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Central nervous system-directed effects of FTY720 (fingolimod)

      Abstract

      FTY720, also known as fingolimod, is an orally administered sphingosine-1-phosphate (S1P) analogue that is under investigation as a therapy for both relapsing–remitting (RR) and progressive forms of multiple sclerosis (MS). The demonstrated beneficial effect of FTY720 on disease activity in RR–MS patients and in the animal model experimental autoimmune encephalomyelitis (EAE) is largely attributed to effects on the systemic immune system. In addition, unlike other current systemic immuno-modulators used in MS, the lipophilic nature of FTY720 allows it to cross the blood-brain barrier (BBB). Since S1P receptors are expressed on all cell types, FTY720 has the potential to exert effects directly on the BBB and on resident cells of the CNS. The latter include cells implicated in regulating immune reactivity within the CNS (astrocytes, microglia), those that are targeted by the disease process (oligodendrocytes, neurons), and those involved in repair (oligodendrocyte progenitor cells). In vitro studies document the dose-dependent effects of FTY720 on neural cell survival, differentiation, and cytoskeletal dynamics. Animal model studies, specifically EAE, indicate an overall neuroprotective effect of FTY720 mediated at least in part by its actions within the CNS. Ongoing studies will need to define the direct and indirect (via immune-modulation) effects of FTY720 on the CNS across the broad clinical spectrum of MS.

      Keywords

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      References

        • Kappos L.
        • Antel J.
        • Comi G.
        • Montalban X.
        • O'Connor P.
        • Polman C.H.
        • Haas T.
        • Korn A.A.
        • Karlsson G.
        • Radue E.W.
        Oral fingolimod (FTY720) for relapsing multiple sclerosis.
        N Engl J Med. 2006; 355: 1124-1140
        • Graler M.H.
        • Goetzl E.J.
        The immunosuppressant FTY720 down-regulates sphingosine 1-phosphate G-protein-coupled receptors.
        FASEB J. 2004; 18: 551-553
        • Sanchez T.
        • Hla T.
        Structural and functional characteristics of S1P receptors.
        J Cell Biochem. 2004; 92: 913-922
        • Chun J.
        • Weiner J.A.
        • Fukushima N.
        • Contos J.J.
        • Zhang G.
        • Kimura Y.
        • Dubin A.
        • Ishii I.
        • Hecht J.H.
        • Akita C.
        • Kaushal D.
        Neurobiology of receptor-mediated lysophospholipid signaling. From the first lysophospholipid receptor to roles in nervous system function and development.
        Ann NY Acad Sci. 2000; 905: 110-117
        • 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: 295-298
        • Goetzl E.J.
        • Rosen H.
        Regulation of immunity by lysosphingolipids and their G protein-coupled receptors.
        J Clin Invest. 2004; 114: 1531-1537
        • Anelli V.
        • Bassi R.
        • Tettamanti G.
        • Viani P.
        • Riboni L.
        Extracellular release of newly synthesized sphingosine-1-phosphate by cerebellar granule cells and astrocytes.
        J Neurochem. 2005; 92: 1204-1215
        • Singleton P.A.
        • Moreno-Vinasco L.
        • Sammani S.
        • Wanderling S.L.
        • Moss J.
        • Garcia J.G.
        Attenuation of vascular permeability by methylnaltrexone: role of mOP-R and S1P3 transactivation.
        Am J Respir Cell Mol Biol. 2007; 37: 222-231
        • Bassi R.
        • Anelli V.
        • Giussani P.
        • Tettamanti G.
        • Viani P.
        • Riboni L.
        Sphingosine-1-phosphate is released by cerebellar astrocytes in response to bFGF and induces astrocyte proliferation through Gi-protein-coupled receptors.
        Glia. 2006; 53: 621-630
        • Kajimoto T.
        • Okada T.
        • Yu H.
        • Goparaju S.K.
        • Jahangeer S.
        • Nakamura S.
        Involvement of sphingosine-1-phosphate in glutamate secretion in hippocampal neurons.
        Mol Cell Biol. 2007; 27: 3429-3440
        • Yamagata K.
        • Tagami M.
        • Torii Y.
        • Takenaga F.
        • Tsumagari S.
        • Itoh S.
        • Yamori Y.
        • Nara Y.
