Drug Treatment of Epilepsy: From Serendipitous Discovery to Evolutionary
Mechanisms

Shengying       Lou; Sunliang       Cui
doi:10.2174/0929867328666210910124727
Abstract

Epilepsy is a chronic brain disorder caused by the abnormal firing of neurons. Up to now, the use of antiepileptic drugs is the main method of epilepsy treatment. The development of antiepileptic drugs lasted for centuries. In general, most agents entering clinical practice act on the balance mechanisms of brain “excitability-inhibition”. More specifically, they target voltage-gated ion channels, GABAergic transmission and glutamatergic transmission. In recent years, some novel drugs representing new mechanisms of action have been discovered. Although there are about 30 available drugs in the market, it is still in urgent need of discovering more effective and safer drugs. The development of new antiepileptic drugs is into a new era: from serendipitous discovery to evolutionary mechanism-based design. This article presents an overview of drug treatment of epilepsy, including a series of traditional and novel drugs.
Keywords: Antiepileptic drugs, mechanism of action, voltage-gated ion channels, glutamate, GABA, synaptic vesicles.
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[1] 
Stafstrom, C.E. Epilepsy: A review of selected clinical syndromes and advances in basic science. J. Cereb. Blood Flow Metab.,  2006, 26(8), 983-1004.
[http://dx.doi.org/10.1038/sj.jcbfm.9600265] [PMID: 16437061] 
[2] 
Abram, M.; Jakubiec, M.; Kamiński, K. Chirality as an important factor for the development of new antiepileptic drugs. ChemMedChem,  2019, 14(20), 1744-1761.
[http://dx.doi.org/10.1002/cmdc.201900367] [PMID: 31476107] 
[3] 
Fisher, R.S.; Acevedo, C.; Arzimanoglou, A.; Bogacz, A.; Cross, J.H.; Elger, C.E.; Engel, J., Jr; Forsgren, L.; French, J.A.; Glynn, M.; Hesdorffer, D.C.; Lee, B.I.; Mathern, G.W.; Moshé, S.L.; Perucca, E.; Scheffer, I.E.; Tomson, T.; Watanabe, M.; Wiebe, S. ILAE official report: A practical clinical definition of epilepsy. Epilepsia,  2014, 55(4), 475-482.
[http://dx.doi.org/10.1111/epi.12550] [PMID: 24730690] 
[4] 
Devinsky, O.; Spruill, T.; Thurman, D.; Friedman, D. Recognizing and preventing epilepsy-related mortality: A call for action. Neurology,  2016, 86(8), 779-786.
[http://dx.doi.org/10.1212/WNL.0000000000002253] [PMID: 26674330] 
[5] 
Manolis, T.A.; Manolis, A.A.; Melita, H.; Manolis, A.S. Sudden unexpected death in epilepsy: The neuro-cardio-respiratory connection. Seizure,  2019, 64, 65-73.
[http://dx.doi.org/10.1016/j.seizure.2018.12.007] [PMID: 30566897] 
[6] 
Devinsky, O.; Vezzani, A.; O’Brien, T.J.; Jette, N.; Scheffer, I.E.; de Curtis, M.; Perucca, P. Epilepsy. Nat. Rev. Dis. Primers,  2018, 4, 18024.
[http://dx.doi.org/10.1038/nrdp.2018.24] [PMID: 29722352] 
[7] 
Lucke-Wold, B.P.; Nguyen, L.; Turner, R.C.; Logsdon, A.F.; Chen, Y-W.; Smith, K.E.; Huber, J.D.; Matsumoto, R.; Rosen, C.L.; Tucker, E.S.; Richter, E. Traumatic brain injury and epilepsy: Underlying mechanisms leading to seizure. Seizure,  2015, 33, 13-23.
[http://dx.doi.org/10.1016/j.seizure.2015.10.002] [PMID: 26519659] 
[8] 
Goldberg, E.M.; Coulter, D.A. Mechanisms of epileptogenesis: A convergence on neural circuit dysfunction. Nat. Rev. Neurosci.,  2013, 14(5), 337-349.
