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Current Neuropharmacology

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ISSN (Print): 1570-159X
ISSN (Online): 1875-6190

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Review Article

From the Molecular Mechanism to Pre-clinical Results: Anti-epileptic Effects of Fingolimod

Author(s): Yam Nath Paudel*, Efthalia Angelopoulou, Christina Piperi, Vadym Gnatkovsky, Iekhsan Othman and Mohd. Farooq Shaikh*

Volume 18, Issue 11, 2020

Page: [1126 - 1137] Pages: 12

DOI: 10.2174/1570159X18666200420125017

Price: $65

Abstract

Epilepsy is a devastating neurological condition characterized by long-term tendency to generate unprovoked seizures, affecting around 1-2 % of the population worldwide. Epilepsy is a serious health concern which often associates with other neurobehavioral comorbidities that further worsen disease conditions. Despite tremendous research, the mainstream anti-epileptic drugs (AEDs) exert only symptomatic relief leading to 30% of untreatable patients. This reflects the complexity of the disease pathogenesis and urges the precise understanding of underlying mechanisms in order to explore novel therapeutic strategies that might alter the disease progression as well as minimize the epilepsy-associated comorbidities. Unfortunately, the development of novel AEDs might be a difficult process engaging huge funds, tremendous scientific efforts and stringent regulatory compliance with a possible chance of end-stage drug failure. Hence, an alternate strategy is drug repurposing, where anti-epileptic effects are elicited from drugs that are already used to treat non-epileptic disorders.

Herein, we provide evidence of the anti-epileptic effects of Fingolimod (FTY720), a modulator of sphingosine-1-phosphate (S1P) receptor, USFDA approved already for Relapsing-Remitting Multiple Sclerosis (RRMS). Emerging experimental findings suggest that Fingolimod treatment exerts disease-modifying anti-epileptic effects based on its anti-neuroinflammatory properties, potent neuroprotection, anti-gliotic effects, myelin protection, reduction of mTOR signaling pathway and activation of microglia and astrocytes. We further discuss the underlying molecular crosstalk associated with the anti-epileptic effects of Fingolimod and provide evidence for repurposing Fingolimod to overcome the limitations of current AEDs.

Keywords: Epilepsy, fingolimod, drug repurposing, S1P receptor, neuroinflammation.

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[1]
Thijs, R.D.; Surges, R.; O’Brien, T.J.; Sander, J.W. Epilepsy in adults. Lancet, 2019, 393(10172), 689-701.
[http://dx.doi.org/10.1016/S0140-6736(18)32596-0] [PMID: 30686584]
[2]
Paudel, Y.N.; Shaikh, M.F.; Shah, S.; Kumari, Y.; Othman, I. Role of inflammation in epilepsy and neurobehavioral comorbidities: Implication for therapy. Eur. J. Pharmacol., 2018, 837, 145-155.
[http://dx.doi.org/10.1016/j.ejphar.2018.08.020] [PMID: 30125565]
[3]
Dichter, M.A. Posttraumatic epilepsy: the challenge of translating discoveries in the laboratory to pathways to a cure. Epilepsia, 2009, 50(Suppl. 2), 41-45.
[http://dx.doi.org/10.1111/j.1528-1167.2008.02009.x] [PMID: 19187293]
[4]
Pitkänen, A.; Engel, J., Jr Past and present definitions of epileptogenesis and its biomarkers. Neurotherapeutics, 2014, 11(2), 231-241.
[http://dx.doi.org/10.1007/s13311-014-0257-2]] [PMID: 24492975]
[5]
Scheffer, I.E.; Berkovic, S.; Capovilla, G.; Connolly, M.B.; French, J.; Guilhoto, L.; Hirsch, E.; Jain, S.; Mathern, G.W.; Moshé, S.L.; Nordli, D.R.; Perucca, E.; Tomson, T.; Wiebe, S.; Zhang, Y.H.; Zuberi, S.M. ILAE classification of the epilepsies: Position paper of the ILAE commission for classification and terminology. Epilepsia, 2017, 58(4), 512-521.
[http://dx.doi.org/10.1111/epi.13709] [PMID: 28276062]
[6]
Vezzani, A.; Balosso, S.; Ravizza, T. Neuroinflammatory pathways as treatment targets and biomarkers in epilepsy. Nat. Rev. Neurol., 2019, 15(8), 459-472.
[http://dx.doi.org/10.1038/s41582-019-0217-x] [PMID: 31263255]
[7]
Kwan, P.; Brodie, M.J. Early identification of refractory epilepsy. N. Engl. J. Med., 2000, 342(5), 314-319.
[http://dx.doi.org/10.1056/NEJM200002033420503] [PMID: 10660394]
[8]
H S. N.; Paudel, Y.N.; K L, K. Envisioning the neuroprotective effect of Metformin in experimental epilepsy: A portrait of molecular crosstalk. Life Sci., 2019, 233 116686
[http://dx.doi.org/10.1016/j.lfs.2019.116686]] [PMID: 31348946]
[9]
Zhao, R.R.; Xu, X.C.; Xu, F.; Zhang, W.L.; Zhang, W.L.; Liu, L.M.; Wang, W.P. Metformin protects against seizures, learning and memory impairments and oxidative damage induced by pentylenetetrazole-induced kindling in mice. Biochem. Biophys. Res. Commun., 2014, 448(4), 414-417.
[http://dx.doi.org/10.1016/j.bbrc.2014.04.130] [PMID: 24802403]
[10]
Mehrabi, S.; Sanadgol, N.; Barati, M.; Shahbazi, A.; Vahabzadeh, G.; Barzroudi, M.; Seifi, M.; Gholipourmalekabadi, M.; Golab, F. Evaluation of metformin effects in the chronic phase of spontaneous seizures in pilocarpine model of temporal lobe epilepsy. Metab. Brain Dis., 2018, 33(1), 107-114.
