Mechanism of Action of Oral Fingolimod (FTY720) in Multiple Sclerosis

Clinical Neuropharmacology - Tập 33 Số 2 - Trang 91-101 - 2010
Jerold Chun1, Hans‐Peter Hartung2
1Department of Molecular Biology, Helen L. Dorris Child and Adolescent Neuropsychiatric Disorder Institute, The Scripps Research Institute, La Jolla, CA
2Department of Neurology, Heinrich Heine University, Düsseldorf, Germany

Tóm tắt

Từ khóa


Tài liệu tham khảo

Confavreux, 2006, Accumulation of irreversible disability in multiple sclerosis: from epidemiology to treatment., Clin Neurol Neurosurg, 108, 327, 10.1016/j.clineuro.2005.11.018

Noseworthy, 2000, Multiple sclerosis., N Engl J Med, 343, 938, 10.1056/NEJM200009283431307

Dev, 2008, Brain sphingosine-1-phosphate receptors: implication for FTY720 in the treatment of multiple sclerosis., Pharmacol Ther, 117, 77, 10.1016/j.pharmthera.2007.08.005

Frohman, 2006, Multiple sclerosis-the plaque and its pathogenesis., N Engl J Med, 354, 942, 10.1056/NEJMra052130

Odoardi, 2007, Blood-borne soluble protein antigen intensifies T cell activation in autoimmune CNS lesions and exacerbates clinical disease., Proc Natl Acad Sci U S A, 104, 18625, 10.1073/pnas.0705033104

Trapp, 1998, Axonal transection in the lesions of multiple sclerosis., N Engl J Med, 338, 278, 10.1056/NEJM199801293380502

Peterson, 2007, Inflammation, demyelination, neurodegeneration and neuroprotection in the pathogenesis of multiple sclerosis., J Neuroimmunol, 184, 37, 10.1016/j.jneuroim.2006.11.015

Compston, 2002, Multiple sclerosis., Lancet, 359, 1221, 10.1016/S0140-6736(02)08220-X

Frohman, 2005, Characterizing the mechanisms of progression in multiple sclerosis: evidence and new hypotheses for future directions., Arch Neurol, 62, 1345, 10.1001/archneur.62.9.1345

Kerschensteiner, 2004, Remodeling of axonal connections contributes to recovery in an animal model of multiple sclerosis., J Exp Med, 200, 1027, 10.1084/jem.20040452

Hemmer, 2007, Toward the development of rational therapies in multiple sclerosis: what is on the horizon?, Ann Neurol, 62, 314, 10.1002/ana.21289

Virley, 2005, Developing therapeutics for the treatment of multiple sclerosis., NeuroRx, 2, 638, 10.1602/neurorx.2.4.638

Goodin, 2002, Disease modifying therapies in multiple sclerosis: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and the MS Council for Clinical Practice Guidelines., Neurology, 58, 169, 10.1212/WNL.58.2.169

Miller, 2007, Primary-progressive multiple sclerosis., Lancet Neurol, 6, 903, 10.1016/S1474-4422(07)70243-0

Polman, 2006, A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis., N Engl J Med, 354, 899, 10.1056/NEJMoa044397

Kleinschmidt-DeMasters, 2005, Progressive multifocal leukoencephalopathy complicating treatment with natalizumab and interferon beta-1a for multiple sclerosis., N Engl J Med, 353, 369, 10.1056/NEJMoa051782

Langer-Gould, 2005, Progressive multifocal leukoencephalopathy in a patient treated with natalizumab., N Engl J Med, 353, 375, 10.1056/NEJMoa051847

Berger, 2005, Progressive multifocal leukoencephalopathy and natalizumab-unforeseen consequences., N Engl J Med, 353, 414, 10.1056/NEJMe058122

Samuel, 2006, Recurrent injection site reactions from interferon beta 1-b., J Drugs Dermatol, 5, 366

Cox, 2006, Managing self-injection difficulties in patients with relapsing-remitting multiple sclerosis., J Neurosci Nurs, 38, 167, 10.1097/01376517-200606000-00005

Cohen, 2007, Emerging oral therapies for multiple sclerosis., Int J Clin Pract, 61, 1922, 10.1111/j.1742-1241.2007.01561..x

Baumruker, 2007, FTY720, an immunomodulatory sphingolipid mimetic: translation of a novel mechanism into clinical benefit in multiple sclerosis., Expert Opin Investig Drugs, 16, 283, 10.1517/13543784.16.3.283