[http://dx.doi.org/10.1038/nrn3482] [PMID: 23595016] 
[9] 
Wang, Y.; Chen, Z. An update for epilepsy research and antiepileptic drug development: Toward precise circuit therapy. Pharmacol. Ther.,  2019, 201, 77-93.
[http://dx.doi.org/10.1016/j.pharmthera.2019.05.010] [PMID: 31128154] 
[10] 
Franco, V.; French, J.A.; Perucca, E. Challenges in the clinical development of new antiepileptic drugs. Pharmacol. Res.,  2016, 103, 95-104.
[http://dx.doi.org/10.1016/j.phrs.2015.11.007] [PMID: 26611249] 
[11] 
Moshé, S.L.; Perucca, E.; Ryvlin, P.; Tomson, T. Epilepsy: New advances. Lancet,  2015, 385(9971), 884-898.
[http://dx.doi.org/10.1016/S0140-6736(14)60456-6] [PMID: 25260236] 
[12] 
Shorvon, S.D. Drug treatment of epilepsy in the century of the ILAE: The first 50 years, 1909-1958. Epilepsia,  2009, 50(Suppl. 3), 69-92.
[http://dx.doi.org/10.1111/j.1528-1167.2009.02041.x] [PMID: 19298434] 
[13] 
Löscher, W. Animal models of seizures and epilepsy: Past, present, and future role for the discovery of antiseizure drugs. Neurochem. Res.,  2017, 42(7), 1873-1888.
[http://dx.doi.org/10.1007/s11064-017-2222-z] [PMID: 28290134] 
[14] 
Brodie, M.J. Antiepileptic drug therapy the story so far. Seizure,  2010, 19(10), 650-655.
[http://dx.doi.org/10.1016/j.seizure.2010.10.027] [PMID: 21075011] 
[15] 
Shorvon, S.D. Drug treatment of epilepsy in the century of the ILAE: the second 50 years, 1959-2009. Epilepsia,  2009, 50(Suppl. 3), 93-130.
[http://dx.doi.org/10.1111/j.1528-1167.2009.02042.x] [PMID: 19298435] 
[16] 
Bialer, M.; White, H.S. Key factors in the discovery and development of new antiepileptic drugs. Nat. Rev. Drug Discov.,  2010, 9(1), 68-82.
[http://dx.doi.org/10.1038/nrd2997] [PMID: 20043029] 
[17] 
de Lera Ruiz, M.; Kraus, R.L. Voltage-gated sodium channels: Structure, function, pharmacology, and clinical indications. J. Med. Chem.,  2015, 58(18), 7093-7118.
[http://dx.doi.org/10.1021/jm501981g] [PMID: 25927480] 
[18] 
Mantegazza, M.; Curia, G.; Biagini, G.; Ragsdale, D.S.; Avoli, M. Voltage-gated sodium channels as therapeutic targets in epilepsy and other neurological disorders. Lancet Neurol.,  2010, 9(4), 413-424.
[http://dx.doi.org/10.1016/S1474-4422(10)70059-4] [PMID: 20298965] 
[19] 
Payandeh, J.; Scheuer, T.; Zheng, N.; Catterall, W.A. The crystal structure of a voltage-gated sodium channel. Nature,  2011, 475(7356), 353-358.
[http://dx.doi.org/10.1038/nature10238] [PMID: 21743477] 
[20] 
Zhang, Y.; Wang, K.; Yu, Z. Drug development in channelopathies: Allosteric modulation of ligand-gated and voltage-gated Ion channels. J. Med. Chem.,  2020, 63(24), 15258-15278.
[http://dx.doi.org/10.1021/acs.jmedchem.0c01304] [PMID: 33253554] 
[21] 
Chow, C.Y.; Absalom, N.; Biggs, K.; King, G.F.; Ma, L. Venom-derived modulators of epilepsy-related ion channels. Biochem. Pharmacol.,  2020, 181, 114043.
[http://dx.doi.org/10.1016/j.bcp.2020.114043] [PMID: 32445870] 
[22] 
Löscher, W.; Klitgaard, H.; Twyman, R.E.; Schmidt, D. New avenues for anti-epileptic drug discovery and development. Nat. Rev. Drug Discov.,  2013, 12(10), 757-776.