[http://dx.doi.org/10.1007/s11011-017-0132-z] [PMID: 29080083]
[11]
Zeng, L.H.; Xu, L.; Gutmann, D.H.; Wong, M. Rapamycin prevents epilepsy in a mouse model of tuberous sclerosis complex. Ann. Neurol., 2008, 63(4), 444-453.
[http://dx.doi.org/10.1002/ana.21331] [PMID: 18389497]
[12]
Huang, X.; Zhang, H.; Yang, J.; Wu, J.; McMahon, J.; Lin, Y.; Cao, Z.; Gruenthal, M.; Huang, Y. Pharmacological inhibition of the mammalian target of rapamycin pathway suppresses acquired epilepsy. Neurobiol. Dis., 2010, 40(1), 193-199.
[http://dx.doi.org/10.1016/j.nbd.2010.05.024] [PMID: 20566381]
[13]
Lee, J-K.; Won, J-S.; Singh, A.K.; Singh, I. Statin inhibits kainic acid-induced seizure and associated inflammation and hippocampal cell death. Neurosci. Lett., 2008, 440(3), 260-264.
[http://dx.doi.org/10.1016/j.neulet.2008.05.112] [PMID: 18583044]
[14]
Pereira, M.G.; Becari, C.; Oliveira, J.A.; Salgado, M.C.O.; Garcia-Cairasco, N.; Costa-Neto, C.M. Inhibition of the renin-angiotensin system prevents seizures in a rat model of epilepsy. Clin. Sci. (Lond.), 2010, 119(11), 477-482.
[http://dx.doi.org/10.1042/CS20100053] [PMID: 20533906]
[15]
Georgiev, V.P.; Lazarova, M.B.; Kambourova, T.S. Effects of non-peptide angiotensin II-receptor antagonists on pentylenetetrazol kindling in mice. Neuropeptides, 1996, 30(5), 401-404.
[http://dx.doi.org/10.1016/S0143-4179(96)90000-1] [PMID: 8923498]
[16]
Shafiq, N.; Malhotra, S.; Pandhi, P. Anticonvulsant action of celecoxib (alone and in combination with sub-threshold dose of phenytoin) in electroshock induced convulsion. Methods Find. Exp. Clin. Pharmacol., 2003, 25(2), 87-90.
[http://dx.doi.org/10.1358/mf.2003.25.2.723681] [PMID: 12731453]
[17]
Jung, K-H.; Chu, K.; Lee, S-T.; Kim, J.; Sinn, D-I.; Kim, J-M.; Park, D-K.; Lee, J-J.; Kim, S.U.; Kim, M.; Lee, S.K.; Roh, J.K. Cyclooxygenase-2 inhibitor, celecoxib, inhibits the altered hippocampal neurogenesis with attenuation of spontaneous recurrent seizures following pilocarpine-induced status epilepticus. Neurobiol. Dis., 2006, 23(2), 237-246.
[http://dx.doi.org/10.1016/j.nbd.2006.02.016] [PMID: 16806953]
[18]
Du, C.; Zheng, F.; Wang, X. Exploring novel AEDs from drugs used for treatment of non-epileptic disorders. Expert Rev. Neurother., 2016, 16(4), 449-461.
[http://dx.doi.org/10.1586/14737175.2016.1158101] [PMID: 27010915]
[19]
Mirza, N.; Sills, G.J.; Pirmohamed, M.; Marson, A.G. Identifying new antiepileptic drugs through genomics-based drug repurposing. Hum. Mol. Genet., 2017, 26(3), 527-537.
[http://dx.doi.org/10.1093/hmg/ddw410] [PMID: 28053048]
[20]
Chun, J.; Kihara, Y.; Jonnalagadda, D.; Blaho, V.A. Fingolimod: lessons learned and new opportunities for treating multiple sclerosis and other disorders. Annu. Rev. Pharmacol. Toxicol., 2019, 59, 149-170.
[http://dx.doi.org/10.1146/annurev-pharmtox-010818-021358] [PMID: 30625282]
[21]
Angelopoulou, E.; Piperi, C. Beneficial effects of fingolimod in Alzheimer’s Disease: Molecular mechanisms and therapeutic potential. Neuromolecular Med., 2019, 21(3), 227-238.
[http://dx.doi.org/10.1007/s12017-019-08558-2] [PMID: 31313064]
[22]
Carreras, I.; Aytan, N.; Choi, J-K.; Tognoni, C.M.; Kowall, N.W.; Jenkins, B.G.; Dedeoglu, A. Dual dose-dependent effects of fingolimod in a mouse model of Alzheimer’s disease. Sci. Rep., 2019, 9(1), 10972.
[http://dx.doi.org/10.1038/s41598-019-47287-1] [PMID: 31358793]
[23]
Motyl, J.; Przykaza, Ł.; Boguszewski, P.M.; Kosson, P.; Strosznajder, J.B. Pramipexole and Fingolimod exert neuroprotection in a mouse model of Parkinson’s disease by activation of sphingosine kinase 1 and Akt kinase. Neuropharmacology, 2018, 135, 139-150.
[http://dx.doi.org/10.1016/j.neuropharm.2018.02.023] [PMID: 29481916]
[24]
Zhao, P.; Yang, X.; Yang, L.; Li, M.; Wood, K.; Liu, Q.; Zhu, X. Neuroprotective effects of fingolimod in mouse models of Parkinson’s disease. FASEB J., 2017, 31(1), 172-179.