Adachi, 2007, FTY720 story. Its discovery and the following accelerated development of sphingosine 1-phosphate receptor agonists as immunomodulators based on reverse pharmacology., Perspect Medicin Chem, 1, 11, 10.1177/1177391X0700100002

Kappos, 2006, Oral fingolimod (FTY720) for relapsing multiple sclerosis., N Engl J Med, 355, 1124, 10.1056/NEJMoa052643

Spiegel, 2003, Sphingosine-1-phosphate: an enigmatic signalling lipid., Nat Rev Mol Cell Biol, 4, 397, 10.1038/nrm1103

Fukushima, 2001, Lysophospholipid receptors., Annu Rev Pharmacol Toxicol, 41, 507, 10.1146/annurev.pharmtox.41.1.507

Anliker, 2004, Lysophospholipid G protein-coupled receptors., J Biol Chem, 279, 20555, 10.1074/jbc.R400013200

Ishii, 2004, Lysophospholipid receptors: signaling and biology., Annu Rev Biochem, 73, 321, 10.1146/annurev.biochem.73.011303.073731

Chun, 2007, How the lysophospholipid got its receptor., Scientist, 21, 48

Chun, 2007, Immunology. The sources of a lipid conundrum., Science, 316, 208, 10.1126/science.1142239

Mandala, 2002, Alteration of lymphocyte trafficking by sphingosine-1-phosphate receptor agonists., Science, 296, 346, 10.1126/science.1070238

Brinkmann, 2007, Sphingosine 1-phosphate receptors in health and disease: mechanistic insights from gene deletion studies and reverse pharmacology., Pharmacol Ther, 115, 84, 10.1016/j.pharmthera.2007.04.006

Brinkmann, 2004, FTY720: sphingosine 1-phosphate receptor-1 in the control of lymphocyte egress and endothelial barrier function., Am J Transplant, 4, 1019, 10.1111/j.1600-6143.2004.00476.x

Toman, 2004, Differential transactivation of sphingosine-1-phosphate receptors modulates NGF-induced neurite extension., J Cell Biol, 166, 381, 10.1083/jcb.200402016

Pyne, 2000, Sphingosine 1-phosphate signalling via the endothelial differentiation gene family of G-protein-coupled receptors., Pharmacol Ther, 88, 115, 10.1016/S0163-7258(00)00084-X

Pyne, 2000, Sphingosine 1-phosphate signalling in mammalian cells., Biochem J, 349, 385, 10.1042/bj3490385

Pappu, 2007, Promotion of lymphocyte egress into blood and lymph by distinct sources of sphingosine-1-phosphate., Science, 316, 295, 10.1126/science.1139221

Gardell, 2006, Emerging medicinal roles for lysophospholipid signaling., Trends Mol Med, 12, 65, 10.1016/j.molmed.2005.12.001

Herr, 2007, Effects of LPA and S1P on the nervous system and implications for their involvement in disease., Curr Drug Targets, 8, 155, 10.2174/138945007779315669

Gardell, 2007, Evidence for neural S1P receptor signaling in EAE and FTY720 efficacy., Mult Scler, 13, S70

Webb, 2004, Sphingosine 1-phosphate receptor agonists attenuate relapsing-remitting experimental autoimmune encephalitis in SJL mice., J Neuroimmunol, 153, 108, 10.1016/j.jneuroim.2004.04.015

Wheeler, 2008, A defect of sphingolipid metabolism modifies the properties of normal appearing white matter in multiple sclerosis., Brain, 131, 3092, 10.1093/brain/awn190

Zhang, 1999, Comparative analysis of three murine G-protein coupled receptors activated by sphingosine-1-phosphate., Gene, 227, 89, 10.1016/S0378-1119(98)00589-7

Sanchez, 2004, Structural and functional characteristics of S1P receptors., J Cell Biochem, 92, 913, 10.1002/jcb.20127

Chun, 1999, Lysophospholipid receptors: implications for neural signaling., Crit Rev Neurobiol, 13, 151, 10.1615/CritRevNeurobiol.v13.i2.20

Chun, 1999, A growing family of receptor genes for lysophosphatidic acid (LPA) and other lysophospholipids (LPs)., Cell Biochem Biophys, 30, 213, 10.1007/BF02738068

Chun, 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, 10.1111/j.1749-6632.2000.tb06543.x

Chun, 2005, Lysophospholipids in the nervous system., Prostaglandins Other Lipid Mediat, 77, 46, 10.1016/j.prostaglandins.2004.09.009