[http://dx.doi.org/10.1038/nrd4126] [PMID: 24052047] 
[23] 
Patocka, J.; Wu, Q.; Nepovimova, E.; Kuca, K. Phenytoin - An anti-seizure drug: Overview of its chemistry, pharmacology and toxicology. Food Chem. Toxicol.,  2020, 142, 111393.
[http://dx.doi.org/10.1016/j.fct.2020.111393] [PMID: 32376339] 
[24] 
Anger, T.; Madge, D.J.; Mulla, M.; Riddall, D. Medicinal chemistry of neuronal voltage-gated sodium channel blockers. J. Med. Chem.,  2001, 44(2), 115-137.
[http://dx.doi.org/10.1021/jm000155h] [PMID: 11170622] 
[25] 
Keppel Hesselink, J.M. Phenytoin: a step by step insight into its multiple mechanisms of action-80 years of mechanistic studies in neuropharmacology. J. Neurol.,  2017, 264(9), 2043-2047.
[http://dx.doi.org/10.1007/s00415-017-8465-4] [PMID: 28349209] 
[26] 
Patejdl, R.; Leroux, A-C.; Noack, T. Phenytoin inhibits contractions of rat gastrointestinal and portal vein smooth muscle by inhibiting calcium entry. Neurogastroenterol. Motil.,  2015, 27(10), 1453-1465.
[http://dx.doi.org/10.1111/nmo.12645] [PMID: 26265316] 
[27] 
Brodie, M.J. Sodium channel blockers in the treatment of epilepsy. CNS Drugs,  2017, 31(7), 527-534.
[http://dx.doi.org/10.1007/s40263-017-0441-0] [PMID: 28523600] 
[28] 
Booker, S.A.; Pires, N.; Cobb, S.; Soares-da-Silva, P.; Vida, I. Carbamazepine and oxcarbazepine, but not eslicarbazepine, enhance excitatory synaptic transmission onto hippocampal CA1 pyramidal cells through an antagonist action at adenosine A1 receptors. Neuropharmacology,  2015, 93, 103-115.
[http://dx.doi.org/10.1016/j.neuropharm.2015.01.019] [PMID: 25656478] 
[29] 
Beydoun, A.; DuPont, S.; Zhou, D.; Matta, M.; Nagire, V.; Lagae, L. Current role of carbamazepine and oxcarbazepine in the management of epilepsy. Seizure,  2020, 83, 251-263.
[http://dx.doi.org/10.1016/j.seizure.2020.10.018] [PMID: 33334546] 
[30] 
Bosak, M.; Słowik, A.; Iwańska, A.; Lipińska, M.; Turaj, W. Co-medication and potential drug interactions among patients with epilepsy. Seizure,  2019, 66, 47-52.
[http://dx.doi.org/10.1016/j.seizure.2019.01.014] [PMID: 30798113] 
[31] 
Patsalos, P.N.; Stephenson, T.J.; Krishna, S.; Elyas, A.A.; Lascelles, P.T.; Wiles, C.M. Side-effects induced by carbamazepine-10,11-epoxide. Lancet,  1985, 2(8453), 496.
[http://dx.doi.org/10.1016/S0140-6736(85)90420-9] [PMID: 2863509] 
[32] 
Lawthom, C. Carbamazepine: Out with the old, in with the new? Seizure,  2020, 83, 246-248.
[http://dx.doi.org/10.1016/j.seizure.2020.10.026] [PMID: 33334544] 
[33] 
Bagal, S.K.; Brown, A.D.; Cox, P.J.; Omoto, K.; Owen, R.M.; Pryde, D.C.; Sidders, B.; Skerratt, S.E.; Stevens, E.B.; Storer, R.I.; Swain, N.A. Ion channels as therapeutic targets: A drug discovery perspective. J. Med. Chem.,  2013, 56(3), 593-624.
