431)
139. Pinschewer DD, Ochsenbein AF, Odermatt B, et al. FTY720 immunosuppression impairs effector T cell peripheral homing without affecting induction, expansion, and memory. J Immunol 2000; 164: 5761-5770. (Pubitemid 30389819)
140. Schmouder R, Boulton C, Wang N, David OJ,. Effects of fingolimod on antibody response following steady-state dosing in healthy volunteers: a 4-week randomised, placebo-controlled study (P412). Mult Scler 2010; 16 (suppl 10): S135.
141. Novartis. FTY720 in patients with primary progressive multiple sclerosis (INFORMS). ClinicalTrials.gov Identifier: NCT00731692. Available at:. Accessed March 23, 2011.
142. Khatri B, Barkhof F, Comi G, et al. 24-month efficacy and safety from the TRANSFORMS extension study of oral fingolimod (FTY720) in patients with relapsing-remitting multiple sclerosis(P03.125). Neurology 2010; 74 (suppl 2): A239.
143. Calabresi PA, Goodin D, Jeffery D, et al. Oral fingolimod (FTY720) in relapsing-remitting multiple sclerosis: baseline patient demographics and disease characteristics from a 2-year phase III trial (FREEDOMS II) (P05.038). Neurology 2010; 74 (suppl 2): A416-A417.
144. Novartis. Efficacy and safety of fingolimod (FTY720) in patients with relapsing-remitting multiple sclerosis (FREEDOMS II). ClinicalTrials.gov Identifier: NCT00355134. Available at:. Accessed March 23, 2011.
145. Novartis and Mitsubishi Tanabe Pharma. Efficacy and safety of FTY720 in patients with relapsing multiple sclerosis (MS). ClinicalTrials.gov Identifier: NCT00537082. Available at:. Accessed March 23, 2011.
146. Vogel P, Donoviel MS, Read R, et al. Incomplete inhibition of sphingosine 1-phosphate lyase modulates immune system function yet prevents early lethality and non-lymphoid lesions. PLoS ONE 2009; 4: e4112.
147. Lin CI, Chen CN, Lin PW, Lee H,. Sphingosine 1-phosphate regulates inflammation-related genes in human endothelial cells through S1P1 and S1P3.
148. Saini HS, Coelho RP, Goparaju SK, et al. Novel role of sphingosine kinase 1 as a mediator of neurotrophin-3 action in oligodendrocyte progenitors. J Neurochem 2005; 95: 1298-1310. (Pubitemid 41779255)