Mutoh, 2008, Lysophospholipid activation of G protein-coupled receptors., Subcell Biochem, 49, 269, 10.1007/978-1-4020-8831-5_10

Rivera, 2008, Biological effects of lysophospholipids., Rev Physiol Biochem Pharmacol, 160, 25

Watterson, 2003, Pleiotropic actions of sphingosine-1-phosphate., Prog Lipid Res, 42, 344, 10.1016/S0163-7827(03)00015-8

Miron, 2008, FTY720 modulates human oligodendrocyte progenitor process extension and survival., Ann Neurol, 63, 61, 10.1002/ana.21227

Matloubian, 2004, Lymphocyte egress from thymus and peripheral lymphoid organs is dependent on S1P receptor 1., Nature, 427, 355, 10.1038/nature02284

Jaillard, 2005, Edg8/S1P5: an oligodendroglial receptor with dual function on process retraction and cell survival., J Neurosci, 25, 1459, 10.1523/JNEUROSCI.4645-04.2005

Kimura, 2007, 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, 25, 115, 10.1634/stemcells.2006-0223

Schwab, 2007, Finding a way out: lymphocyte egress from lymphoid organs., Nat Immunol, 8, 1295, 10.1038/ni1545

Mizugishi, 2005, Essential role for sphingosine kinases in neural and vascular development., Mol Cell Biol, 25, 11113, 10.1128/MCB.25.24.11113-11121.2005

de Sampaio, 2008, Lysophosphatidic acid receptor-dependent secondary effects via astrocytes promote neuronal differentiation., J Biol Chem, 283, 7470, 10.1074/jbc.M707758200

Gergely, 2009, Phase I study with the selective S1P1/S1P5 receptor modulator BAF312 indicates that S1P1 rather than S1P3 mediates transient heart rate reduction in humans., Mult Scler, 15, S125

Brinkmann, 2006, Pulmonary and vascular pharmacology of sphingosine 1-phosphate., Curr Opin Pharmacol, 6, 244, 10.1016/j.coph.2005.12.004

Nofer, 2007, FTY720, a synthetic sphingosine 1 phosphate analogue, inhibits development of atherosclerosis in low-density lipoprotein receptor-deficient mice., Circulation, 115, 501, 10.1161/CIRCULATIONAHA.106.641407

Billich, 2003, Phosphorylation of the immunomodulatory drug FTY720 by sphingosine kinases., J Biol Chem, 278, 47408, 10.1074/jbc.M307687200

Brinkmann, 2002, The immune modulator FTY720 targets sphingosine 1-phosphate receptors., J Biol Chem, 277, 21453, 10.1074/jbc.C200176200

Pinschewer, 2000, FTY720 immunosuppression impairs effector T cell peripheral homing without affecting induction, expansion, and memory., J Immunol, 164, 5761, 10.4049/jimmunol.164.11.5761

Mehling, 2008, FTY720 therapy exerts differential effects on T cell subsets in multiple sclerosis., Neurology, 71, 1261, 10.1212/01.wnl.0000327609.57688.ea

Mehling, 2008, Oral fingolimod (FTY720) treatment reduces peripheral IL-17-producing TH17 cells in patients with multiple sclerosis., Mult Scler, 14, S234

Oo, 2007, Immunosuppressive and anti-angiogenic sphingosine 1-phosphate receptor-1 agonists induce ubiquitinylation and proteasomal degradation of the receptor., J Biol Chem, 282, 9082, 10.1074/jbc.M610318200

Graler, 2004, The immunosuppressant FTY720 down-regulates sphingosine 1-phosphate G-protein-coupled receptors., FASEB J, 18, 551, 10.1096/fj.03-0910fje

Fujino, 2003, Amelioration of experimental autoimmune encephalomyelitis in Lewis rats by FTY720 treatment., J Pharmacol Exp Ther, 305, 70, 10.1124/jpet.102.045658

Brinkmann, 2006, The mode of action of fingolimod (FTY720), an oral sphingosine 1-phosphate receptor modulator that is highly effective in human multiple sclerosis (phase II)., Mult Scler, 12, S100

Tzartos, 2008, Interleukin-17 production in central nervous system-infiltrating T cells and glial cells is associated with active disease in multiple sclerosis., Am J Pathol, 172, 146, 10.2353/ajpath.2008.070690

Kebir, 2007, Human TH17 lymphocytes promote blood-brain barrier disruption and central nervous system inflammation., Nat Med, 13, 1173, 10.1038/nm1651