[http://dx.doi.org/10.1021/jm3011433] [PMID: 23121096] 
[34] 
Romoli, M.; Mazzocchetti, P.; D’Alonzo, R.; Siliquini, S.; Rinaldi, V.E.; Verrotti, A.; Calabresi, P.; Costa, C. Valproic acid and epilepsy: From molecular mechanisms to clinical evidences. Curr. Neuropharmacol.,  2019, 17(10), 926-946.
[http://dx.doi.org/10.2174/1570159X17666181227165722] [PMID: 30592252] 
[35] 
Campos, M.S.A.; Ayres, L.R.; Morelo, M.R.S.; Carizio, F.A.M.; Pereira, L.R.L. Comparative efficacy of antiepileptic drugs for patients with generalized epileptic seizures: systematic review and network meta-analyses. Int. J. Clin. Pharm.,  2018, 40(3), 589-598.
[http://dx.doi.org/10.1007/s11096-018-0641-9] [PMID: 29744790] 
[36] 
Andrade, C. Valproate in pregnancy: Recent research and regulatory responses. J. Clin. Psychiatry.,  2018, 79(3), 18f12351.
[http://dx.doi.org/10.4088/JCP.18f12351] [PMID: 29873961] 
[37] 
Mitra-Ghosh, T.; Callisto, S.P.; Lamba, J.K.; Remmel, R.P.; Birnbaum, A.K.; Barbarino, J.M.; Klein, T.E.; Altman, R.B. PharmGKB summary: lamotrigine pathway, pharmacokinetics and pharmacodynamics. Pharmacogenet. Genomics,  2020, 30(4), 81-90.
[http://dx.doi.org/10.1097/FPC.0000000000000397] [PMID: 32187155] 
[38] 
Kuo, C-C. A common anticonvulsant binding site for phenytoin, carbamazepine, and lamotrigine in neuronal Na+ channels. Mol. Pharmacol.,  1998, 54(4), 712-721.
[PMID: 9765515] 
[39] 
Maryanoff, B.E. Phenotypic assessment and the discovery of topiramate. ACS Med. Chem. Lett.,  2016, 7(7), 662-665.
[http://dx.doi.org/10.1021/acsmedchemlett.6b00176] [PMID: 27437073] 
[40] 
Maryanoff, B.E. 2009 Edward E Smissman Award. Pharmaceutical “gold” from neurostabilizing agents: Topiramate and successor molecules. J. Med. Chem.,  2009, 52(11), 3431-3440.
[http://dx.doi.org/10.1021/jm900141j] [PMID: 19385640] 
[41] 
Zaraei, S-O.; Abduelkarem, A.R.; Anbar, H.S.; Kobeissi, S.; Mohammad, M.; Ossama, A.; El-Gamal, M.I. Sulfamates in drug design and discovery: Pre-clinical and clinical investigations. Eur. J. Med. Chem.,  2019, 179, 257-271.
[http://dx.doi.org/10.1016/j.ejmech.2019.06.052] [PMID: 31255926] 
[42] 
Hoy, S.M. Topiramate extended release: A review in epilepsy. CNS Drugs,  2016, 30(6), 559-566.
[http://dx.doi.org/10.1007/s40263-016-0344-5] [PMID: 27224993] 
[43] 
Biton, V. Clinical pharmacology and mechanism of action of zonisamide. Clin. Neuropharmacol.,  2007, 30(4), 230-240.
[http://dx.doi.org/10.1097/wnf.0b013e3180413d7d] [PMID: 17762320] 
[44] 
Leppik, I.E. Zonisamide: Chemistry, mechanism of action, and pharmacokinetics. Seizure,  2004, 13(S1)(Suppl. 1), S5-S9.
[http://dx.doi.org/10.1016/j.seizure.2004.04.016] [PMID: 15511691] 
[45] 
Baulac, M.; Brodie, M.J.; Patten, A.; Segieth, J.; Giorgi, L. Efficacy and tolerability of zonisamide versus controlled release carbamazepine for newly diagnosed partial epilepsy: a phase 3, randomised, double-blind, non-inferiority trial. Lancet Neurol.,  2012, 11(7), 579-588.