        Sphingosine 1-phosphate induces the production of glial cell line-derived neurotrophic factor and cellular proliferation in astrocytes.
        Glia. 2003; 41: 199-206
        • Mechtcheriakova D.
        • Wlachos A.
        • Sobanov J.
        • Kopp T.
        • Reuschel R.
        • Bornancin F.
        • Cai R.
        • Zemann B.
        • Urtz N.
        • Stingl G.
        • Zlabinger G.
        • Woisetschlager M.
        • Baumruker T.
        • Billich A.
        Sphingosine 1-phosphate phosphatase 2 is induced during inflammatory responses.
        Cell Signal. 2007; 19: 748-760
        • Blondeau N.
        • Lai Y.
        • Tyndall S.
        • Popolo M.
        • Topalkara K.
        • Pru J.K.
        • Zhang L.
        • Kim H.
        • Liao J.K.
        • Ding K.
        • Waeber C.
        Distribution of sphingosine kinase activity and mRNA in rodent brain.
        J Neurochem. 2007; 103: 509-517
        • 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: 115-124
        • Beer M.S.
        • Stanton J.A.
        • Salim K.
        • Rigby M.
        • Heavens R.P.
        • Smith D.
        • McAllister G.
        EDG receptors as a therapeutic target in the nervous system.
        Ann NY Acad Sci. 2000; 905: 118-131
        • Brinkmann V.
        • Davis M.D.
        • Heise C.E.
        • Albert R.
        • Cottens S.
        • Hof R.
        • Bruns C.
        • Prieschl E.
        • Baumruker T.
        • Hiestand P.
        • Foster C.A.
        • Zollinger M.
        • Lynch K.R.
        The immune modulator FTY720 targets sphingosine 1-phosphate receptors.
        J Biol Chem. 2002; 277: 21453-21457
        • Billich A.
        • Bornancin F.
        • Devay P.
        • Mechtcheriakova D.
        • Urtz N.
        • Baumruker T.
        Phosphorylation of the immunomodulatory drug FTY720 by sphingosine kinases.
        J Biol Chem. 2003; 278: 47408-47415
        • Zemann B.
        • Kinzel B.
        • Muller M.
        • Reuschel R.
        • Mechtcheriakova D.
        • Urtz N.
        • Bornancin F.
        • Baumruker T.
        • Billich A.
        Sphingosine kinase type 2 is essential for lymphopenia induced by the immunomodulatory drug FTY720.
        Blood. 2006; 107: 1454-1458
        • Jo E.
        • Sanna M.G.
        • Gonzalez-Cabrera P.J.
        • Thangada S.
        • Tigyi G.
        • Osborne D.A.
        • Hla T.
        • Parrill A.L.
        • Rosen H.
        S1P1-selective in vivo-active agonists from high-throughput screening: off-the-shelf chemical probes of receptor interactions, signaling, and fate.
        Chem Biol. 2005; 12: 703-715
        • Gonzalez-Cabrera P.J.
        • Hla T.
        • Rosen H.
        Mapping pathways downstream of sphingosine 1-phosphate subtype 1 by differential chemical perturbation and proteomics.
        J Biol Chem. 2007; 282: 7254-7264
        • Oo M.L.
        • Thangada S.
        • Wu M.T.
        • Liu C.H.
        • Macdonald T.L.
        • Lynch K.R.
        • Lin C.Y.
        • Hla T.
        Immunosuppressive and anti-angiogenic sphingosine 1-phosphate receptor-1 agonists induce ubiquitinylation and proteasomal degradation of the receptor.
        J Biol Chem. 2007; 282: 9082-9089
        • Gardell S.E.
        • Dubin A.E.
        • Chun J.
        Emerging medicinal roles for lysophospholipid signaling.
        Trends Mol Med. 2006; 12: 65-75
        • Sindern E.
        Role of chemokines and their receptors in the pathogenesis of multiple sclerosis.
        Front Biosci. 2004; 9: 457-463
        • Pyne S.
        • Pyne N.J.
        Sphingosine 1-phosphate signalling in mammalian cells.
        Biochem J. 2000; 349: 385-402
        • Singleton P.A.
        • Dudek S.M.
        • Ma S.F.
        • Garcia J.G.