[http://dx.doi.org/10.1096/fj.201600751r] [PMID: 27671228]
[25]
Wang, Z.; Kawabori, M.; Houkin, K. FTY720 (Fingolimod) Ameliorates brain injury through multiple mechanisms and is a strong candidate for stroke treatment. Curr. Med. Chem., 2019, 26, 1-14.
[http://dx.doi.org/10.2174/0929867326666190308133732] [PMID: 31785606]
[26]
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]
[27]
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]
[28]
Li, W.; Xu, H.; Testai, F.D. Mechanism of action and clinical potential of fingolimod for the treatment of stroke. Front. Neurol., 2016, 7, 139.
[http://dx.doi.org/10.3389/fneur.2016.00139] [PMID: 27617002]
[29]
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]
[30]
Pitsch, J.; Kuehn, J.C.; Gnatkovsky, V.; Müller, J.A.; van Loo, K.M.J.; de Curtis, M.; Vatter, H.; Schoch, S.; Elger, C.E.; Becker, A.J. Anti-epileptogenic and anti-convulsive effects of fingolimod in experimental temporal lobe epilepsy. Mol. Neurobiol., 2019, 56(3), 1825-1840.
[http://dx.doi.org/10.1007/s12035-018-1181-y] [PMID: 29934763]
[31]
Gol, M.; Ghorbanian, D.; Hassanzadeh, S.; Javan, M.; Mirnajafi-Zadeh, J.; Ghasemi-Kasman, M. Fingolimod enhances myelin repair of hippocampus in pentylenetetrazol-induced kindling model. Eur. J. Pharm. Sci., 2017, 96, 72-83.
[http://dx.doi.org/10.1016/j.ejps.2016.09.016] [PMID: 27634580]
[32]
Zhu, X-D.; Chen, J-S.; Zhou, F.; Liu, Q-C.; Chen, G.; Zhang, J-M. Relationship between plasma high mobility group box-1 protein levels and clinical outcomes of aneurysmal subarachnoid hemorrhage. J. Neuroinflammation, 2012, 9, 194.
[http://dx.doi.org/10.1186/1742-2094-9-194] [PMID: 22883976]
[33]
Adachi, K.; Kohara, T.; Nakao, N.; Arita, M.; Chiba, K.; Mishina, T.; Sasaki, S.; Fujita, T. 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.
[http://dx.doi.org/10.1016/0960-894X(95)00127-F]
[34]
Spiegel, S.; Milstien, S. The outs and the ins of sphingosine-1-phosphate in immunity. Nat. Rev. Immunol., 2011, 11(6), 403-415.
[http://dx.doi.org/10.1038/nri2974] [PMID: 21546914]
[35]
Chun, J.; Hartung, H-P. Mechanism of action of oral fingolimod (FTY720) in multiple sclerosis. Clin. Neuropharmacol., 2010, 33(2), 91-101.
[http://dx.doi.org/10.1097/WNF.0b013e3181cbf825] [PMID: 20061941]
[36]
Noguchi, K.; Chun, J. Roles for lysophospholipid S1P receptors in multiple sclerosis. Crit. Rev. Biochem. Mol. Biol., 2011, 46(1), 2-10.
[http://dx.doi.org/10.3109/10409238.2010.522975] [PMID: 20979571]
[37]
Mutoh, T.; Rivera, R.; Chun, J. Insights into the pharmacological relevance of lysophospholipid receptors. Br. J. Pharmacol., 2012, 165(4), 829-844.
[http://dx.doi.org/10.1111/j.1476-5381.2011.01622.x] [PMID: 21838759]
[38]
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(24), 21453-21457.
[http://dx.doi.org/10.1074/jbc.C200176200] [PMID: 11967257]
[39]
Mandala, S.; Hajdu, R.; Bergstrom, J.; Quackenbush, E.; Xie, J.; Milligan, J.; Thornton, R.; Shei, G-J.; Card, D.; Keohane, C.; Rosenbach, M.; Hale, J.; Lynch, C.L.; Rupprecht, K.; Parsons, W.; Rosen, H. Alteration of lymphocyte trafficking by sphingosine-1-phosphate receptor agonists. Science, 2002, 296(5566), 346-349.
[http://dx.doi.org/10.1126/science.1070238] [PMID: 11923495]
[40]
Chalfant, C.E.; Spiegel, S. Sphingosine 1-phosphate and ceramide 1-phosphate: expanding roles in cell signaling. J. Cell Sci., 2005, 118(Pt 20), 4605-4612.
[http://dx.doi.org/10.1242/jcs.02637] [PMID: 16219683]
[41]
Rosen, H.; Goetzl, E.J. Sphingosine 1-phosphate and its receptors: an autocrine and paracrine network. Nat. Rev. Immunol., 2005, 5(7), 560-570.
[http://dx.doi.org/10.1038/nri1650] [PMID: 15999095]
[42]
Tsai, H-C.; Han, M.H. Sphingosine-1-phosphate (S1P) and S1P signaling pathway: therapeutic targets in autoimmunity and inflammation. Drugs, 2016, 76(11), 1067-1079.
[http://dx.doi.org/10.1007/s40265-016-0603-2] [PMID: 27318702]
[43]
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]
[44]
Piccinini, M.; Scandroglio, F.; Prioni, S.; Buccinnà, B.; Loberto, N.; Aureli, M.; Chigorno, V.; Lupino, E.; DeMarco, G.; Lomartire, A.; Rinaudo, M.T.; Sonnino, S.; Prinetti, A. Deregulated sphingolipid metabolism and membrane organization in neurodegenerative disorders. Mol. Neurobiol., 2010, 41(2-3), 314-340.
