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Review Article

FTY720 (Fingolimod)通过多种机制改善脑损伤，是中风治疗的有力候选药物

卷 27, 期 18, 2020

页: [2979 - 2993] 页: 15

弟呕挨: 10.2174/0929867326666190308133732

open access plus

摘要

FTY720 (Fingolimod)是一种已知的具有强烈抗炎作用的鞘糖苷-1-磷酸(S1P)受体激动剂，于2010年被美国食品和药物管理局(FDA)批准为第一种治疗多发性硬化症的口服药物。FTY720主要与独特的功能性“拮抗剂”和“激动剂”机制有关。其功能拮抗机制是通过淋巴细胞上的S1P受体短暂的下调和降解，阻止淋巴细胞从淋巴结进入血流。这随后导致淋巴细胞减少和减少淋巴细胞炎症的发展。功能激动机制是通过表达在神经元、星形胶质细胞、小胶质细胞和血管内皮细胞等多种细胞表面的S1P受体来实现的。这些功能可能在调节抗凋亡系统、调节脑免疫和吞噬活性、维持血脑屏障(BBB)和神经前体细胞的增殖等方面发挥重要作用。最近，FTY720显示出了不依赖受体的作用，包括细胞内目标结合和表观遗传调节。许多研究人员已经认识到FTY720的积极作用，并开展了基础和临床实验来测试该制剂对中风的使用。虽然FTY720的作用机制尚未完全阐明，但其对脑卒中的疗效正在逐渐明确，不仅在动物模型中，在缺血性脑卒中患者中也通过临床试验得到证实。在本文中，我们回顾了使用FTY720治疗中风的实验室结果和初步临床试验的数据。

关键词: FTY720

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[1]
Fujita, T.; Inoue, K.; Yamamoto, S.; Ikumoto, T.; Sasaki, S.; Toyama, R.; Chiba, K.; Hoshino, Y.; Okumoto, T. Fungal metabolites. Part 11. A potent immunosuppressive activity found in Isaria sinclairii metabolite. J. Antibiot. (Tokyo), 1994, 47(2), 208-215.
[http://dx.doi.org/10.7164/antibiotics.47.208] [PMID: 8150717]
[2]
(a)Chiba, K.; Kataoka, H.; Seki, N.; Shimano, K.; Koyama, M.; Fukunari, A.; Sugahara, K.; Sugita, T. Fingolimod (FTY720), sphingosine 1-phosphate receptor modulator, shows superior efficacy as compared with interferon-β in mouse experimental autoimmune encephalomyelitis. Int. Immunopharmacol., 2011, 11(3), 366-372.
[http://dx.doi.org/10.1016/j.intimp.2010.10.005] [PMID: 20955831]
(b)Moon, E.; Han, J.E.; Jeon, S.; Ryu, J.H.; Choi, J.W.; Chun, J. Exogenous S1P exposure potentiates ischemic stroke damage that is reduced possibly by inhibiting S1P receptor signaling. Mediators Inflamm., 2015, 2015492659
[http://dx.doi.org/10.1155/2015/492659] [PMID: 26576074]
[3]
Singh, I.N.; Hall, E.D. Multifaceted roles of sphingosine-1-phosphate: how does this bioactive sphingolipid fit with acute neurological injury? J. Neurosci. Res., 2008, 86(7), 1419-1433.
[http://dx.doi.org/10.1002/jnr.21586] [PMID: 18058948]
[4]
Kawabori, M.; Kacimi, R.; Karliner, J.S.; Yenari, M.A. Sphingolipids in cardiovascular and cerebrovascular systems: Pathological implications and potential therapeutic targets. World J. Cardiol., 2013, 5(4), 75-86.
[http://dx.doi.org/10.4330/wjc.v5.i4.75] [PMID: 23675553]
[5]
Bikman, B.T.; Summers, S.A. Ceramides as modulators of cellular and whole-body metabolism. J. Clin. Invest., 2011, 121(11), 4222-4230.
[http://dx.doi.org/10.1172/JCI57144] [PMID: 22045572]
[6]
aChang, Y.; Abe, A.; Shayman, J.A. Ceramide formation during heat shock: A potential mediator of alpha B-crystallin transcription. Proc. Natl. Acad. Sci. USA, 2001, 92(26), 12275-12279.
[http://dx.doi.org/10.1073/pnas.92.26.12275] [PMID: 8618884]
[7]
(a)Okazaki, T.; Bielawska, A.; Bell, R.M.; Hannun, Y.A. Role of ceramide as a lipid mediator of 1 alpha,25-dihydroxyvitamin D3-induced HL-60 cell differentiation. J. Biol. Chem., 1990, 265(26), 15823-15831.
[PMID: 2394750]
(b)Taniguchi, M.; Kitatani, K.; Kondo, T.; Hashimoto-Nishimura, M.; Asano, S.; Hayashi, A.; Mitsutake, S.; Igarashi, Y.; Umehara, H.; Takeya, H.; Kigawa, J.; Okazaki, T. Regulation of autophagy and its associated cell death by “sphingolipid rheostat”: reciprocal role of ceramide and sphingosine 1-phosphate in the mammalian target of rapamycin pathway. J. Biol. Chem., 2012, 287(47), 39898-39910.
[http://dx.doi.org/10.1074/jbc.M112.416552] [PMID: 23035115]
(c)Obeid, L.M.; Linardic, C.M.; Karolak, L.A.; Hannun, Y.A. Programmed cell death induced by ceramide. Science, 1993, 259(5102), 1769-1771.
[http://dx.doi.org/10.1126/science.8456305] [PMID: 8456305]
(d)Scarlatti, F.; Bauvy, C.; Ventruti, A.; Sala, G.; Cluzeaud, F.; Vandewalle, A.; Ghidoni, R.; Codogno, P. Ceramide-mediated macroautophagy involves inhibition of protein kinase B and up-regulation of beclin 1. J. Biol. Chem., 2004, 279(18), 18384-18391.
