Mechanizm działania fingolimodu w terapii stwardnienia rozsianego

• Authors: Małgorzata Turniak , Andrzej Głąbiński

Title variants

EN

The mechanism of action of fingolimod in multiple sclerosis therapy

• Languages of publication: PL

Abstracts

PL

Fingolimod jest pierwszym zarejestrowanym doustnym lekiem stosowanym w terapii stwardnienia rozsianego. Jego aktywny metabolit – fosforan fingolimodu poprzez działanie na receptory S1PR reguluje uwalnianie limfocytów z tkanek limfoidalnych do krążenia, wykazując efekt immunosupresyjny. Najnowsze badania dowodzą jednak, że na korzystny efekt działania fingolimodu składa się również wielopłaszczyznowe działanie neuroprotekcyjne. Fingolimod przenika przez barierę krew–mózg i wpływa na wykazujące ekspresję receptorów S1PR komórki ośrodkowego układu nerwowego: astrocyty, progenitory oligodendrocytów, mikroglej, a także neurony. Fingolimod pobudza produkcję czynników neurotroficznych oraz hamuje produkcję tlenku azotu przez komórki astrogleju, zmniejszając nasilenie proceu neurodegeneracji. Co więcej, zmniejsza ekspresję prozapalnych cytokin indukowanych przez TNF w astrocytach, zmniejszając ich potencjał prozapalny. Pobudza zarówno migrację, jak i  proliferację komórek progenitorowych oligodendrocytów, będących źródłem oligodendrocytów  – jedynych komórek ośrodkowego układu nerwowego zdolnych do syntezy mieliny. Leczenie fingolimodem znacząco nasila mechanizmy regeneracyjne w przebiegu autoimmunologicznego zapalenia mózgu i rdzenia kręgowego. Ponadto zmniejsza reaktywność mikrogleju i spowalnia związany z odpowiedzią zapalną proces nuerodegeneracji. Długotrwała aplikacja fingolimodu redukuje wrażliwość komórek nerwowych na czynniki neurotoksyczne, sugeruje bezpośrednie działanie neuroprotekcyjne. Obecnie w różnych fazach badań klinicznych znajdują się selektywne inhibitory poszczególnych podtypów receptorów dla S1P, pozbawione charakterystycznych dla fingolimodu działań niepożądanych oraz posiadające korzystniejsze właściwości farmakokinetyczne. Należą do nich: siponimod, ponesimod oraz ozanimod.

EN

Fingolimod is the first registered oral drug effective in the treatment of multiple sclerosis. Its active metabolite, fingolimod phosphate, affects S1PR receptors, and regulates the release of lymphocytes from the lymphoid tissues, showing an immunosuppressive effect. However, recent studies have also shown fingolimod to have neuroprotective properties. Fingolimod is able to cross the brain–blood barrier, and thus affect the central nervous system cells expresing S1PR receptors, such as astrocytes, oligodendrocyte progenitor cells, microglia and neurons. It stimulates the production of neurotrophic factors, and decreases the production of nitric oxide in astrocytes, thus relieving the severity of the neurodegenerative process. Furthermore, it limits the expression of pro-inflammatory TNF-induced cytokines in astrocytes, reducing their pro-inflammatory potential. It stimulates the migration and proliferation of oligodendrocyte progenitor cells, which are the source of oligodendrocytes – the only cells in central nervous system capable of synthesizing myelin. Fingolimod treatment significantly enhances the regenerative mechanisms in experimental autoimmune encephalomyelitis. It reduces microglial reactivity, and slows down the nuerodegenerative process caused by inflammatory response. Long-term application of fingolimod reduces the sensitivity of nerve cells to neurotoxic agents, suggesting a direct neuroprotective effect. Currently, clinical trials of several selective S1PR inhibitors are in progress, such as siponimod, ponesimod and ozanimod. They seem to show an improved safety profile and pharmacokinetic properties compared to fingolimod.