        Transactivation of sphingosine 1-phosphate receptors is essential for vascular barrier regulation. Novel role for hyaluronan and CD44 receptor family.
        J Biol Chem. 2006; 281: 34381-34393
        • Butler J.
        • Lana D.
        • Round O.
        • LaMontagne K.
        Functional characterization of sphingosine 1-phosphate receptor agonist in human endothelial cells.
        Prostaglandins Other Lipid Mediat. 2004; 73: 29-45
        • Brinkmann V.
        • Cyster J.G.
        • 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
        • Lee J.F.
        • Zeng Q.
        • Ozaki H.
        • Wang L.
        • Hand A.R.
        • Hla T.
        • Wang E.
        • Lee M.J.
        Dual roles of tight junction-associated protein, zonula occludens-1, in sphingosine 1-phosphate-mediated endothelial chemotaxis and barrier integrity.
        J Biol Chem. 2006; 281: 29190-29200
        • Meno-Tetang G.M.
        • Li H.
        • Mis S.
        • Pyszczynski N.
        • Heining P.
        • Lowe P.
        • Jusko W.J.
        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
        • Foster C.A.
        • Howard L.M.
        • Schweitzer A.
        • Persohn E.
        • Hiestand P.C.
        • Balatoni B.
        • Reuschel R.
        • Beerli C.
        • Schwartz M.
        • Billich A.
        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
        • Mullershausen F.
        • Craveiro L.M.
        • Shin Y.
        • Cortes-Cros M.
        • Bassilana F.
        • Osinde M.
        • Wishart W.L.
        • Guerini D.
        • Thallmair M.
        • Schwab M.E.
        • Sivasankaran R.
        • Seuwen K.
        • Dev K.K.
        Phosphorylated FTY720 promotes astrocyte migration through sphingosine-1-phosphate receptors.
        J Neurochem. 2007; 102: 1151-1161
        • Terai K.
        • Soga T.
        • Takahashi M.
        • Kamohara M.
        • Ohno K.
        • Yatsugi S.
        • Okada M.
        • Yamaguchi T.
        Edg-8 receptors are preferentially expressed in oligodendrocyte lineage cells of the rat CNS.
        Neuroscience. 2003; 116: 1053-1062
        • 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: 1459-1469
        • Mizugishi K.
        • Yamashita T.
        • Olivera A.
        • Miller G.F.
        • Spiegel S.
        • Proia R.L.
        Essential role for sphingosine kinases in neural and vascular development.
        Mol Cell Biol. 2005; 25: 11113-11121
        • Sospedra M.
        • Martin R.
        Immunology of multiple sclerosis.
        Annu Rev Immunol. 2005; 23: 683-747
        • Pebay A.
        • Toutant M.
        • Premont J.
        • Calvo C.F.
        • Venance L.
        • Cordier J.
        • Glowinski J.
        • Tence M.
        Sphingosine-1-phosphate induces proliferation of astrocytes: regulation by intracellular signalling cascades.
        Eur J Neurosci. 2001; 13: 2067-2076
        • Sato K.
        • Tomura H.
        • Igarashi Y.
        • Ui M.
        • Okajima F.
        Possible involvement of cell surface receptors in sphingosine 1-phosphate-induced activation of extracellular signal-regulated kinase in C6 glioma cells.
        Mol Pharmacol. 1999; 55: 126-133
        • Osinde M.
        • Mullershausen F.
        • Dev K.K.
        Phosphorylated FTY720 stimulates ERK phosphorylation in astrocytes via S1P receptors.
        Neuropharmacology. 2007; 52: 1210-1218
        • Baumruker T.
        • Billich A.
        • Brinkmann V.
        FTY720, an immunomodulatory sphingolipid mimetic: translation of a novel mechanism into clinical benefit in multiple sclerosis.
        Expert Opin Investig Drugs. 2007; 16: 283-289
        • Streit W.J.
        Microglia as neuroprotective, immunocompetent cells of the CNS.
        Glia. 2002; 40: 133-139
        • Gebicke-Haerter P.J.
        Microglia in neurodegeneration: molecular aspects.
        Microsc Res Tech. 2001; 54: 47-58
        • Tham C.S.
        • Lin F.F.
        • Rao T.S.
        • Yu N.
        • Webb M.
        Microglial activation state and lysophospholipid acid receptor expression.