[http://dx.doi.org/10.1074/jbc.M313561200] [PMID: 14970205]
(e)Wakita, H.; Tokura, Y.; Yagi, H.; Nishimura, K.; Furukawa, F.; Takigawa, M. Keratinocyte differentiation is induced by cell-permeant ceramides and its proliferation is promoted by sphingosine. Arch. Dermatol. Res., 1994, 286(6), 350-354.
[http://dx.doi.org/10.1007/BF00402228] [PMID: 7979551]
[8]
(a)Suzuki, E.; Handa, K.; Toledo, M.S.; Hakomori, S. Sphingosine-dependent apoptosis: a unified concept based on multiple mechanisms operating in concert. Proc. Natl. Acad. Sci. USA, 2004, 101(41), 14788-14793.
[http://dx.doi.org/10.1073/pnas.0406536101] [PMID: 15466700]
(b)Hannun, Y.A.; Loomis, C.R.; Merrill, A.H., Jr; Bell, R.M. Sphingosine inhibition of protein kinase C activity and of phorbol dibutyrate binding in vitro and in human platelets. J. Biol. Chem., 1986, 261(27), 12604-12609.
[PMID: 3462188]
(c)Ohta, H.; Sweeney, E.A.; Masamune, A.; Yatomi, Y.; Hakomori, S.; Igarashi, Y. Induction of apoptosis by sphingosine in human leukemic HL-60 cells: a possible endogenous modulator of apoptotic DNA fragmentation occurring during phorbol ester-induced differentiation. Cancer Res., 1995, 55(3), 691-697.
[PMID: 7834642]
(d)McDonough, P.M.; Yasui, K.; Betto, R.; Salviati, G.; Glembotski, C.C.; Palade, P.T.; Sabbadini, R.A. Control of cardiac Ca2+ levels. Inhibitory actions of sphingosine on Ca2+ transients and L-type Ca2+ channel conductance. Circ. Res., 1994, 75(6), 981-989.
[http://dx.doi.org/10. 1161/01.RES.75.6.981] [PMID: 7955152]
[9]
Vessey, D.A.; Li, L.; Kelley, M.; Zhang, J.; Karliner, J.S. Sphingosine can pre- and post-condition heart and utilizes a different mechanism from sphingosine 1-phosphate. J. Biochem. Mol. Toxicol., 2008, 22(2), 113-118.
[http://dx.doi.org/10.1002/jbt.20227] [PMID: 18418901]
[10]
Chun, J.; Goetzl, E.J.; Hla, T.; Igarashi, Y.; Lynch, K.R.; Moolenaar, W.; Pyne, S.; Tigyi, G. International Union of Pharmacology. XXXIV. Lysophospholipid receptor nomenclature. Pharmacol. Rev., 2002, 54(2), 265-269.
[http://dx.doi.org/10.1124/pr.54.2.265] [PMID: 12037142]
[11]
(a)Murata, N.; Sato, K.; Kon, J.; Tomura, H.; Yanagita, M.; Kuwabara, A.; Ui, M.; Okajima, F. Interaction of sphingosine 1-phosphate with plasma components, including lipoproteins, regulates the lipid receptor-mediated actions. Biochem. J., 2000, 352(Pt 3), 809-815.
[http://dx.doi.org/10.1042/bj3520809] [PMID: 11104690]
(b)Okajima, F. Plasma lipoproteins behave as carriers of extracellular sphingosine 1-phosphate: is this an atherogenic mediator or an anti-atherogenic mediator? Biochim. Biophys. Acta, 2002, 1582(1-3), 132-137.
[http://dx.doi.org/10.1016/S1388-1981(02)00147-6] [PMID: 12069820]
[12]
(a)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(5822), 295-298.
[http://dx.doi.org/10.1126/science.1139221] [PMID: 17363629]
(b)Yatomi, Y.; Ruan, F.; Hakomori, S.; Igarashi, Y. Sphingosine-1-phosphate: a platelet-activating sphingolipid released from agonist-stimulated human platelets. Blood, 1995, 86(1), 193-202.
[http://dx.doi.org/10.1182/blood.V86.1.193.bloodjournal861193] [PMID: 7795224]
[13]
Schwab, S.R.; Pereira, J.P.; Matloubian, M.; Xu, Y.; Huang, Y.; Cyster, J.G. Lymphocyte sequestration through S1P lyase inhibition and disruption of S1P gradients. Science, 2005, 309(5741), 1735-1739.
[http://dx.doi.org/10.1126/science.1113640] [PMID: 16151014]
[14]
(a)Igarashi, N.; Okada, T.; Hayashi, S.; Fujita, T.; Jahangeer, S.; Nakamura, S. Sphingosine kinase 2 is a nuclear protein and inhibits DNA synthesis. J. Biol. Chem., 2003, 278(47), 46832-46839.
[http://dx.doi.org/10.1074/jbc.M306577200] [PMID: 12954646]
(b)Pfeilschifter, W.; Czech-Zechmeister, B.; Sujak, M.; Mirceska, A.; Koch, A.; Rami, A.; Steinmetz, H.; Foerch, C.; Huwiler, A.; Pfeilschifter, J. Activation of sphingosine kinase 2 is an endogenous protective mechanism in cerebral ischemia. Biochem. Biophys. Res. Commun., 2011, 413(2), 212-217.
[http://dx.doi.org/10.1016/j.bbrc.2011.08.070] [PMID: 21872577]
(c)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(2), 509-517.
[http://dx.doi.org/10.1111/j.1471-4159.2007.04755.x] [PMID: 17623044]
[15]
Inagaki, Y.; Li, P.Y.; Wada, A.; Mitsutake, S.; Igarashi, Y. Identification of functional nuclear export sequences in human sphingosine kinase 1. Biochem. Biophys. Res. Commun., 2003, 311(1), 168-173.
[http://dx.doi.org/10.1016/j.bbrc.2003.09.194] [PMID: 14575709]
[16]
(a)Kohama, T.; Olivera, A.; Edsall, L.; Nagiec, M.M.; Dickson, R.; Spiegel, S. Molecular cloning and functional characterization of murine sphingosine kinase. J. Biol. Chem., 1998, 273(37), 23722-23728.