Keywords

EN

S1P; fingolimod; mechanizm działania; selektywne modulatory S1PR; stwardnienie rozsiane

Discipline

• MEDICINE: MEDICINE

• Publisher: Medical Communications
• Journal: Aktualności Neurologiczne
• Year: 2017
• Volume: 17
• Issue: 2
• Pages: 96–103

Contributors

author

Małgorzata Turniak

• Klinika Neurologii i Udarów Mózgu, Uniwersytet Medyczny w Łodzi, Uniwersytecki Szpital Kliniczny im. Wojskowej Akademii Medycznej – Centralny Szpital Weteranów, Łódź, Polska

author

Andrzej Głąbiński

• Klinika Neurologii i Udarów Mózgu, Uniwersytet Medyczny w Łodzi, Uniwersytecki Szpital Kliniczny im. Wojskowej Akademii Medycznej – Centralny Szpital Weteranów, Łódź, Polska

References

• Adachi K, Kohara T, Nakao N et al.: Design, synthesis, and structure activity relationships of 2-substituted-2-amino-1,3-propanediols: discovery of a novel immunosuppressant, FTY720. Bioorg Med Chem Lett 1995; 5: 853–856.
• Allende ML, Proia RL: Sphingosine-1-phosphate receptors and the development of the vascular system. Biochim Biophys Acta 2002; 1582: 222–227.
• Allende ML, Yamashita T, Proia RL: G-protein-coupled receptor S1P1 acts within endothelial cells to regulate vascular maturation. Blood 2003; 102: 3665–3667.
• Alsop JC, Bergvall N, Cornelissen C et al.: Confirmed disability improvement in patients with active multiple sclerosis treated with fingolimod versus BRACE: a matched comparison of treatments from the PANGAEA and PEARL registry studies. Value Health 2015; 18: A750.
• Anastasiadou S, Knöll B: The multiple sclerosis drug fingolimod (FTY720) stimulates neuronal gene expression, axonal growth and regeneration. Exp Neurol 2016; 279: 243–260.
• 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.
• Braune S, Lang M, Bergmann A; NeuroTransData Study Group: Efficacy of fingolimod is superior to injectable disease modifying therapies in second-line therapy of relapsing remitting multiple sclerosis. J Neurol 2016; 263: 327–333.
• Brinkmann V: FTY720 (fingolimod) in Multiple Sclerosis: therapeutic effects in the immune and the central nervous system. Br J Pharmacol 2009; 158: 1173–1182.
• Brinkmann V, Billich A, Baumruker T et al.: Fingolimod (FTY720): discovery and development of an oral drug to treat multiple sclerosis. Nat Rev Drug Discov 2010; 9: 883–897.
• Brinkmann V, Davis MD, Heise CE et al.: The immune modulator FTY720 targets sphingosine 1-phosphate receptors. J Biol Chem 2002; 277: 21453–21457.
• Brossard P, Derendorf H, Xu J et al.: Pharmacokinetics and pharmacodynamics of ponesimod, a selective S1P1 receptor modulator, in the first-in-human study. Br J Clin Pharmacol 2013; 76: 888–896.
• Calabresi PA, Radue EW, Goodin D et al.: 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 2014; 13: 545–556.
• Candido K, Soufi H, Bandyopadhyay M et al.: Therapeutic impact of sphingosine 1-phosphate receptor signaling in multiple sclerosis. Mini Rev Med Chem 2016; 16: 547–554.
• Choi JW, Gardell SE, Herr DR et al.: FTY720 (fingolimod) efficacy in an animal model of multiple sclerosis requires astrocyte sphingosine 1-phosphate receptor 1 (S1P1) modulation. Proc Natl Acad Sci U S A 2011; 108: 751–756.
• Chu HX, Arumugam TV, Gelderblom M et al.: Role of CCR2 in inflammatory conditions of the central nervous system. J Cereb Blood Flow Metab 2014; 34: 1425–1429.
• Cipriani R, Chara JC, Rodríguez-Antigüedad A et al.: FTY720 attenuates excitotoxicity and neuroinflammation. J Neuroinflammation 2015; 12: 86.
• 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.
• Colombo E, Di Dario M, Capitolo E et al.: Fingolimod may support neuroprotection via blockade of astrocyte nitric oxide. Ann Neurol 2014; 76: 325–337.
• Compston A, Coles A: Multiple sclerosis. Lancet 2008; 372: 1502–1517.
• D’Ambrosio D, Freedman MS, Prinz J: Ponesimod, a selective S1P1 receptor modulator: a potential treatment for multiple sclerosis and other immune-mediated diseases. Ther Adv Chronic Dis 2016; 7: 18–33.
• Delgado A, Martínez-Cartro M: Therapeutic potential of the modulation of sphingosine-1-phosphate receptors. Curr Med Chem 2016; 23: 242–264.