Masopust, 2001, Preferential localization of effector memory cells in nonlymphoid tissue., Science, 291, 2413, 10.1126/science.1058867

Sallusto, 1999, Two subsets of memory T lymphocytes with distinct homing potentials and effector functions., Nature, 401, 708, 10.1038/44385

Sallusto, 2004, Central memory and effector memory T cell subsets: function, generation, and maintenance., Annu Rev Immunol, 22, 745, 10.1146/annurev.immunol.22.012703.104702

Schluns, 2003, Cytokine control of memory T-cell development and survival., Nat Rev Immunol, 3, 269, 10.1038/nri1052

Hofmann, 2006, FTY720 preferentially depletes naive T cells from peripheral and lymphoid organs., Int Immunopharmacol, 6, 1902, 10.1016/j.intimp.2006.07.030

Schmouder, 2006, Pharmacodynamic effects of oral fingolimod (FTY720)., Mult Scler, 12, S101

Westermann, 1992, Distribution of lymphocyte subsets and natural killer cells in the human body., Clin Investig, 70, 539, 10.1007/BF00184787

Brinkmann, 2001, FTY720 alters lymphocyte homing and protects allografts without inducing general immunosuppression., Transplant Proc, 33, 530, 10.1016/S0041-1345(00)02126-6

Xie, 2003, Sphingosine-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, 170, 3662, 10.4049/jimmunol.170.7.3662

Metzler, 2008, Modulation of T cell homeostasis and alloreactivity under continuous FTY720 exposure., Int Immunol, 20, 633, 10.1093/intimm/dxn023

Kappos, 2006, Oral fingolimod (FTY720) in relapsing ms: 24-month results of the phase II study., Mult Scler, 12, S101

Yopp, 2004, FTY720-enhanced T cell homing is dependent on CCR2, CCR5, CCR7, and CXCR4: evidence for distinct chemokine compartments., J Immunol, 173, 855, 10.4049/jimmunol.173.2.855

Kursar, 2008, Requirement of secondary lymphoid tissues for the induction of primary and secondary T cell responses against Listeria monocytogenes., Eur J Immunol, 38, 127, 10.1002/eji.200737142

Foster, 2007, Brain penetration of the oral immunomodulatory drug FTY720 and its phosphorylation in the CNS during experimental autoimmune encephalomyelitis: consequences for mode of action in multiple sclerosis., J Pharmacol Exp Ther, 323, 469, 10.1124/jpet.107.127183

Birgbauer, 2006, New developments in the biological functions of lysophospholipids., Cell Mol Life Sci, 63, 2695, 10.1007/s00018-006-6155-y

Chun, 2006, Lysophospholipid receptors as potential drug targets in tissue transplantation and autoimmune diseases., Curr Pharm Des, 12, 161, 10.2174/138161206775193109

McGiffert, 2002, Embryonic brain expression analysis of lysophospholipid receptor genes suggests roles for s1p(1) in neurogenesis and s1p(1-3) in angiogenesis., FEBS Lett, 531, 103, 10.1016/S0014-5793(02)03404-X

Herr, 2007, Sphingosine 1-phosphate (S1P) signaling is required for maintenance of hair cells mainly via activation of S1P2., J Neurosci, 27, 1474, 10.1523/JNEUROSCI.4245-06.2007

Miron, 2008, Central nervous system-directed effects of FTY720 (fingolimod)., J Neurol Sci, 274, 13, 10.1016/j.jns.2008.06.031

Saini, 2005, Novel role of sphingosine kinase 1 as a mediator of neurotrophin-3 action in oligodendrocyte progenitors., J Neurochem, 95, 1298, 10.1111/j.1471-4159.2005.03451.x

Novgorodov, 2007, Activation of sphingosine-1-phosphate receptor S1P5 inhibits oligodendrocyte progenitor migration., FASEB J, 21, 1503, 10.1096/fj.06-7420com

Barske, 2007, FTY720 (fingolimod) enhances the number of progenitor and mature oligodendrocytes., Mult Scler, 13, S148

Coelho, 2007, The immunomodulator FTY720 has a direct cytoprotective effect in oligodendrocyte progenitors., J Pharmacol Exp Ther, 323, 626, 10.1124/jpet.107.123927

Harada, 2004, Sphingosine-1-phosphate induces proliferation and morphological changes of neural progenitor cells., J Neurochem, 88, 1026, 10.1046/j.1471-4159.2003.02219.x