[http://dx.doi.org/10.1074/jbc.273.37.23722] [PMID: 9726979]
(b)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(24), 11113-11121.
[http://dx.doi.org/10.1128/MCB.25.24.11113-11121.2005] [PMID: 16314531]
[17]
Paugh, S.W.; Payne, S.G.; Barbour, S.E.; Milstien, S.; Spiegel, S. The immunosuppressant FTY720 is phosphorylated by sphingosine kinase type 2. FEBS Lett., 2003, 554(1-2), 189-193.
[http://dx.doi.org/10.1016/S0014-5793(03)01168-2] [PMID: 14596938]
[18]
Hisano, Y.; Kobayashi, N.; Kawahara, A.; Yamaguchi, A.; Nishi, T. The sphingosine 1-phosphate transporter, SPNS2, functions as a transporter of the phosphorylated form of the immunomodulating agent FTY720. J. Biol. Chem., 2011, 286(3), 1758-1766.
[http://dx.doi.org/10.1074/jbc.M110.171116] [PMID: 21084291]
[19]
Huwiler, A.; Zangemeister-Wittke, U. The sphingosine 1-phosphate receptor modulator fingolimod as a therapeutic agent: Recent findings and new perspectives. Pharmacol. Ther., 2018, 185, 34-49.
[http://dx.doi.org/10.1016/j.pharmthera.2017.11.001] [PMID: 29127024]
[20]
(a)Limaye, V.; Li, X.; Hahn, C.; Xia, P.; Berndt, M.C.; Vadas, M.A.; Gamble, J.R. Sphingosine kinase-1 enhances endothelial cell survival through a PECAM-1-dependent activation of PI-3K/Akt and regulation of Bcl-2 family members. Blood, 2005, 105(8), 3169-3177.
[http://dx.doi.org/10.1182/blood-2004-02-0452] [PMID: 15632208]
(b)Kluk, M.J.; Hla, T. Signaling of sphingosine-1-phosphate via the S1P/EDG-family of G-protein-coupled receptors. Biochim. Biophys. Acta, 2002, 1582(1-3), 72-80.
[http://dx.doi.org/10.1016/S1388-1981(02)00139-7] [PMID: 12069812]
[21]
Pébay, A.; Toutant, M.; Prémont, J.; Calvo, C.F.; Venance, L.; Cordier, J.; Glowinski, J.; Tencé, M. Sphingosine-1-phosphate induces proliferation of astrocytes: regulation by intracellular signalling cascades. Eur. J. Neurosci., 2001, 13(12), 2067-2076.
[http://dx.doi.org/10.1046/j.0953-816x.2001.01585.x] [PMID: 11467306]
[22]
Agudo-López, A.; Miguel, B.G.; Fernández, I.; Martínez, A.M. Involvement of mitochondria on neuroprotective effect of sphingosine-1-phosphate in cell death in an in vitro model of brain ischemia. Neurosci. Lett., 2010, 470(2), 130-133.
[http://dx.doi.org/10.1016/j.neulet.2009.12.070] [PMID: 20045720]
[23]
Chiba, K.; Yanagawa, Y.; Masubuchi, Y.; Kataoka, H.; Kawaguchi, T.; Ohtsuki, M.; Hoshino, Y. 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(10), 5037-5044.
[PMID: 9590253]
[24]
Brait, V.H.; Tarrasón, G.; Gavaldà, A.; Godessart, N.; Planas, A.M. Selective sphingosine 1-phosphate receptor 1 agonist is protective against ischemia/reperfusion in mice. Stroke, 2016, 47(12), 3053-3056.
[http://dx.doi.org/10.1161/STROKEAHA.116.015371] [PMID: 27827329]
[25]
Pfeilschifter, W.; Czech-Zechmeister, B.; Sujak, M.; Foerch, C.; Wichelhaus, T.A.; Pfeilschifter, J. Treatment with the immunomodulator FTY720 does not promote spontaneous bacterial infections after experimental stroke in mice. Exp. Transl. Stroke Med., 2011, 3, 2.
[http://dx.doi.org/10.1186/2040-7378-3-2] [PMID: 21388542]
[26]
Herz, J.; Köster, C.; Crasmöller, M.; Abberger, H.; Hansen, W.; Felderhoff-Müser, U.; Bendix, I. Peripheral T cell depletion by FTY720 exacerbates hypoxic-ischemic brain injury in neonatal mice. Front. Immunol., 2018, 9, 1696.
[http://dx.doi.org/10.3389/fimmu.2018.01696] [PMID: 30127782]
[27]
Kleinschnitz, C.; Kraft, P.; Dreykluft, A.; Hagedorn, I.; Göbel, K.; Schuhmann, M.K.; Langhauser, F.; Helluy, X.; Schwarz, T.; Bittner, S.; Mayer, C.T.; Brede, M.; Varallyay, C.; Pham, M.; Bendszus, M.; Jakob, P.; Magnus, T.; Meuth, S.G.; Iwakura, Y.; Zernecke, A.; Sparwasser, T.; Nieswandt, B.; Stoll, G.; Wiendl, H. Regulatory T cells are strong promoters of acute ischemic stroke in mice by inducing dysfunction of the cerebral microvasculature. Blood, 2013, 121(4), 679-691.
[http://dx.doi.org/10.1182/blood-2012-04-426734] [PMID: 23160472]
[28]
(a)Kraft, P.; Göb, E.; Schuhmann, M.K.; Göbel, K.; Deppermann, C.; Thielmann, I.; Herrmann, A.M.; Lorenz, K.; Brede, M.; Stoll, G.; Meuth, S.G.; Nieswandt, B.; Pfeilschifter, W.; Kleinschnitz, C. FTY720 ameliorates acute ischemic stroke in mice by reducing thrombo-inflammation but not by direct neuroprotection. Stroke, 2013, 44(11), 3202-3210.