        Int J Dev Neurosci. 2003; 21: 431-443
        • Zhang Z.
        • Zhang Z.
        • Fauser U.
        • Artelt M.
        • Burnet M.
        • Schluesener H.J.
        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
        • Coelho R.P.
        • Payne S.G.
        • Bittman R.
        • Spiegel S.
        • Sato-Bigbee C.
        The immunomodulator FTY720 has a direct cytoprotective effect in oligodendrocyte progenitors.
        J Pharmacol Exp Ther. 2007; 323: 626-635
        • Jung C.G.
        • Kim H.J.
        • Miron V.E.
        • Cook S.
        • Kennedy T.E.
        • Foster C.A.
        • Antel J.P.
        • Soliven B.
        Functional consequences of S1P receptor modulation in rat oligodendroglial lineage cells.
        Glia. 2007; 55: 1656-1667
        • Miron V.E.
        • Kennedy T.E.
        • Soliven B.
        • Antel J.P.
        Dose- and treatment duration-dependent effects of FTY720 on human oligodendroglial process dynamics.
        in: Abstract 651111 American Academy of Neurology Conference. 2008
        • 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: 61-71
        • Bruck W.
        • Kuhlmann T.
        • Stadelmann C.
        Remyelination in multiple sclerosis.
        J Neurol Sci. 2003; 206: 181-185
        • Chen J.T.
        • Collins D.L.
        • Atkins H.L.
        • Freedman M.S.
        • Arnold D.L.
        Magnetization transfer ratio evolution with demyelination and remyelination in multiple sclerosis lesions.
        Ann Neurol. 2008; 63: 254-262
        • Merkler D.
        • Ernsting T.
        • Kerschensteiner M.
        • Bruck W.
        • Stadelmann C.
        A new focal EAE model of cortical demyelination: multiple sclerosis-like lesions with rapid resolution of inflammation and extensive remyelination.
        Brain. 2006; 129: 1972-1983
        • Blakemore W.F.
        • Franklin R.J.
        Remyelination in experimental models of toxin-induced demyelination.
        Curr Top Microbiol Immunol. 2008; 318: 193-212
        • Windrem M.S.
        • Roy N.S.
        • Wang J.
        • Nunes M.
        • Benraiss A.
        • Goodman R.
        • McKhann G.M.
        • Goldman S.A.
        Progenitor cells derived from the adult human subcortical white matter disperse and differentiate as oligodendrocytes within demyelinated lesions of the rat brain.
        J Neurosci Res. 2002; 69: 966-975
        • Harada J.
        • Foley M.
        • Moskowitz M.A.
        • Waeber C.
        Sphingosine-1-phosphate induces proliferation and morphological changes of neural progenitor cells.
        J Neurochem. 2004; 88: 1026-1039
        • 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: 1503-1514
        • Malek R.L.
        • Toman R.E.
        • Edsall L.C.
        • Wong S.
        • Chiu J.
        • Letterle C.A.
        • Van Brocklyn J.R.
        • Milstien S.
        • Spiegel S.
        • Lee N.H.
        Nrg-1 belongs to the endothelial differentiation gene family of G protein-coupled sphingosine-1-phosphate receptors.
        J Biol Chem. 2001; 276: 5692-5699
        • Solly S.K.
        • Thomas J.L.
        • Monge M.
        • Demerens C.
        • Lubetzki C.
        • Gardinier M.V.
        • Matthieu J.M.
        • Zalc B.
        Myelin/oligodendrocyte glycoprotein (MOG) expression is associated with myelin deposition.
        Glia. 1996; 18: 39-48
        • Edsall L.C.
        • Pirianov G.G.
        • Spiegel S.
        Involvement of sphingosine 1-phosphate in nerve growth factor-mediated neuronal survival and differentiation.
        J Neurosci. 1997; 17: 6952-6960
        • Toman R.E.
        • Payne S.G.
        • Watterson K.R.
        • Maceyka M.
        • Lee N.H.
        • Milstien S.
        • Bigbee J.W.
        • Spiegel S.
        Differential transactivation of sphingosine-1-phosphate receptors modulates NGF-induced neurite extension.
        J Cell Biol. 2004; 166: 381-392
        • Moore A.N.
        • Kampfl A.W.
        • Zhao X.