Edsall, 1997, Involvement of sphingosine 1-phosphate in nerve growth factor-mediated neuronal survival and differentiation., J Neurosci, 17, 6952, 10.1523/JNEUROSCI.17-18-06952.1997

Chin, 2002, Distinct effects of different calcium-mobilizing agents on cell death in NG108-15 neuroblastoma X glioma cells., Mol Pharmacol, 61, 486, 10.1124/mol.61.3.486

Shinpo, 1999, Protective effects of the TNF-ceramide pathway against glutamate neurotoxicity on cultured mesencephalic neurons., Brain Res, 819, 170, 10.1016/S0006-8993(98)01354-7

Deogracias, 2008, FTY720 induces BDNF production in neuronal cell cultures., Neurology, 70, A373

Balatoni, 2007, FTY720 sustains and restores neuronal function in the DA rat model of MOG-induced experimental autoimmune encephalomyelitis., Brain Res Bull, 74, 307, 10.1016/j.brainresbull.2007.06.023

Deogracias, 2008, Expression of brain-derived neutrophic factor is regulated by FTY720 in cultured neurons., Mult Scler, 14, S243

Nair, 2008, Astrocytes in multiple sclerosis: a product of their environment., Cell Mol Life Sci, 65, 2702, 10.1007/s00018-008-8059-5

Pekny, 2005, Astrocyte activation and reactive gliosis., Glia, 50, 427, 10.1002/glia.20207

Sorensen, 2003, Common signaling pathways link activation of murine PAR-1, LPA, and S1P receptors to proliferation of astrocytes., Mol Pharmacol, 64, 1199, 10.1124/mol.64.5.1199

Rao, 2003, Pharmacological characterization of lysophospholipid receptor signal transduction pathways in rat cerebrocortical astrocytes., Brain Res, 990, 182, 10.1016/S0006-8993(03)03527-3

Mullershausen, 2007, Phosphorylated FTY720 promotes astrocyte migration through sphingosine-1-phosphate receptors., J Neurochem, 102, 1151, 10.1111/j.1471-4159.2007.04629.x

Rao, 2004, 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, 22, 131, 10.1016/j.ijdevneu.2004.03.005

Yamagata, 2003, Sphingosine 1-phosphate induces the production of glial cell line-derived neurotrophic factor and cellular proliferation in astrocytes., Glia, 41, 199, 10.1002/glia.10180

Osinde, 2007, Phosphorylated FTY720 stimulates ERK phosphorylation in astrocytes via S1P receptors., Neuropharmacology, 52, 1210, 10.1016/j.neuropharm.2006.11.010

Kappos, 2009, Safety findings from a 12-month phase III study (TRANSFORMS) comparing oral fingolimod (FTY720) and intramuscular interferon beta-1a for relapsing-remitting multiple sclerosis., Mult Scler, 15, S245

Cohen, 2009, Oral fingolimod (FTY720) significantly reduced relapse rate compared with intramuscular interferon beta-1a in relapsing-remitting multiple sclerosis: clinical results from a 12-month phase III study (TRANSFORMS)., Mult Scler, 15, S132

Barkhof, 2009, Oral fingolimod (FTY720) significantly reduced MRI inflammatory activity compared with intramuscular interferon beta-1a in relapsing-remitting multiple sclerosis: MRI findings from a 12-month phase III study (TRANSFORMS)., Mult Scler, 15, S21

Kataoka, 2005, FTY720, sphingosine 1-phosphate receptor modulator, ameliorates experimental autoimmune encephalomyelitis by inhibition of T cell infiltration., Cell Mol Immunol, 2, 439

Foster, 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, 10.1111/j.1750-3639.2008.00182.x

Schubart, 2008, FTY720 suppresses ongoing EAE and promotes a remyelinating environment preventing axonal degeneration within the CNS., Neurology, 70, A339

Montalban, 2009, Oral fingolimod (FTY720) shows sustained low rates of clinical and MRI disease activity in patients with relapsing multiple sclerosis: 4-year results from a phase II extension., Neurology, 72, A313

Koyrakh, 2005, The heart rate decrease caused by acute FTY720 administration is mediated by the G protein-gated potassium channel I., Am J Transplant, 5, 529, 10.1111/j.1600-6143.2005.00754.x

Choi, 2008, Biological roles of lysophospholipid receptors revealed by genetic null mice: an update., Biochim Biophys Acta, 1781, 531, 10.1016/j.bbalip.2008.03.004