[http://dx.doi.org/10.1161/STROKEAHA.113.002880] [PMID: 24029635]
(b)Czech, B.; Pfeilschifter, W.; Mazaheri-Omrani, N.; Strobel, M.A.; Kahles, T.; Neumann-Haefelin, T.; Rami, A.; Huwiler, A.; Pfeilschifter, J. The immunomodulatory sphingosine 1-phosphate analog FTY720 reduces lesion size and improves neurological outcome in a mouse model of cerebral ischemia. Biochem. Biophys. Res. Commun., 2009, 389(2), 251-256.
[http://dx.doi.org/10.1016/j.bbrc.2009.08.142] [PMID: 19720050]
(c)Liesz, A.; Sun, L.; Zhou, W.; Schwarting, S.; Mracsko, E.; Zorn, M.; Bauer, H.; Sommer, C.; Veltkamp, R. FTY720 reduces post-ischemic brain lymphocyte influx but does not improve outcome in permanent murine cerebral ischemia. PLoS One, 2011, 6(6)e21312
[http://dx.doi.org/10.1371/journal.pone.0021312] [PMID: 21701599]
[29]
Wei, Y.; Yemisci, M.; Kim, H.H.; Yung, L.M.; Shin, H.K.; Hwang, S.K.; Guo, S.; Qin, T.; Alsharif, N.; Brinkmann, V.; Liao, J.K.; Lo, E.H.; Waeber, C. Fingolimod provides long-term protection in rodent models of cerebral ischemia. Ann. Neurol., 2011, 69(1), 119-129.
[http://dx.doi.org/10.1002/ana.22186] [PMID: 21280082]
[30]
Spampinato, S.F.; Obermeier, B.; Cotleur, A.; Love, A.; Takeshita, Y.; Sano, Y.; Kanda, T.; Ransohoff, R.M. Sphingosine 1 phosphate at the blood brain barrier: Can the modulation of S1P receptor 1 influence the response of endothelial cells and astrocytes to inflammatory Stimuli? PLoS One, 2015, 10(7)e0133392
[http://dx.doi.org/10.1371/journal.pone.0133392] [PMID: 26197437]
[31]
Zhao, Z.; Wang, J.; Huo, Z.; Wang, Z.; Mei, Q. FTY720 elevates smooth muscle contraction of aorta and blood pressure in rats via ERK activation. Pharmacol. Res. Perspect., 2017, 5(3)e00308
[http://dx.doi.org/10.1002/prp2.308] [PMID: 28480040]
[32]
Ransohoff, R.M.; Engelhardt, B. The anatomical and cellular basis of immune surveillance in the central nervous system. Nat. Rev. Immunol., 2012, 12(9), 623-635.
[http://dx.doi.org/10.1038/nri3265] [PMID: 22903150]
[33]
Kaur, C.; Ling, E.A. Blood brain barrier in hypoxic-ischemic conditions. Curr. Neurovasc. Res., 2008, 5(1), 71-81.
[http://dx.doi.org/10.2174/156720208783565645] [PMID: 18289024]
[34]
aLan, R.; Xiang, J.; Wang, G.H.; Li, W.W.; Zhang, W.; Xu, L.L.; Cai, D.F. Xiao-Xu-Ming decoction protects against blood-brain barrier disruption and neurological injury induced by cerebral is-chemia and reperfusion in rats. Evid. Based Complement. Alternat. Med., 2013, 2013629782
[http://dx.doi.org/10.1155/2013/629782] [PMID: 23710225]
[35]
Brown, R.C.; Davis, T.P. Calcium modulation of adherens and tight junction function: a potential mechanism for blood-brain barrier disruption after stroke. Stroke, 2002, 33(6), 1706-1711.
[http://dx.doi.org/10.1161/01.STR.0000016405.06729.83] [PMID: 12053015]
[36]
Abbott, N.J.; Rönnbäck, L.; Hansson, E. Astrocyte-endothelial interactions at the blood-brain barrier. Nat. Rev. Neurosci., 2006, 7(1), 41-53.
[http://dx.doi.org/10.1038/nrn1824] [PMID: 16371949]
[37]
Hawkins, B.T.; Davis, T.P. The blood-brain barrier/neurovascular unit in health and disease. Pharmacol. Rev., 2005, 57(2), 173-185.
[http://dx.doi.org/10.1124/pr.57.2.4] [PMID: 15914466]
[38]
Camp, S.M.; Bittman, R.; Chiang, E.T.; Moreno-Vinasco, L.; Mirzapoiazova, T.; Sammani, S.; Lu, X.; Sun, C.; Harbeck, M.; Roe, M.; Natarajan, V.; Garcia, J.G.; Dudek, S.M. Synthetic analogs of FTY720 [2-amino-2-(2-[4-octylphenyl]ethyl)-1,3-propanediol] differentially regulate pulmonary vascular permeability in vivo and in vitro. J. Pharmacol. Exp. Ther., 2009, 331(1), 54-64.
[http://dx.doi.org/10.1124/jpet.109.153544] [PMID: 19592667]
[39]
Prager, B.; Spampinato, S.F.; Ransohoff, R.M. Sphingosine 1-phosphate signaling at the blood-brain barrier. Trends Mol. Med., 2015, 21(6), 354-363.
[http://dx.doi.org/10.1016/j.molmed.2015.03.006] [PMID: 25939882]
[40]
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(7), 1019-1025.
[http://dx.doi.org/10.1111/j.1600-6143.2004.00476.x] [PMID: 15196057]
[41]
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(39), 29190-29200.
[http://dx.doi.org/10.1074/jbc.M604310200] [PMID: 16891661]
[42]
Yanagida, K.; Liu, C.H.; Faraco, G.; Galvani, S.; Smith, H.K.; Burg, N.; Anrather, J.; Sanchez, T.; Iadecola, C.; Hla, T. Size-selective opening of the blood-brain barrier by targeting endothelial sphingosine 1-phosphate receptor 1. Proc. Natl. Acad. Sci. USA, 2017, 114(17), 4531-4536.
[http://dx.doi.org/10.1073/pnas.1618659114] [PMID: 28396408]
[43]
Pilorget, A.; Demeule, M.; Barakat, S.; Marvaldi, J.; Luis, J.; Béliveau, R. Modulation of P-glycoprotein function by sphingosine kinase-1 in brain endothelial cells. J. Neurochem., 2007, 100(5), 1203-1210.