• Derfuss T, Bergvall NK, Sfikas N et al.: Efficacy of fingolimod in patients with highly active relapsing-remitting multiple sclerosis. Curr Med Res Opin 2015; 31: 1687–1691.
• Dev KK, Mullershausen F, Mattes H et al.: Brain sphingosine-1-phosphate receptors: implication for FTY720 in the treatment of multiple sclerosis. Pharmacol Ther 2008; 117: 77–93.
• Efstathopoulos P, Kourgiantaki A, Karali K et al.: Fingolimod induces neurogenesis in adult mouse hippocampus and improves contextual fear memory. Transl Psychiatry 2015; 5: e685.
• Fonseca J: Fingolimod real world experience: efficacy and safety in clinical practice. Neurosci J 2015; 2015: 389360.
• 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.
• Foussat A, Coulomb-L’Hermine A, Gosling J et al.: Fractalkine receptor expression by T lymphocyte subpopulations and in vivo production of fractalkine in human. Eur J Immunol 2000; 30: 87–97.
• Francis G, Kappos L, O’Connor P et al.: Temporal profile of lymphocyte counts and relationship with infections with fingolimod therapy. Mult Scler 2014; 20: 471–480.
• Friess J, Hecker M, Roch L et al.: Fingolimod alters the transcriptome profile of circulating CD4+ cells in multiple sclerosis. Sci Rep 2017; 7: 42087.
• Fujino M, Funeshima N, Kitazawa Y et al.: Amelioration of experimental autoimmune encephalomyelitis in Lewis rats by FTY720 treatment. J Pharmacol Exp Ther 2003; 305: 70–77.
• Garris CS, Wu L, Acharya S et al.: Defective sphingosine 1-phosphate receptor 1 (S1P1) phosphorylation exacerbates TH17-mediated autoimmune neuroinflammation. Nat Immunol 2013; 14: 1166–1172.
• Gergely P, Nuesslein-Hildesheim B, Guerini D et al.: The selective sphingosine 1-phosphate receptor modulator BAF312 redirects lymphocyte distribution and has species-specific effects on heart rate. Br J Pharmacol 2012; 167: 1035–1047.
• Gilenya Assessment Report. London 2011. Halmer R, Walter S, Faßbender K: Sphingolipids: important players in multiple sclerosis. Cell Physiol Biochem 2014; 34: 111–118.
• Hla T, Brinkmann V: Sphingosine 1-phosphate (S1P): Physiology and the effects of S1P receptor modulation. Neurology 2011; 76 (Suppl 3): S3–S8.
• Hoffmann FS, Hofereiter J, Rübsamen H et al.: Fingolimod induces neuroprotective factors in human astrocytes. J Neuroinflammation 2015; 12: 184.
• Hu W, Mahavadi S, Huang J et al.: Characterization of S1P1 and S1P2 receptor function in smooth muscle by receptor silencing and receptor protection. Am J Physiol Gastrointest Liver Physiol 2006; 291: G605–G610.
• 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.
• Kappos L, Cohen J, Collins W et al.: Fingolimod in relapsing multiple sclerosis: an integrated analysis of safety findings. Mult Scler Relat Disord 2014; 3: 494–504.
• Kappos L, O’Connor P, Radue EW et al.: Long-term effects of fingolimod in multiple sclerosis: the randomized FREEDOMS extension trial. Neurology 2015; 84: 1582–1591.
• 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.
• Komunikat z 26 posiedzenia Rady Przejrzystości: Stanowisko w sprawie oceny leku Gilenya (Fingolimod) we wskazaniu leczenie stwardnienia rozsianego fingolimodem po niepowodzeniu terapii lekami pierwszego rzutu ICD-10 G.35. Agencja Oceny Technologii Medycznych i Taryfikacji, 2016.
• 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.
• Koyrakh L, Roman MI, Brinkmann V et al.: 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.
• Krumbholz M, Theil D, Derfuss T et al.: BAFF is produced by astrocytes and up-regulated in multiple sclerosis lesions and primary central nervous system lymphoma. J Exp Med 2005; 201: 195–200.
• Kurtzke JF: Rating neurologic impairment in multiple sclerosis: an Expanded Disability Status Scale (EDSS). Neurology 1983; 33: 1444–1452.
• Lee DH, Seubert S, Huhn K et al.: Fingolimod effects in neuroinflammation: regulation of astroglial glutamate transporters? PLoS One 2017; 12: e0171552.
• 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.