[http://dx.doi.org/10.1007/s12035-009-8096-6] [PMID: 20127207]
[45]
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]
[46]
Leo, A.; Citraro, R.; Marra, R.; Palma, E.; Paola, E.D.D.; Constanti, A.; De Sarro, G.; Russo, E. The sphingosine 1-phosphate signaling pathway in epilepsy: a possible role for the immunomodulator drug fingolimod in epilepsy treatment. CNS Neurol. Disord. Drug Targets, 2017, 16(3), 311-325.
[http://dx.doi.org/10.2174/1871527315666161104163031] [PMID: 27823573]
[47]
Lee, D.H.; Jeon, B.T.; Jeong, E.A.; Kim, J.S.; Cho, Y.W.; Kim, H.J.; Kang, S.S.; Cho, G.J.; Choi, W.S.; Roh, G.S. Altered expression of sphingosine kinase 1 and sphingosine-1-phosphate receptor 1 in mouse hippocampus after kainic acid treatment. Biochem. Biophys. Res. Commun., 2010, 393(3), 476-480.
[http://dx.doi.org/10.1016/j.bbrc.2010.02.027] [PMID: 20152803]
[48]
Terrone, G.; Balosso, S.; Pauletti, A.; Ravizza, T.; Vezzani, A. Inflammation and reactive oxygen species as disease modifiers in epilepsy. Neuropharmacology, 2020, 167 107742
[http://dx.doi.org/10.1016/j.neuropharm.2019.107742] [PMID: 31421074]
[49]
Cipriani, R.; Chara, J.C.; Rodríguez-Antigüedad, A.; Matute, C. FTY720 attenuates excitotoxicity and neuroinflammation. J. Neuroinflammation, 2015, 12, 86.
[http://dx.doi.org/10.1186/s12974-015-0308-6] [PMID: 25953296]
[50]
Poller, B.; Drewe, J.; Krähenbühl, S.; Huwyler, J.; Gutmann, H. Regulation of BCRP (ABCG2) and P-glycoprotein (ABCB1) by cytokines in a model of the human blood-brain barrier. Cell. Mol. Neurobiol., 2010, 30(1), 63-70.
[http://dx.doi.org/10.1007/s10571-009-9431-1] [PMID: 19629677]
[51]
Yu, C.; Kastin, A.J.; Tu, H.; Waters, S.; Pan, W. TNF activates P-glycoprotein in cerebral microvascular endothelial cells. Cell. Physiol. Biochem., 2007, 20(6), 853-858.
[http://dx.doi.org/10.1159/000110445] [PMID: 17982267]
[52]
Yu, N.; Di, Q.; Liu, H.; Hu, Y.; Jiang, Y.; Yan, Y.K.; Zhang, Y.F.; Zhang, Y.D. Nuclear factor-kappa B activity regulates brain expression of P-glycoprotein in the kainic acid-induced seizure rats. Mediators Inflamm., 2011, 2011 670613
[http://dx.doi.org/10.1155/2011/670613] [PMID: 21403895]
[53]
Gao, F.; Gao, Y.; Meng, F.; Yang, C.; Fu, J.; Li, Y. The Sphingosine 1-Phosphate analogue FTY720 alleviates seizure-induced overexpression of p-glycoprotein in rat hippocampus. Basic Clin. Pharmacol. Toxicol., 2018, 123(1), 14-20.
[http://dx.doi.org/10.1111/bcpt.12973] [PMID: 29380527]
[54]
Vezzani, A.; French, J.; Bartfai, T.; Baram, T.Z. The role of inflammation in epilepsy. Nat. Rev. Neurol., 2011, 7(1), 31-40.
[http://dx.doi.org/10.1038/nrneurol.2010.178] [PMID: 21135885]
[55]
Marchi, N.; Angelov, L.; Masaryk, T.; Fazio, V.; Granata, T.; Hernandez, N.; Hallene, K.; Diglaw, T.; Franic, L.; Najm, I.; Janigro, D. Seizure-promoting effect of blood-brain barrier disruption. Epilepsia, 2007, 48(4), 732-742.
[http://dx.doi.org/10.1111/j.1528-1167.2007.00988.x] [PMID: 17319915]
[56]
Singh, N.; Vijayanti, S.; Saha, L. Targeting crosstalk between Nuclear factor (erythroid-derived 2)-like 2 and Nuclear factor kappa beta pathway by Nrf2 activator dimethyl fumarate in epileptogenesis. Int. J. Neurosci., 2018, 128(10), 987-994.
[http://dx.doi.org/10.1080/00207454.2018.1441149] [PMID: 29447051]
[57]
Terrone, G.; Salamone, A.; Vezzani, A. Inflammation and epilepsy: preclinical findings and potential clinical translation. Curr. Pharm. Des., 2017, 23(37), 5569-5576.
[http://dx.doi.org/10.2174/1381612823666170926113754] [PMID: 28950818]
[58]
Fabene, P.F.; Bramanti, P.; Constantin, G. The emerging role for chemokines in epilepsy. J. Neuroimmunol., 2010, 224(1-2), 22-27.
[http://dx.doi.org/10.1016/j.jneuroim.2010.05.016] [PMID: 20542576]
[59]
Scorza, C.A.; Marques, M.J.G.; Gomes da Silva, S.; Naffah-Mazzacoratti, M.D.G.; Scorza, F.A.; Cavalheiro, E.A. Status epilepticus does not induce acute brain inflammatory response in the Amazon rodent Proechimys, an animal model resistant to epileptogenesis. Neurosci. Lett., 2018, 668, 169-173.
[http://dx.doi.org/10.1016/j.neulet.2017.02.049] [PMID: 28235602]
[60]
Maroso, M.; Balosso, S.; Ravizza, T.; Liu, J.; Aronica, E.; Iyer, A.M.; Rossetti, C.; Molteni, M.; Casalgrandi, M.; Manfredi, A.A.; Bianchi, M.E.; Vezzani, A. Toll-like receptor 4 and high-mobility group box-1 are involved in ictogenesis and can be targeted to reduce seizures. Nat. Med., 2010, 16(4), 413-419.