        • Hayes R.L.
        • Dash P.K.
        Sphingosine-1-phosphate induces apoptosis of cultured hippocampal neurons that requires protein phosphatases and activator protein-1 complexes.
        Neuroscience. 1999; 94: 405-415
        • Postma F.R.
        • Jalink K.
        • Hengeveld T.
        • Moolenaar W.H.
        Sphingosine-1-phosphate rapidly induces Rho-dependent neurite retraction: action through a specific cell surface receptor.
        EMBO J. 1996; 15: 2388-2392
        • Sato K.
        • Tomura H.
        • Igarashi Y.
        • Ui M.
        • Okajima F.
        Exogenous sphingosine 1-phosphate induces neurite retraction possibly through a cell surface receptor in PC12 cells.
        Biochem Biophys Res Commun. 1997; 240: 329-334
        • Alemany R.
        • Kleuser B.
        • Ruwisch L.
        • Danneberg K.
        • Lass H.
        • Hashemi R.
        • Spiegel S.
        • Jakobs K.H.
        • Meyer zu H.D.
        Depolarisation induces rapid and transient formation of intracellular sphingosine-1-phosphate.
        FEBS Lett. 2001; 509: 239-244
        • MacLennan A.J.
        • Devlin B.K.
        • Marks L.
        • Gaskin A.A.
        • Neitzel K.L.
        • Lee N.
        Antisense studies in PC12 cells suggest a role for H218, a sphingosine 1-phosphate receptor, in growth-factor-induced cell–cell interaction and neurite outgrowth.
        Dev Neurosci. 2000; 22: 283-295
        • Zhang Y.H.
        • Fehrenbacher J.C.
        • Vasko M.R.
        • Nicol G.D.
        Sphingosine-1-phosphate via activation of a G-protein-coupled receptor(s) enhances the excitability of rat sensory neurons.
        J Neurophysiol. 2006; 96: 1042-1052
        • Oyama Y.
        • Chikahisa L.
        • Kanemaru K.
        • Nakata M.
        • Noguchi S.
        • Nagano T.
        • Okazaki E.
        • Hirata A.
        Cytotoxic actions of FTY720, a novel immunosuppressant, on thymocytes and brain neurons dissociated from the rat.
        Jpn J Pharmacol. 1998; 76: 377-385
        • Fujino M.
        • Funeshima N.
        • Kitazawa Y.
        • Kimura H.
        • Amemiya H.
        • Suzuki S.
        • Li X.K.
        Amelioration of experimental autoimmune encephalomyelitis in Lewis rats by FTY720 treatment.
        J Pharmacol Exp Ther. 2003; 305: 70-77
        • Rausch M.
        • Hiestand P.
        • Foster C.A.
        • Baumann D.R.
        • Cannet C.
        • Rudin M.
        Predictability of FTY720 efficacy in experimental autoimmune encephalomyelitis by in vivo macrophage tracking: clinical implications for ultrasmall superparamagnetic iron oxide-enhanced magnetic resonance imaging.
        J Magn Reson Imaging. 2004; 20: 16-24
        • Kataoka H.
        • Sugahara K.
        • Shimano K.
        • Teshima K.
        • Koyama M.
        • Fukunari A.
        • Chiba K.
        FTY720, sphingosine 1-phosphate receptor modulator, ameliorates experimental autoimmune encephalomyelitis by inhibition of T cell infiltration.
        Cell Mol Immunol. 2005; 2: 439-448
        • Balatoni B.
        • Storch M.K.
        • Swoboda E.M.
        • Schonborn V.
        • Koziel A.
        • Lambrou G.N.
        • Hiestand P.C.
        • Weissert R.
        • Foster C.A.
        FTY720 sustains and restores neuronal function in the DA rat model of MOG-induced experimental autoimmune encephalomyelitis.
        Brain Res Bull. 2007; 74: 307-316
        • Webb M.
        • Tham C.S.
        • Lin F.F.
        • Lariosa-Willingham K.
        • Yu N.
        • Hale J.
        • Mandala S.
        • Chun J.
        • Rao T.S.
        Sphingosine 1-phosphate receptor agonists attenuate relapsing–remitting experimental autoimmune encephalitis in SJL mice.
        J Neuroimmunol. 2004; 153: 108-121