[http://dx.doi.org/10.1016/S1474-4422(12)70105-9] [PMID: 22683226] 
[46] 
Stiff, D.D.; Robicheau, J.T.; Zemaitis, M.A. Reductive metabolism of the anticonvulsant agent zonisamide, a 1,2-benzisoxazole derivative. Xenobiotica,  1992, 22(1), 1-11.
[http://dx.doi.org/10.3109/00498259209053097] [PMID: 1615700] 
[47] 
Holder, J.L., Jr; Wilfong, A.A. Zonisamide in the treatment of epilepsy. Expert Opin. Pharmacother.,  2011, 12(16), 2573-2581.
[http://dx.doi.org/10.1517/14656566.2011.622268] [PMID: 21967409] 
[48] 
Verrotti, A.; Striano, P.; Iapadre, G.; Zagaroli, L.; Bonanni, P.; Coppola, G.; Elia, M.; Mecarelli, O.; Franzoni, E.; Liso, P.; Vigevano, F.; Curatolo, P. The pharmacological management of Lennox-Gastaut syndrome and critical literature review. Seizure,  2018, 63, 17-25.
[http://dx.doi.org/10.1016/j.seizure.2018.10.016] [PMID: 30391662] 
[49] 
Wheless, J.W.; Vazquez, B. Rufinamide: A novel broad-spectrum antiepileptic drug. Epilepsy Curr.,  2010, 10(1), 1-6.
[http://dx.doi.org/10.1111/j.1535-7511.2009.01336.x] [PMID: 20126329] 
[50] 
Arroyo, S. Rufinamide. Neurotherapeutics,  2007, 4(1), 155-162.
[http://dx.doi.org/10.1016/j.nurt.2006.11.006] [PMID: 17199032] 
[51] 
Brodie, M.J. Practical use of newer antiepileptic drugs as adjunctive therapy in focal epilepsy. CNS Drugs,  2015, 29(11), 893-904.
[http://dx.doi.org/10.1007/s40263-015-0285-4] [PMID: 26507832] 
[52] 
Harris, J.A.; Murphy, J.A. Lacosamide and epilepsy. CNS Neurosci. Ther.,  2011, 17(6), 678-682.
[http://dx.doi.org/10.1111/j.1755-5949.2010.00198.x] [PMID: 20950330] 
[53] 
Sheets, P.L.; Heers, C.; Stoehr, T.; Cummins, T.R. Differential block of sensory neuronal voltage-gated sodium channels by lacosamide [(2R)-2-(acetylamino)-N-benzyl-3-methoxypropanamide], lidocaine, and carbamazepine. J. Pharmacol. Exp. Ther.,  2008, 326(1), 89-99.
[http://dx.doi.org/10.1124/jpet.107.133413] [PMID: 18378801] 
[54] 
Catterall, W.A.; Lenaeus, M.J.; El-Din, G.T.M. Structure and pharmacology of voltage-gated sodium and calcium channels. Annu. Rev. Pharmacol. Toxicol.,  2020, 60, 133-154.
[http://dx.doi.org/10.1146/annurev-pharmtox-010818-021757] [PMID: 31537174] 
[55] 
Lees, G.; Errington, A.C. Lacosamide: Novel action mechanisms and emerging targets in epilepsy and pain. Trends Anaesthesia Crit. Care,  2011, 1(5-6), 246-251.
[http://dx.doi.org/10.1016/j.tacc.2011.08.004] 
[56] 
Beydoun, A.; D’Souza, J.; Hebert, D.; Doty, P. Lacosamide: pharmacology, mechanisms of action and pooled efficacy and safety data in partial-onset seizures. Expert Rev. Neurother.,  2009, 9(1), 33-42.
[http://dx.doi.org/10.1586/14737175.9.1.33] [PMID: 19102666] 
[57] 
Errington, A.C.; Stöhr, T.; Heers, C.; Lees, G. The investigational anticonvulsant lacosamide selectively enhances slow inactivation of voltage-gated sodium channels. Mol. Pharmacol.,  2008, 73(1), 157-169.