[http://dx.doi.org/10.1038/nm.2127] [PMID: 20348922]
[61]
Rawat, C. Shivangi; Kushwaha, S.; Sharma, S.; Srivastava, A.K.; Kukreti, R. Altered plasma prostaglandin E2 levels in epilepsy and in response to antiepileptic drug monotherapy. Prostaglandins Leukot. Essent. Fatty Acids, 2020, 153 102056
[http://dx.doi.org/10.1016/j.plefa.2020.102056]] [PMID: 32007745]
[62]
Luo, X.; Li, D.; Cen, D.; He, Z.; Meng, Z.; Liang, L. Effect of intravenous immunoglobulin treatment on brain interferon-gamma and interleukin-6 levels in a rat kindling model. Epilepsy Res., 2010, 88(2-3), 162-167.
[http://dx.doi.org/10.1016/j.eplepsyres.2009.10.014] [PMID: 19944569]
[63]
Ravizza, T.; Vezzani, A. Pharmacological targeting of brain inflammation in epilepsy: Therapeutic perspectives from experimental and clinical studies. Epilepsia Open, 2018, 3(Suppl)(Suppl. 2), 133-142..
[http://dx.doi.org/10.1002/epi4.12242] [PMID: 30564772]
[64]
Sternberg, Z.; Kolb, C.; Chadha, K.; Nir, A.; Nir, R.; George, R.; Johnson, J.; Yu, J.; Hojnacki, D. Fingolimod anti-inflammatory and neuroprotective effects modulation of RAGE axis in multiple sclerosis patients. Neuropharmacology, 2018, 130, 71-76.
[http://dx.doi.org/10.1016/j.neuropharm.2017.11.047] [PMID: 29197515]
[65]
Sehrawat, S.; Rouse, B.T. Anti-inflammatory effects of FTY720 against viral-induced immunopathology: role of drug-induced conversion of T cells to become Foxp3+ regulators. J. Immunol., 2008, 180(11), 7636-7647.
[http://dx.doi.org/10.4049/jimmunol.180.11.7636] [PMID: 18490766]
[66]
Gao, F.; Liu, Y.; Li, X.; Wang, Y.; Wei, D.; Jiang, W. Fingolimod (FTY720) inhibits neuroinflammation and attenuates spontaneous convulsions in lithium-pilocarpine induced status epilepticus in rat model. Pharmacol. Biochem. Behav., 2012, 103(2), 187-196.
[http://dx.doi.org/10.1016/j.pbb.2012.08.025] [PMID: 22960129]
[67]
Devinsky, O.; Vezzani, A.; Najjar, S.; De Lanerolle, N.C.; Rogawski, M.A. Glia and epilepsy: excitability and inflammation. Trends Neurosci., 2013, 36(3), 174-184.
[http://dx.doi.org/10.1016/j.tins.2012.11.008] [PMID: 23298414]
[68]
Crespel, A.; Coubes, P.; Rousset, M-C.; Brana, C.; Rougier, A.; Rondouin, G.; Bockaert, J.; Baldy-Moulinier, M.; Lerner-Natoli, M. Inflammatory reactions in human medial temporal lobe epilepsy with hippocampal sclerosis. Brain Res., 2002, 952(2), 159-169.
[http://dx.doi.org/10.1016/S0006-8993(02)03050-0] [PMID: 12376176]
[69]
Dambach, H.; Hinkerohe, D.; Prochnow, N.; Stienen, M.N.; Moinfar, Z.; Haase, C.G.; Hufnagel, A.; Faustmann, P.M. Glia and epilepsy: experimental investigation of antiepileptic drugs in an astroglia/microglia co-culture model of inflammation. Epilepsia, 2014, 55(1), 184-192.
[http://dx.doi.org/10.1111/epi.12473] [PMID: 24299259]
[70]
Vezzani, A.; Aronica, E.; Mazarati, A.; Pittman, Q.J. Epilepsy and brain inflammation. Exp. Neurol., 2013, 244, 11-21.
[http://dx.doi.org/10.1016/j.expneurol.2011.09.033] [PMID: 21985866]
[71]
Fu, L.; Liu, K.; Wake, H.; Teshigawara, K.; Yoshino, T.; Takahashi, H.; Mori, S.; Nishibori, M. Therapeutic effects of anti-HMGB1 monoclonal antibody on pilocarpine-induced status epilepticus in mice. Sci. Rep., 2017, 7(1), 1179.
[http://dx.doi.org/10.1038/s41598-017-01325-y] [PMID: 28446773]
[72]
Sankar, R.; Shin, D.H.; Liu, H.; Mazarati, A.; Pereira de Vasconcelos, A.; Wasterlain, C.G. Patterns of status epilepticus-induced neuronal injury during development and long-term consequences. J. Neurosci., 1998, 18(20), 8382-8393.
[http://dx.doi.org/10.1523/JNEUROSCI.18-20-08382.1998] [PMID: 9763481]
[73]
Foresti, M.L.; Arisi, G.M.; Shapiro, L.A. Role of glia in epilepsy-associated neuropathology, neuroinflammation and neurogenesis. Brain Res. Brain Res. Rev., 2011, 66(1-2), 115-122.
[http://dx.doi.org/10.1016/j.brainresrev.2010.09.002] [PMID: 20837059]
[74]
Borges, K.; Gearing, M.; McDermott, D.L.; Smith, A.B.; Almonte, A.G.; Wainer, B.H.; Dingledine, R. Neuronal and glial pathological changes during epileptogenesis in the mouse pilocarpine model. Exp. Neurol., 2003, 182(1), 21-34.