[http://dx.doi.org/10.1111/j.1471-4159.2006.04295.x] [PMID: 17316399]
[44]
(a)Brinkmann, V. FTY720 (fingolimod) in Multiple Sclerosis: therapeutic effects in the immune and the central nervous system. Br. J. Pharmacol., 2009, 158(5), 1173-1182.
[http://dx.doi.org/10.1111/j.1476-5381.2009.00451.x] [PMID: 19814729]
(b)Soliven, B.; Miron, V.; Chun, J. The neurobiology of sphingosine 1-phosphate signaling and sphingosine 1-phosphate receptor modulators. Neurology, 2011, 76(8)(Suppl. 3), S9-S14.
[http://dx.doi.org/10.1212/WNL.0b013e31820d9507] [PMID: 21339490]
(c)Hasegawa, Y.; Suzuki, H.; Sozen, T.; Rolland, W.; Zhang, J.H. Activation of sphingosine 1-phosphate receptor-1 by FTY720 is neuroprotective after ischemic stroke in rats. Stroke, 2010, 41(2), 368-374.
[http://dx.doi.org/10.1161/STROKEAHA.109.568899] [PMID: 19940275]
[45]
Hasegawa, Y.; Suzuki, H.; Altay, O.; Rolland, W.; Zhang, J.H. Role of the sphingosine metabolism pathway on neurons against experimental cerebral ischemia in rats. Transl. Stroke Res., 2013, 4(5), 524-532.
[http://dx.doi.org/10.1007/s12975-013-0260-7] [PMID: 24187597]
[46]
Huang, L.; Wu, Z.B.; Zhuge, Q.; Zheng, W.; Shao, B.; Wang, B.; Sun, F.; Jin, K. Glial scar formation occurs in the human brain after ischemic stroke. Int. J. Med. Sci., 2014, 11(4), 344-348.
[http://dx.doi.org/10.7150/ijms.8140] [PMID: 24578611]
[47]
Sospedra, M.; Martin, R. Immunology of multiple sclerosis. Annu. Rev. Immunol., 2005, 23, 683-747.
[http://dx.doi.org/10.1146/annurev.immunol.23.021704.115707] [PMID: 15771584]
[48]
(a)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(4), 1151-1161.
[http://dx.doi.org/10.1111/j.1471-4159.2007.04629.x] [PMID: 17488279]
(b)Osinde, M.; Mullershausen, F.; Dev, K.K. Phosphorylated FTY720 stimulates ERK phosphorylation in astrocytes via S1P receptors. Neuropharmacology, 2007, 52(5), 1210-1218.
[http://dx.doi.org/10.1016/j.neuropharm.2006.11.010] [PMID: 17379261]
[49]
(a)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(2), 199-206.
[http://dx.doi.org/10.1002/glia.10180] [PMID: 12509810]
(b)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(1), 126-133.
[http://dx.doi.org/10.1124/mol.55.1.126] [PMID: 9882706]
[50]
Choi, J.W.; Gardell, S.E.; Herr, D.R.; Rivera, R.; Lee, C.W.; Noguchi, K.; Teo, S.T.; Yung, Y.C.; Lu, M.; Kennedy, G.; Chun, J. FTY720 (fingolimod) efficacy in an animal model of multiple sclerosis requires astrocyte sphingosine 1-phosphate receptor 1 (S1P1) modulation. Proc. Natl. Acad. Sci. USA, 2011, 108(2), 751-756.
[http://dx.doi.org/10.1073/pnas.1014154108] [PMID: 21177428]
[51]
Kang, Z.; Altuntas, C.Z.; Gulen, M.F.; Liu, C.; Giltiay, N.; Qin, H.; Liu, L.; Qian, W.; Ransohoff, R.M.; Bergmann, C.; Stohlman, S.; Tuohy, V.K.; Li, X. Astrocyte-restricted ablation of interleukin-17-induced Act1-mediated signaling ameliorates autoimmune encephalomyelitis. Immunity, 2010, 32(3), 414-425.
[http://dx.doi.org/10.1016/j.immuni.2010.03.004] [PMID: 20303295]
[52]
Brinkmann, V.; Billich, A.; Baumruker, T.; Heining, P.; Schmouder, R.; Francis, G.; Aradhye, S.; Burtin, P. Fingolimod (FTY720): discovery and development of an oral drug to treat multiple sclerosis. Nat. Rev. Drug Discov., 2010, 9(11), 883-897.
[http://dx.doi.org/10.1038/nrd3248] [PMID: 21031003]
[53]
Brunkhorst, R.; Kanaan, N.; Koch, A.; Ferreirós, N.; Mirceska, A.; Zeiner, P.; Mittelbronn, M.; Derouiche, A.; Steinmetz, H.; Foerch, C.; Pfeilschifter, J.; Pfeilschifter, W. FTY720 treatment in the convalescence period improves functional recovery and reduces reactive astrogliosis in photothrombotic stroke. PLoS One, 2013, 8(7)e70124
[http://dx.doi.org/10.1371/journal.pone.0070124] [PMID: 23936150]
[54]
(a)Mizuma, A.; Yenari, M.A. Anti-inflammatory targets for the treatment of reperfusion injury in stroke. Front. Neurol., 2017, 8, 467.
[http://dx.doi.org/10.3389/fneur.2017.00467] [PMID: 28936196]
(b)Bonaventura, A.; Liberale, L.; Vecchié, A.; Casula, M.; Carbone, F.; Dallegri, F.; Montecucco, F. Update on inflammatory biomarkers and treatments in ischemic stroke. Int. J. Mol. Sci., 2016, 17(12)E1967
[http://dx.doi.org/10.3390/ijms17121967] [PMID: 27898011]
[55]
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(1), 115-124.
[http://dx.doi.org/10.1634/stemcells.2006-0223] [PMID: 16990586]
[56]
Das, A.; Arifuzzaman, S.; Kim, S.H.; Lee, Y.S.; Jung, K.H.; Chai, Y.G. FTY720 (fingolimod) regulates key target genes essential for inflammation in microglial cells as defined by high-resolution mRNA sequencing. Neuropharmacology, 2017, 119, 1-14.