[http://dx.doi.org/10.1124/mol.107.039867] [PMID: 17940193] 
[58] 
Rogawski, M.A.; Tofighy, A.; White, H.S.; Matagne, A.; Wolff, C. Current understanding of the mechanism of action of the antiepileptic drug lacosamide. Epilepsy Res.,  2015, 110, 189-205.
[http://dx.doi.org/10.1016/j.eplepsyres.2014.11.021] [PMID: 25616473] 
[59] 
Wulff, H.; Zhorov, B.S.K. K+ channel modulators for the treatment of neurological disorders and autoimmune diseases. Chem. Rev.,  2008, 108(5), 1744-1773.
[http://dx.doi.org/10.1021/cr078234p] [PMID: 18476673] 
[60] 
Robbins, J. KCNQ potassium channels: Physiology, pathophysiology, and pharmacology. Pharmacol. Ther.,  2001, 90(1), 1-19.
[http://dx.doi.org/10.1016/S0163-7258(01)00116-4] [PMID: 11448722] 
[61] 
Barrese, V.; Stott, J.B.; Greenwood, I.A. KCNQ-encoded potassium channels as therapeutic targets. Annu. Rev. Pharmacol. Toxicol.,  2018, 58, 625-648.
[http://dx.doi.org/10.1146/annurev-pharmtox-010617-052912] [PMID: 28992433] 
[62] 
Li, T.; Wu, K.; Yue, Z.; Wang, Y.; Zhang, F.; Shen, H. Structural basis for the modulation of human KCNQ4 by small-molecule drugs. Mol. Cell,  2021, 81(1), 25-37.e4.
[http://dx.doi.org/10.1016/j.molcel.2020.10.037] [PMID: 33238160] 
[63] 
Grunnet, M.; Strøbæk, D.; Hougaard, C.; Christophersen, P. Kv7 channels as targets for anti-epileptic and psychiatric drug-development. Eur. J. Pharmacol.,  2014, 726, 133-137.
[http://dx.doi.org/10.1016/j.ejphar.2014.01.017] [PMID: 24457124] 
[64] 
Boscia, F.; Annunziato, L.; Taglialatela, M. Retigabine and flupirtine exert neuroprotective actions in organotypic hippocampal cultures. Neuropharmacology,  2006, 51(2), 283-294.
[http://dx.doi.org/10.1016/j.neuropharm.2006.03.024] [PMID: 16697426] 
[65] 
Surur, A.S.; Bock, C.; Beirow, K.; Wurm, K.; Schulig, L.; Kindermann, M.K.; Siegmund, W.; Bednarski, P.J.; Link, A. Flupirtine and retigabine as templates for ligand-based drug design of KV7.2/3 activators. Org. Biomol. Chem.,  2019, 17(18), 4512-4522.
[http://dx.doi.org/10.1039/C9OB00511K] [PMID: 30990511] 
[66] 
Jankovic, S.; Ilickovic, I. The preclinical discovery and development of ezogabine for the treatment of epilepsy. Expert Opin. Drug Discov.,  2013, 8(11), 1429-1437.
[http://dx.doi.org/10.1517/17460441.2013.837882] [PMID: 24053653] 
[67] 
Wickenden, A.D.; Yu, W.; Zou, A.; Jegla, T.; Wagoner, P.K. Retigabine, a novel anti-convulsant, enhances activation of KCNQ2/Q3 potassium channels. Mol. Pharmacol.,  2000, 58(3), 591-600.
[http://dx.doi.org/10.1124/mol.58.3.591] [PMID: 10953053] 
[68] 
Tatulian, L.; Delmas, P.; Abogadie, F.C.; Brown, D.A. Activation of expressed KCNQ potassium currents and native neuronal M-type potassium currents by the anti-convulsant drug retigabine. J. Neurosci.,  2001, 21(15), 5535-5545.
[http://dx.doi.org/10.1523/JNEUROSCI.21-15-05535.2001] [PMID: 11466425] 
[69] 
Czuczwar, P.; Wojtak, A.; Cioczek-Czuczwar, A.; Parada-Turska, J.; Maciejewski, R.; Czuczwar, S.J. Retigabine: The newer potential antiepileptic drug. Pharmacol. Rep.,  2010, 62(2), 211-219.