[http://dx.doi.org/10.1016/S0014-4886(03)00086-4] [PMID: 12821374]
[75]
Groves, A.; Kihara, Y.; Chun, J. Fingolimod: direct CNS effects of sphingosine 1-phosphate (S1P) receptor modulation and implications in multiple sclerosis therapy. J. Neurol. Sci., 2013, 328(1-2), 9-18.
[http://dx.doi.org/10.1016/j.jns.2013.02.011] [PMID: 23518370]
[76]
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]
[77]
Mao, X-Y.; Zhou, H-H.; Jin, W-L. Redox-related neuronal death and crosstalk as drug targets: Focus on epilepsy. Front. Neurosci., 2019, 13, 512.
[http://dx.doi.org/10.3389/fnins.2019.00512] [PMID: 31191222]
[78]
Fricker, M.; Tolkovsky, A.M.; Borutaite, V.; Coleman, M.; Brown, G.C. Neuronal cell death. Physiol. Rev., 2018, 98(2), 813-880.
[http://dx.doi.org/10.1152/physrev.00011.2017] [PMID: 29488822]
[79]
Li, Q.; Li, Q-Q.; Jia, J-N.; Cao, S.; Wang, Z-B.; Wang, X.; Luo, C.; Zhou, H-H.; Liu, Z-Q.; Mao, X-Y. Sodium valproate ameliorates neuronal apoptosis in a kainic acid model of epilepsy via Enhancing PKC-Dependent GABAAR γ2 Serine 327 phosphorylation. Neurochem. Res., 2018, 43(12), 2343-2352.
[http://dx.doi.org/10.1007/s11064-018-2659-8] [PMID: 30311181]
[80]
McEwen, B.S. Allostasis, allostatic load, and the aging nervous system: role of excitatory amino acids and excitotoxicity. Neurochem. Res., 2000, 25(9-10), 1219-1231.
[http://dx.doi.org/10.1023/A:1007687911139] [PMID: 11059796]
[81]
Reyes-Mendoza, J.; Morales, T. Post-treatment with prolactin protects hippocampal CA1 neurons of the ovariectomized female rat against kainic acid-induced neurodegeneration. Neuroscience, 2016, 328, 58-68.
[http://dx.doi.org/10.1016/j.neuroscience.2016.04.030] [PMID: 27126559]
[82]
Friedman, L.K.; Pellegrini-Giampietro, D.E.; Sperber, E.F.; Bennett, M.V.; Moshé, S.L.; Zukin, R.S. Kainate-induced status epilepticus alters glutamate and GABAA receptor gene expression in adult rat hippocampus: an in situ hybridization study. J. Neurosci., 1994, 14(5 Pt 1), 2697-2707.
[http://dx.doi.org/10.1523/JNEUROSCI.14-05-02697.1994] [PMID: 8182436]
[83]
Wang, Q.; Yu, S.; Simonyi, A.; Sun, G.Y.; Sun, A.Y. Kainic acid-mediated excitotoxicity as a model for neurodegeneration. Mol. Neurobiol., 2005, 31(1-3), 3-16.
[http://dx.doi.org/10.1385/MN:31:1-3:003] [PMID: 15953808]
[84]
Meng, X-F.; Yu, J-T.; Song, J-H.; Chi, S.; Tan, L. Role of the mTOR signaling pathway in epilepsy. J. Neurol. Sci., 2013, 332(1-2), 4-15.
[http://dx.doi.org/10.1016/j.jns.2013.05.029] [PMID: 23773767]
[85]
Galanopoulou, A.S.; Gorter, J.A.; Cepeda, C. Finding a better drug for epilepsy: the mTOR pathway as an antiepileptogenic target. Epilepsia, 2012, 53(7), 1119-1130.
[http://dx.doi.org/10.1111/j.1528-1167.2012.03506.x] [PMID: 22578218]
[86]
Zeng, L-H.; Rensing, N.R.; Wong, M. The mammalian target of rapamycin signaling pathway mediates epileptogenesis in a model of temporal lobe epilepsy. J. Neurosci., 2009, 29(21), 6964-6972.
[http://dx.doi.org/10.1523/JNEUROSCI.0066-09.2009] [PMID: 19474323]
[87]
You, Y.; Bai, H.; Wang, C.; Chen, L-W.; Liu, B.; Zhang, H.; Gao, G-D. Myelin damage of hippocampus and cerebral cortex in rat pentylenetetrazol model. Brain Res., 2011, 1381, 208-216.
[http://dx.doi.org/10.1016/j.brainres.2011.01.011] [PMID: 21256118]
[88]
Concha, L.; Beaulieu, C.; Collins, D.L.; Gross, D.W. White-matter diffusion abnormalities in temporal-lobe epilepsy with and without mesial temporal sclerosis. J. Neurol. Neurosurg. Psychiatry, 2009, 80(3), 312-319.
[http://dx.doi.org/10.1136/jnnp.2007.139287] [PMID: 18977826]
[89]
Nilsson, D.; Go, C.; Rutka, J.T.; Rydenhag, B.; Mabbott, D.J.; Snead, O.C., III; Raybaud, C.R.; Widjaja, E. Bilateral diffusion tensor abnormalities of temporal lobe and cingulate gyrus white matter in children with temporal lobe epilepsy. Epilepsy Res., 2008, 81(2-3), 128-135.
[http://dx.doi.org/10.1016/j.eplepsyres.2008.05.002] [PMID: 18595664]
[90]
Scanlon, C.; Mueller, S.G.; Cheong, I.; Hartig, M.; Weiner, M.W.; Laxer, K.D. Grey and white matter abnormalities in temporal lobe epilepsy with and without mesial temporal sclerosis. J. Neurol., 2013, 260(9), 2320-2329.