[http://dx.doi.org/10.1016/j.neuropharm.2017.03.034] [PMID: 28373076]
[57]
(a)Qin, C.; Fan, W.H.; Liu, Q.; Shang, K.; Murugan, M.; Wu, L.J.; Wang, W.; Tian, D.S. Fingolimod protects against ischemic white matter damage by modulating microglia toward M2 polarization via STAT3 pathway. Stroke, 2017, 48(12), 3336-3346.
[http://dx.doi.org/10.1161/STROKEAHA.117.018505] [PMID: 29114096]
(b)Gaire, B.P.; Song, M.R.; Choi, J.W. Sphingosine 1-phosphate receptor subtype 3 (S1P3) contributes to brain injury after transient focal cerebral ischemia via modulating microglial activation and their M1 polarization. J. Neuroinflammation, 2018, 15(1), 284.
[http://dx.doi.org/10.1186/s12974-018-1323-1] [PMID: 30305119]
[58]
Dev, K.K.; Mullershausen, F.; Mattes, H.; Kuhn, R.R.; Bilbe, G.; Hoyer, D.; Mir, A. Brain sphingosine-1-phosphate receptors: implication for FTY720 in the treatment of multiple sclerosis. Pharmacol. Ther., 2008, 117(1), 77-93.
[http://dx.doi.org/10.1016/j.pharmthera.2007.08.005] [PMID: 17961662]
[59]
(a)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(4), 1026-1039.
[http://dx.doi.org/10.1046/j.1471-4159.2003.02219.x] [PMID: 14756825]
(b)Rao, T.S.; Lariosa-Willingham, K.D.; Lin, F.F.; Palfreyman, E.L.; Yu, N.; Chun, J.; Webb, M. Pharmacological characterization of lysophospholipid receptor signal transduction pathways in rat cerebrocortical astrocytes. Brain Res., 2003, 990(1-2), 182-194.
[http://dx.doi.org/10.1016/S0006-8993(03)03527-3] [PMID: 14568343]
(c)Rao, T.S.; Lariosa-Willingham, K.D.; Lin, F.F.; Yu, N.; Tham, C.S.; Chun, J.; Webb, M. 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(3), 131-135.
[http://dx.doi.org/10.1016/j.ijdevneu.2004.03.005] [PMID: 15140466]
[60]
Miron, V.E.; Schubart, A.; Antel, J.P. Central nervous system-directed effects of FTY720 (fingolimod). J. Neurol. Sci., 2008, 274(1-2), 13-17.
[http://dx.doi.org/10.1016/j.jns.2008.06.031] [PMID: 18678377]
[61]
Nazari, M.; Keshavarz, S.; Rafati, A.; Namavar, M.R.; Haghani, M. Fingolimod (FTY720) improves hippocampal synaptic plasticity and memory deficit in rats following focal cerebral ischemia. Brain Res. Bull., 2016, 124, 95-102.
[http://dx.doi.org/10.1016/j.brainresbull.2016.04.004] [PMID: 27066884]
[62]
(a)Ravikumar, B.; Sarkar, S.; Davies, J.E.; Futter, M.; Garcia-Arencibia, M.; Green-Thompson, Z.W.; Jimenez-Sanchez, M.; Korolchuk, V.I.; Lichtenberg, M.; Luo, S.; Massey, D.C.; Menzies, F.M.; Moreau, K.; Narayanan, U.; Renna, M.; Siddiqi, F.H.; Underwood, B.R.; Winslow, A.R.; Rubinsztein, D.C. Regulation of mammalian autophagy in physiology and pathophysiology. Physiol. Rev., 2010, 90(4), 1383-1435.
[http://dx.doi.org/10.1152/physrev.00030.2009] [PMID: 20959619]
(b)Yue, Z.; Friedman, L.; Komatsu, M.; Tanaka, K. The cellular pathways of neuronal autophagy and their implication in neurodegenerative diseases. Biochim. Biophys. Acta, 2009, 1793(9), 1496-1507.
[http://dx.doi.org/10.1016/j.bbamcr.2009.01.016] [PMID: 19339210]
[63]
Li, X.; Wang, M.H.; Qin, C.; Fan, W.H.; Tian, D.S.; Liu, J.L. Fingolimod suppresses neuronal autophagy through the mTOR/p70S6K pathway and alleviates ischemic brain damage in mice. PLoS One, 2017, 12(11)e0188748
[http://dx.doi.org/10.1371/journal.pone.0188748] [PMID: 29186197]
[64]
(a)Wen, Y.D.; Sheng, R.; Zhang, L.S.; Han, R.; Zhang, X.; Zhang, X.D.; Han, F.; Fukunaga, K.; Qin, Z.H. Neuronal injury in rat model of permanent focal cerebral ischemia is associated with activation of autophagic and lysosomal pathways. Autophagy, 2008, 4(6), 762-769.
[http://dx.doi.org/10.4161/auto.6412] [PMID: 18567942]
(b)Zheng, Y.Q.; Liu, J.X.; Li, X.Z.; Xu, L.; Xu, Y.G. RNA interference-mediated downregulation of Beclin1 attenuates cerebral ischemic injury in rats. Acta Pharmacol. Sin., 2009, 30(7), 919-927.
[http://dx.doi.org/10.1038/aps.2009.79] [PMID: 19574998]
[65]
Laplante, M.; Sabatini, D.M. mTOR signaling in growth control and disease. Cell, 2012, 149(2), 274-293.
[http://dx.doi.org/10.1016/j.cell.2012.03.017] [PMID: 22500797]
[66]
Rajan, W.D.; Wojtas, B.; Gielniewski, B.; Gieryng, A.; Zawadzka, M.; Kaminska, B. Dissecting functional phenotypes of microglia and macrophages in the rat brain after transient cerebral ischemia. Glia, 2019, 67(2), 232-245.