[http://dx.doi.org/10.1016/S1734-1140(10)70260-7] [PMID: 20508276] 
[70] 
Gunthorpe, M.J.; Large, C.H.; Sankar, R. The mechanism of action of retigabine (ezogabine), a first-in-class K+ channel opener for the treatment of epilepsy. Epilepsia,  2012, 53(3), 412-424.
[http://dx.doi.org/10.1111/j.1528-1167.2011.03365.x] [PMID: 22220513] 
[71] 
Seefeld, M.A.; Lin, H.; Holenz, J.; Downie, D.; Donovan, B.; Fu, T.; Pasikanti, K.; Zhen, W.; Cato, M.; Chaudhary, K.W.; Brady, P.; Bakshi, T.; Morrow, D.; Rajagopal, S.; Samanta, S.K.; Madhyastha, N.; Kuppusamy, B.M.; Dougherty, R.W.; Bhamidipati, R.; Mohd, Z.; Higgins, G.A.; Chapman, M.; Rouget, C.; Lluel, P.; Matsuoka, Y. Novel KV7 ion channel openers for the treatment of epilepsy and implications for detrusor tissue contraction. Bioorg. Med. Chem. Lett.,  2018, 28(23-24), 3793-3797.
[http://dx.doi.org/10.1016/j.bmcl.2018.09.036] [PMID: 30327146] 
[72] 
Douros, A.; Bronder, E.; Andersohn, F.; Klimpel, A.; Thomae, M.; Orzechowski, H-D.; Kreutz, R.; Garbe, E. Flupirtine-induced liver injury-seven cases from the berlin case-control surveillance study and review of the German spontaneous adverse drug reaction reporting database. Eur. J. Clin. Pharmacol.,  2014, 70(4), 453-459.
[http://dx.doi.org/10.1007/s00228-013-1631-4] [PMID: 24366502] 
[73] 
Garin Shkolnik, T.; Feuerman, H.; Didkovsky, E.; Kaplan, I.; Bergman, R.; Pavlovsky, L.; Hodak, E. Blue-gray mucocutaneous discoloration: A new adverse effect of ezogabine. JAMA Dermatol.,  2014, 150(9), 984-989.
[http://dx.doi.org/10.1001/jamadermatol.2013.8895] [PMID: 25006968] 
[74] 
Neumaier, F.; Dibué-Adjei, M.; Hescheler, J.; Schneider, T. Voltage-gated calcium channels: Determinants of channel function and modulation by inorganic cations. Prog. Neurobiol.,  2015, 129, 1-36.
[http://dx.doi.org/10.1016/j.pneurobio.2014.12.003] [PMID: 25817891] 
[75] 
Zamponi, G.W. Targeting voltage-gated calcium channels in neurological and psychiatric diseases. Nat. Rev. Drug Discov.,  2016, 15(1), 19-34.
[http://dx.doi.org/10.1038/nrd.2015.5] [PMID: 26542451] 
[76] 
Simms, B.A.; Zamponi, G.W. Neuronal voltage-gated calcium channels: Structure, function, and dysfunction. Neuron,  2014, 82(1), 24-45.
[http://dx.doi.org/10.1016/j.neuron.2014.03.016] [PMID: 24698266] 
[77] 
Catterall, W.A.; Perez-Reyes, E.; Snutch, T.P.; Striessnig, J. International Union of Pharmacology. XLVIII. Nomenclature and structure-function relationships of voltage-gated calcium channels. Pharmacol. Rev.,  2005, 57(4), 411-425.
[http://dx.doi.org/10.1124/pr.57.4.5] [PMID: 16382099] 
[78] 
Park, C-G.; Suh, B-C. Modulation mechanisms of voltage-gated calcium channels. Curr. Opin. Physiol.,  2018, 2, 77-83.
[http://dx.doi.org/10.1016/j.cophys.2018.01.005] 
[79] 
Song, I.; Kim, D.; Choi, S.; Sun, M.; Kim, Y.; Shin, H-S. Role of the α1G T-type calcium channel in spontaneous absence seizures in mutant mice. J. Neurosci.,  2004, 24(22), 5249-5257.