[http://dx.doi.org/10.1007/s00415-013-6974-3] [PMID: 23754695]
[91]
Zattoni, M.; Mura, M.L.; Deprez, F.; Schwendener, R.A.; Engelhardt, B.; Frei, K.; Fritschy, J-M. Brain infiltration of leukocytes contributes to the pathophysiology of temporal lobe epilepsy. J. Neurosci., 2011, 31(11), 4037-4050.
[http://dx.doi.org/10.1523/JNEUROSCI.6210-10.2011] [PMID: 21411646]
[92]
McFarland, H.F.; Martin, R. Multiple sclerosis: a complicated picture of autoimmunity. Nat. Immunol., 2007, 8(9), 913-919.
[http://dx.doi.org/10.1038/ni1507] [PMID: 17712344]
[93]
Compston, A.; Coles, A. Multiple sclerosis. Lancet, 2008, 372(9648), 1502-1517.
[http://dx.doi.org/10.1016/S0140-6736(08)61620-7] [PMID: 18970977]
[94]
Volpi, C.; Orabona, C.; Macchiarulo, A.; Bianchi, R.; Puccetti, P.; Grohmann, U. Preclinical discovery and development of fingolimod for the treatment of multiple sclerosis. Expert Opin. Drug Discov., 2019, 14(11), 1199-1212.
[http://dx.doi.org/10.1080/17460441.2019.1646244] [PMID: 31389262]
[95]
Pack, A. Is There a Relationship Between Multiple Sclerosis and Epilepsy? If So What Does It Tell Us About Epileptogenesis? Epilepsy Curr., 2018, 18(2), 95-96.
[http://dx.doi.org/10.5698/1535-7597.18.2.95] [PMID: 29645004]
[96]
Gasparini, S.; Ferlazzo, E.; Ascoli, M.; Sueri, C.; Cianci, V.; Russo, C.; Pisani, L.R.; Striano, P.; Elia, M.; Beghi, E.; Colica, C.; Aguglia, U. Epilepsy Study Group of the Italian Neurological Society. Risk factors for unprovoked epileptic seizures in multiple sclerosis: a systematic review and meta-analysis. Neurol. Sci., 2017, 38(3), 399-406.
[http://dx.doi.org/10.1007/s10072-016-2803-7] [PMID: 28054170]
[97]
Marrie, R.A.; Reider, N.; Cohen, J.; Trojano, M.; Sorensen, P.S.; Cutter, G.; Reingold, S.; Stuve, O. A systematic review of the incidence and prevalence of sleep disorders and seizure disorders in multiple sclerosis. Mult. Scler., 2015, 21(3), 342-349.
[http://dx.doi.org/10.1177/1352458514564486] [PMID: 25533301]
[98]
Koch, M.; Uyttenboogaart, M.; Polman, S.; De Keyser, J. Seizures in multiple sclerosis. Epilepsia, 2008, 49(6), 948-953.
[http://dx.doi.org/10.1111/j.1528-1167.2008.01565.x] [PMID: 18336559]
[99]
Poser, C.M.; Brinar, V.V. Epilepsy and multiple sclerosis. Epilepsy Behav., 2003, 4(1), 6-12.
[http://dx.doi.org/10.1016/S1525-5050(02)00646-7] [PMID: 12609222]
[100]
Chou, I.J.; Kuo, C.F.; Tanasescu, R.; Tench, C.R.; Tiley, C.G.; Constantinescu, C.S.; Whitehouse, W.P. Epilepsy and associated mortality in patients with multiple sclerosis. Eur. J. Neurol., 2019, 26(2), 342-e23.
[http://dx.doi.org/10.1111/ene.13821] [PMID: 30312502]
[101]
Forsgren, L.; Beghi, E.; Oun, A.; Sillanpää, M. The epidemiology of epilepsy in Europe - a systematic review. Eur. J. Neurol., 2005, 12(4), 245-253.
[http://dx.doi.org/10.1111/j.1468-1331.2004.00992.x] [PMID: 15804240]
[102]
Lapato, A.S.; Szu, J.I.; Hasselmann, J.P.C.; Khalaj, A.J.; Binder, D.K.; Tiwari-Woodruff, S.K. Chronic demyelination-induced seizures. Neuroscience, 2017, 346, 409-422.
[http://dx.doi.org/10.1016/j.neuroscience.2017.01.035] [PMID: 28153692]
[103]
Lucchinetti, C.F.; Popescu, B.F.; Bunyan, R.F.; Moll, N.M.; Roemer, S.F.; Lassmann, H.; Brück, W.; Parisi, J.E.; Scheithauer, B.W.; Giannini, C.; Weigand, S.D.; Mandrekar, J.; Ransohoff, R.M. Inflammatory cortical demyelination in early multiple sclerosis. N. Engl. J. Med., 2011, 365(23), 2188-2197.
[http://dx.doi.org/10.1056/NEJMoa1100648] [PMID: 22150037]
[104]
Kutzelnigg, A.; Lucchinetti, C.F.; Stadelmann, C.; Brück, W.; Rauschka, H.; Bergmann, M.; Schmidbauer, M.; Parisi, J.E.; Lassmann, H. Cortical demyelination and diffuse white matter injury in multiple sclerosis. Brain, 2005, 128(Pt 11), 2705-2712.
[http://dx.doi.org/10.1093/brain/awh641] [PMID: 16230320]
[105]
Calabrese, M.; De Stefano, N.; Atzori, M.; Bernardi, V.; Mattisi, I.; Barachino, L.; Rinaldi, L.; Morra, A.; McAuliffe, M.M.; Perini, P.; Battistin, L.; Gallo, P. Extensive cortical inflammation is associated with epilepsy in multiple sclerosis. J. Neurol., 2008, 255(4), 581-586.