[http://dx.doi.org/10.1002/glia.23536] [PMID: 30485549]
[67]
Müller, J.; von Bernstorff, W.; Heidecke, C.D.; Schulze, T. Differential S1P receptor profiles on M1- and M2-polarized macrophages affect macrophage cytokine production and migration. BioMed Res. Int., 2017, 20177584621
[http://dx.doi.org/10.1155/2017/7584621] [PMID: 28367448]
[68]
Park, S.J.; Lee, K.P.; Kang, S.; Lee, J.; Sato, K.; Chung, H.Y.; Okajima, F.; Im, D.S. Sphingosine 1-phosphate induced anti-atherogenic and atheroprotective M2 macrophage polarization through IL-4. Cell. Signal., 2014, 26(10), 2249-2258.
[http://dx.doi.org/10.1016/j.cellsig.2014.07.009] [PMID: 25035231]
[69]
Hughes, J.E.; Srinivasan, S.; Lynch, K.R.; Proia, R.L.; Ferdek, P.; Hedrick, C.C. Sphingosine-1-phosphate induces an antiinflammatory phenotype in macrophages. Circ. Res., 2008, 102(8), 950-958.
[http://dx.doi.org/10.1161/CIRCRESAHA.107.170779] [PMID: 18323526]
[70]
(a)Zhao, S.; Adebiyi, M.G.; Zhang, Y.; Couturier, J.P.; Fan, X.; Zhang, H.; Kellems, R.E.; Lewis, D.E.; Xia, Y. Sphingosine-1-phosphate receptor 1 mediates elevated IL-6 signaling to promote chronic inflammation and multitissue damage in sickle cell disease. FASEB J., 2018, 32(5), 2855-2865.
[http://dx.doi.org/10.1096/fj.201600788RR] [PMID: 29401601]
(b)Liang, J.; Nagahashi, M.; Kim, E.Y.; Harikumar, K.B.; Yamada, A.; Huang, W.C.; Hait, N.C.; Allegood, J.C.; Price, M.M.; Avni, D.; Takabe, K.; Kordula, T.; Milstien, S.; Spiegel, S. Sphingosine-1-phosphate links persistent STAT3 activation, chronic intestinal inflammation, and development of colitis-associated cancer. Cancer Cell, 2013, 23(1), 107-120.
[http://dx.doi.org/10.1016/j.ccr.2012.11.013] [PMID: 23273921]
[71]
Maceyka, M.; Harikumar, K.B.; Milstien, S.; Spiegel, S. Sphingosine-1-phosphate signaling and its role in disease. Trends Cell Biol., 2012, 22(1), 50-60.
[http://dx.doi.org/10.1016/j.tcb.2011.09.003] [PMID: 22001186]
[72]
Kappos, L.; Antel, J.; Comi, G.; Montalban, X.; O’Connor, P.; Polman, C.H.; Haas, T.; Korn, A.A.; Karlsson, G.; Radue, E.W.; Group, F.D.S. Oral fingolimod (FTY720) for relapsing multiple sclerosis. N. Engl. J. Med., 2006, 355(11), 1124-1140.
[http://dx.doi.org/10.1056/NEJMoa052643] [PMID: 16971719]
[73]
(a)Hait, N.C.; Wise, L.E.; Allegood, J.C.; O’Brien, M.; Avni, D.; Reeves, T.M.; Knapp, P.E.; Lu, J.; Luo, C.; Miles, M.F.; Milstien, S.; Lichtman, A.H.; Spiegel, S. Active, phosphorylated fingolimod inhibits histone deacetylases and facilitates fear extinction memory. Nat. Neurosci., 2014, 17(7), 971-980.
[http://dx.doi.org/10.1038/nn.3728] [PMID: 24859201]
(b)Gardner, N.M.; Riley, R.T.; Showker, J.L.; Voss, K.A.; Sachs, A.J.; Maddox, J.R.; Gelineau-van Waes, J.B. Elevated nuclear and cytoplasmic FTY720-phosphate in mouse embryonic fibroblasts suggests the potential for multiple mechanisms in FTY720-induced neural tube defects. Toxicol. Sci., 2016, 150(1), 161-168.
[http://dx.doi.org/10.1093/toxsci/kfv321] [PMID: 26719367]
(c)Segura-Ulate, I.; Yang, B.; Vargas-Medrano, J.; Perez, R.G. FTY720 (Fingolimod) reverses α-synuclein-induced downregulation of brain-derived neurotrophic factor mRNA in OLN-93 oligodendroglial cells. Neuropharmacology, 2017, 117, 149-157.
[http://dx.doi.org/10.1016/j.neuropharm.2017.01.028] [PMID: 28153532]
(d)Leo, A.; Citraro, R.; Amodio, N.; De Sarro, C.; Gallo Cantafio, M.E.; Constanti, A.; De Sarro, G.; Russo, E. Fingolimod exerts only temporary antiepileptogenic effects but longer-lasting positive effects on behavior in the WAG/Rij rat absence epilepsy model. Neurotherapeutics, 2017, 14(4), 1134-1147.
[http://dx.doi.org/10.1007/s13311-017-0550-y] [PMID: 28653281]
(e)Baer, A.; Colon-Moran, W.; Bhattarai, N. Characterization of the effects of immunomodulatory drug fingolimod (FTY720) on human T cell receptor signaling pathways. Sci. Rep., 2018, 8(1), 10910.
[http://dx.doi.org/10.1038/s41598-018-29355-0] [PMID: 30026610]
(f)Saddoughi, S.A.; Gencer, S.; Peterson, Y.K.; Ward, K.E.; Mukhopadhyay, A.; Oaks, J.; Bielawski, J.; Szulc, Z.M.; Thomas, R.J.; Selvam, S.P.; Senkal, C.E.; Garrett-Mayer, E.; De Palma, R.M.; Fedarovich, D.; Liu, A.; Habib, A.A.; Stahelin, R.V.; Perrotti, D.; Ogretmen, B. Sphingosine analogue drug FTY720 targets I2PP2A/SET and mediates lung tumour suppression via activation of PP2A-RIPK1-dependent necroptosis. EMBO Mol. Med., 2013, 5(1), 105-121.