• McGiffert C, Contos JJ, Friedman B et al.: Embryonic brain expression analysis of lysophospholipid receptor genes suggests roles for s1p1 in neurogenesis and s1p1–3 in angiogenesis. FEBS Lett 2002; 531: 103–108.
• Miron VE, Jung CG, Kim HJ et al.: FTY720 modulates human oligodendrocyte progenitor process extension and survival. Ann Neurol 2008; 63: 61–71.
• 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.
• Moran LB, Graeber MB: The facial nerve axotomy model. Brain Res Brain Res Rev 2004; 44: 154–178.
• Moreno M, Guo F, Mills Ko E et al.: Origins and significance of astrogliosis in the multiple sclerosis model, MOG peptide EAE. J Neurol Sci 2013; 333: 55–59.
• Mullershausen F, Craveiro LM, Shin Y et al.: Phosphorylated FTY720 promotes astrocyte migration through sphingosine-1-phosphate receptors. J Neurochem 2007; 102: 1151–1161.
• 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.
• Noda H, Takeuchi H, Mizuno T et al.: Fingolimod phosphate promotes the neuroprotective effects of microglia. J Neuroimmunol 2013; 256: 13–18.
• Piali L, Froidevaux S, Hess P et al.: The selective sphingosine 1-phosphate receptor 1 agonist ponesimod protects against lymphocyte-mediated tissue inflammation. J Pharmacol Exp Ther 2011; 337: 547–556.
• Pittock SJ, McClelland RL, Mayr WT et al.: Clinical implications of benign multiple sclerosis: a 20-year population-based follow-up study. Ann Neurol 2004; 56: 303–306.
• Poser CM: The epidemiology of multiple sclerosis: a general overview. Ann Neurol 1994; 36 Suppl 2: S180–S193.
• Sanford M: Fingolimod: a review of its use in relapsing-remitting multiple sclerosis. Drugs 2014; 74: 1411–1433.
• Sato DK, Nakashima I, Bar-Or A et al.: Changes in Th17 and regulatory T cells after fingolimod initiation to treat multiple sclerosis. J Neuroimmunol 2014; 268: 95–98.
• Scott FL, Clemons B, Brooks J et al.: Ozanimod (RPC1063) is a potent sphingosine-1-phosphate receptor-1 (S1P1) and receptor-5 (S1P5) agonist with autoimmune disease-modifying activity. Br J Pharmacol 2016; 173: 1778–1792.
• Sorensen PS: Effects of fingolimod in relapsing-remitting multiple sclerosis. Lancet Neurol 2014; 13: 526–527.
• 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.
• Strochlic L, Dwivedy A, van Horck FP et al.: A role for S1P signalling in axon guidance in the Xenopus visual system. Development 2008; 135: 333–342.
• Thangada S, Khanna KM, Blaho VA et al.: Cell-surface residence of sphingosine 1-phosphate receptor 1 on lymphocytes determines lymphocyte egress kinetics. J Exp Med 2010; 207: 1475–1483.
• Tran JQ, Hartung JP, Peach RJ et al.: Results from the first-in-human study with ozanimod, a novel, selective sphingosine-1-phosphate receptor modulator. J Clin Pharmacol 2017; 57: 988–996.
• Tremlett H, Paty D, Devonshire V: Disability progression in multiple sclerosis is slower than previously reported. Neurology 2006; 66: 172–177.
• Vukusic S, Confavreux C: Natural history of multiple sclerosis: risk factors and prognostic indicators. Curr Opin Neurol 2007; 20: 269–274.
• Watterson KR, Ratz PH, Spiegel S: The role of sphingosine-1-phosphate in smooth muscle contraction. Cell Signal 2005; 17: 289–298.
• Webb M, Tham CS, Lin FF et al.: Sphingosine 1-phosphate receptor agonists attenuate relapsing–remitting experimental autoimmune encephalitis in SJL mice. J Neuroimmunol 2004; 153: 108–121.
• Yanagawa Y, Sugahara K, Kataoka H et al.: FTY720, a novel immunosuppressant, induces sequestration of circulating mature lymphocytes by acceleration of lymphocyte homing in rats. II. FTY720 prolongs skin allograft survival by decreasing T cell infiltration into grafts but not cytokine production in vivo. J Immunol 1998; 160: 5493–5499.
• You S, Piali L, Kuhn C et al.: Therapeutic use of a selective S1P1 receptor modulator ponesimod in autoimmune diabetes. PLoS One 2013; 8: e77296.
• Zhang J, Zhang ZG, Li Y et al.: Fingolimod treatment promotes proliferation and differentiation of oligodendrocyte progenitor cells in mice with experimental autoimmune encephalomyelitis. Neurobiol Dis 2015; 76: 57–66.

• Document Type: article