[http://dx.doi.org/10.1007/s00415-008-0752-7] [PMID: 18227989]
[106]
Uribe-San-Martín, R.; Ciampi-Díaz, E.; Suarez-Hernández, F.; Vásquez-Torres, M.; Godoy-Fernández, J.; Cárcamo-Rodríguez, C. Prevalence of epilepsy in a cohort of patients with multiple sclerosis. Seizure, 2014, 23(1), 81-83.
[http://dx.doi.org/10.1016/j.seizure.2013.09.008] [PMID: 24099836]
[107]
Kelley, B.J.; Rodriguez, M. Seizures in patients with multiple sclerosis: epidemiology, pathophysiology and management. CNS Drugs, 2009, 23(10), 805-815.
[http://dx.doi.org/10.2165/11310900-000000000-00000] [PMID: 19739692]
[108]
Moreau, T.; Sochurkova, D.; Lemesle, M.; Madinier, G.; Billiar, T.; Giroud, M.; Dumas, R. Epilepsy in patients with multiple sclerosis: radiological-clinical correlations. Epilepsia, 1998, 39(8), 893-896.
[http://dx.doi.org/10.1111/j.1528-1157.1998.tb01187.x] [PMID: 9701383]
[109]
Olafsson, E.; Benedikz, J.; Hauser, W.A. Risk of epilepsy in patients with multiple sclerosis: a population-based study in Iceland. Epilepsia, 1999, 40(6), 745-747.
[http://dx.doi.org/10.1111/j.1528-1157.1999.tb00772.x] [PMID: 10368072]
[110]
Solaro, C.; Brichetto, G.; Battaglia, M.A.; Messmer Uccelli, M.; Mancardi, G.L. Antiepileptic medications in multiple sclerosis: adverse effects in a three-year follow-up study. Neurol. Sci., 2005, 25(6), 307-310.
[http://dx.doi.org/10.1007/s10072-004-0362-9] [PMID: 15729492]
[111]
Zhang, J.; Zhang, Z.G.; Li, Y.; Ding, X.; Shang, X.; Lu, M.; Elias, S.B.; Chopp, M. Fingolimod treatment promotes proliferation and differentiation of oligodendrocyte progenitor cells in mice with experimental autoimmune encephalomyelitis. Neurobiol. Dis., 2015, 76, 57-66.
[http://dx.doi.org/10.1016/j.nbd.2015.01.006] [PMID: 25680941]
[112]
Singh, A.; Trevick, S. The epidemiology of global epilepsy. Neurol. Clin., 2016, 34(4), 837-847.
[http://dx.doi.org/10.1016/j.ncl.2016.06.015] [PMID: 27719996]
[113]
Patel, D.C.; Tewari, B.P.; Chaunsali, L.; Sontheimer, H. Neuron-glia interactions in the pathophysiology of epilepsy. Nat. Rev. Neurosci., 2019, 20(5), 282-297.
[http://dx.doi.org/10.1038/s41583-019-0126-4] [PMID: 30792501]
[114]
Sivapalarajah, S.; Krishnakumar, M.; Bickerstaffe, H.; Chan, Y.; Clarkson, J.; Hampden-Martin, A.; Mirza, A.; Tanti, M.; Marson, A.; Pirmohamed, M.; Mirza, N. The prescribable drugs with efficacy in experimental epilepsies (PDE3) database for drug repurposing research in epilepsy. Epilepsia, 2018, 59(2), 492-501.
[http://dx.doi.org/10.1111/epi.13994] [PMID: 29341109]
[115]
Klein, P.; Friedman, A.; Hameed, M.Q.; Kaminski, R.M.; Bar-Klein, G.; Klitgaard, H.; Koepp, M.; Jozwiak, S.; Prince, D.A.; Rotenberg, A.; Twyman, R.; Vezzani, A.; Wong, M.; Löscher, W. Repurposed molecules for antiepileptogenesis: Missing an opportunity to prevent epilepsy? Epilepsia, 2020, 61(3), 359-386.
[http://dx.doi.org/10.1111/epi.16450] [PMID: 32196665]
[116]
Dadas, A.; Janigro, D. Breakdown of blood brain barrier as a mechanism of post-traumatic epilepsy. Neurobiol. Dis., 2019, 123, 20-26.
[http://dx.doi.org/10.1016/j.nbd.2018.06.022] [PMID: 30030025]
[117]
Nishihara, H.; Shimizu, F.; Sano, Y.; Takeshita, Y.; Maeda, T.; Abe, M.; Koga, M.; Kanda, T. Fingolimod prevents blood-brain barrier disruption induced by the sera from patients with multiple sclerosis. PLoS One, 2015, 10(3) e0121488
[http://dx.doi.org/10.1371/journal.pone.0121488] [PMID: 25774903]
[118]
Mehling, M.; Kappos, L.; Derfuss, T. Fingolimod for multiple sclerosis: mechanism of action, clinical outcomes, and future directions. Curr. Neurol. Neurosci. Rep., 2011, 11(5), 492-497.
[http://dx.doi.org/10.1007/s11910-011-0216-9] [PMID: 21789537]
[119]
Calabresi, P.A.; Radue, E-W.; Goodin, D.; Jeffery, D.; Rammohan, K.W.; Reder, A.T.; Vollmer, T.; Agius, M.A.; Kappos, L.; Stites, T.; Li, B.; Cappiello, L.; von Rosenstiel, P.; Lublin, F.D. 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(6), 545-556.
[http://dx.doi.org/10.1016/S1474-4422(14)70049-3] [PMID: 24685276]

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