[http://dx.doi.org/10.1002/emmm.201201283] [PMID: 23180565]
[74]
Cristóbal, I.; Manso, R.; Rincón, R.; Caramés, C.; Senin, C.; Borrero, A.; Martínez-Useros, J.; Rodriguez, M.; Zazo, S.; Aguilera, O.; Madoz-Gúrpide, J.; Rojo, F.; García-Foncillas, J. PP2A inhibition is a common event in colorectal cancer and its restoration using FTY720 shows promising therapeutic potential. Mol. Cancer Ther., 2014, 13(4), 938-947.
[http://dx.doi.org/10.1158/1535-7163.MCT-13-0150] [PMID: 24448818]
[75]
Saver, J.L.; Albers, G.W.; Dunn, B.; Johnston, K.C.; Fisher, M.; Consortium, S.V. Stroke Therapy Academic Industry Roundtable (STAIR) recommendations for extended window acute stroke therapy trials. Stroke, 2009, 40(7), 2594-2600.
[http://dx.doi.org/10.1161/STROKEAHA.109.552554] [PMID: 19478212]
[76]
Wacker, B.K.; Park, T.S.; Gidday, J.M. Hypoxic preconditioning-induced cerebral ischemic tolerance: role of microvascular sphingosine kinase 2. Stroke, 2009, 40(10), 3342-3348.
[http://dx.doi.org/10.1161/STROKEAHA.109.560714] [PMID: 19644058]
[77]
Shichita, T.; Sugiyama, Y.; Ooboshi, H.; Sugimori, H.; Nakagawa, R.; Takada, I.; Iwaki, T.; Okada, Y.; Iida, M.; Cua, D.J.; Iwakura, Y.; Yoshimura, A. Pivotal role of cerebral interleukin-17-producing gammadeltaT cells in the delayed phase of ischemic brain injury. Nat. Med., 2009, 15(8), 946-950.
[http://dx.doi.org/10.1038/nm.1999] [PMID: 19648929]
[78]
Rolland, W.B.; Krafft, P.R.; Lekic, T.; Klebe, D.; LeGrand, J.; Weldon, A.J.; Xu, L.; Zhang, J.H. Fingolimod confers neuroprotection through activation of Rac1 after experimental germinal matrix hemorrhage in rat pups. J. Neurochem., 2017, 140(5), 776-786.
[http://dx.doi.org/10.1111/jnc.13946] [PMID: 28054340]
[79]
(a)Rolland, W.B.; Lekic, T.; Krafft, P.R.; Hasegawa, Y.; Altay, O.; Hartman, R.; Ostrowski, R.; Manaenko, A.; Tang, J.; Zhang, J.H. Fingolimod reduces cerebral lymphocyte infiltration in experimental models of rodent intracerebral hemorrhage. Exp. Neurol., 2013, 241, 45-55.
[http://dx.doi.org/10.1016/j.expneurol.2012.12.009] [PMID: 23261767]
(b)Lu, L.; Barfejani, A.H.; Qin, T.; Dong, Q.; Ayata, C.; Waeber, C. Fingolimod exerts neuroprotective effects in a mouse model of intracerebral hemorrhage. Brain Res., 2014, 1555, 89-96.
[http://dx.doi.org/10.1016/j.brainres.2014.01.048] [PMID: 24502984]
[80]
(a)Xu, H.L.; Pelligrino, D.A.; Paisansathan, C.; Testai, F.D. Protective role of fingolimod (FTY720) in rats subjected to subarachnoid hemorrhage. J. Neuroinflammation, 2015, 12, 16.
[http://dx.doi.org/10.1186/s12974-015-0234-7] [PMID: 25622980]
(b)Hasegawa, Y.; Uekawa, K.; Kawano, T.; Suzuki, H.; Kim-Mitsuyama, S. Blockage of central sphingosine-1-phosphate receptor does not abolish the protective effect of FTY720 in early brain injury after experimental subarachnoid hemorrhage. Curr. Drug Deliv., 2017, 14(6), 861-866.
[http://dx.doi.org/10.2174/1567201813666160907094401] [PMID: 27605019]
[81]
(a)Zhu, Z.; Fu, Y.; Tian, D.; Sun, N.; Han, W.; Chang, G.; Dong, Y.; Xu, X.; Liu, Q.; Huang, D.; Shi, F.D. Combination of the Immune modulator fingolimod with alteplase in acute ischemic stroke: a pilot trial. Circulation, 2015, 132(12), 1104-1112.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.115.016371] [PMID: 26202811]
(b)Fu, Y.; Hao, J.; Zhang, N.; Ren, L.; Sun, N.; Li, Y.J.; Yan, Y.; Huang, D.; Yu, C.; Shi, F.D. Fingolimod for the treatment of intracerebral hemorrhage: a 2-arm proof-of-concept study. JAMA Neurol., 2014, 71(9), 1092-1101.
[http://dx.doi.org/10.1001/jamaneurol.2014.1065] [PMID: 25003359]
(c)Fu, Y.; Zhang, N.; Ren, L.; Yan, Y.; Sun, N.; Li, Y.J.; Han, W.; Xue, R.; Liu, Q.; Hao, J.; Yu, C.; Shi, F.D. Impact of an immune modulator fingolimod on acute ischemic stroke. Proc. Natl. Acad. Sci. USA, 2014, 111(51), 18315-18320.
[http://dx.doi.org/10.1073/pnas.1416166111] [PMID: 25489101]
[82]
Racca, V.; Di Rienzo, M.; Cavarretta, R.; Toccafondi, A.; Vaini, E.; Ferratini, M.; Rovaris, M. Fingolimod effects on left ventricular function in multiple sclerosis. Mult. Scler., 2016, 22(2), 201-211.
[http://dx.doi.org/10.1177/1352458515587753] [PMID: 26041795]
[83]
Karlsson, G.; Francis, G.; Koren, G.; Heining, P.; Zhang, X.; Cohen, J.A.; Kappos, L.; Collins, W. Pregnancy outcomes in the clinical development program of fingolimod in multiple sclerosis. Neurology, 2014, 82(8), 674-680.
[http://dx.doi.org/10.1212/WNL.0000000000000137] [PMID: 24463630]

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