[http://dx.doi.org/10.1523/JNEUROSCI.5546-03.2004] [PMID: 15175395] 
[80] 
Chen, Y.; Parker, W.D.; Wang, K. The role of T-type calcium channel genes in absence seizures. Front. Neurol.,  2014, 5, 45.
[http://dx.doi.org/10.3389/fneur.2014.00045] [PMID: 24847307] 
[81] 
Rajakulendran, S.; Hanna, M.G. The role of calcium channels in epilepsy. Cold Spring Harb. Perspect. Med.,  2016, 6(1), a022723.
[http://dx.doi.org/10.1101/cshperspect.a022723] [PMID: 26729757] 
[82] 
Calandre, E.P.; Rico-Villademoros, F.; Slim, M. Alpha2delta ligands, gabapentin, pregabalin and mirogabalin: a review of their clinical pharmacology and therapeutic use. Expert Rev. Neurother.,  2016, 16(11), 1263-1277.
[http://dx.doi.org/10.1080/14737175.2016.1202764] [PMID: 27345098] 
[83] 
Bryans, J.S.; Davies, N.; Gee, N.S.; Dissanayake, V.U.K.; Ratcliffe, G.S.; Horwell, D.C.; Kneen, C.O.; Morrell, A.I.; Oles, R.J.; O’Toole, J.C.; Perkins, G.M.; Singh, L.; Suman-Chauhan, N.; O’Neill, J.A. Identification of novel ligands for the gabapentin binding site on the α2δ subunit of a calcium channel and their evaluation as anticonvulsant agents. J. Med. Chem.,  1998, 41(11), 1838-1845.
[http://dx.doi.org/10.1021/jm970649n] [PMID: 9599234] 
[84] 
Sills, G.J. The mechanisms of action of gabapentin and pregabalin. Curr. Opin. Pharmacol.,  2006, 6(1), 108-113.
[http://dx.doi.org/10.1016/j.coph.2005.11.003] [PMID: 16376147] 
[85] 
Gee, N.S.; Brown, J.P.; Dissanayake, V.U.; Offord, J.; Thurlow, R.; Woodruff, G.N. The novel anticonvulsant drug, gabapentin (Neurontin), binds to the α2δ subunit of a calcium channel. J. Biol. Chem.,  1996, 271(10), 5768-5776.
[http://dx.doi.org/10.1074/jbc.271.10.5768] [PMID: 8621444] 
[86] 
Taylor, C.P.; Angelotti, T.; Fauman, E. Pharmacology and mechanism of action of pregabalin: the calcium channel alpha2-delta (alpha2-delta) subunit as a target for antiepileptic drug discovery. Epilepsy Res.,  2007, 73(2), 137-150.
[http://dx.doi.org/10.1016/j.eplepsyres.2006.09.008] [PMID: 17126531] 
[87] 
Gören, M.Z.; Onat, F. Ethosuximide: from bench to bedside. CNS Drug Rev.,  2007, 13(2), 224-239.
[http://dx.doi.org/10.1111/j.1527-3458.2007.00009.x] [PMID: 17627674] 
[88] 
Shalomov, B.; Dabbah, S.; Dascal, N. Antiepileptic drug ethosuximide may regulate absence seizures through different ion channels. Biophys. J.,  2020, 118(3), 588a.
[http://dx.doi.org/10.1016/j.bpj.2019.11.3189] 
[89] 
Hainsworth, A.H.; McNaughton, N.C.L.; Pereverzev, A.; Schneider, T.; Randall, A.D. Actions of sipatrigine, 202W92 and lamotrigine on R-type and T-type Ca2+ channel currents. Eur. J. Pharmacol.,  2003, 467(1-3), 77-80.
[http://dx.doi.org/10.1016/S0014-2999(03)01625-X] [PMID: 12706458] 
[90] 
Kuzmiski, J.B.; Barr, W.; Zamponi, G.W.; MacVicar, B.A. Topiramate inhibits the initiation of plateau potentials in CA1 neurons by depressing R-type calcium channels. Epilepsia,  2005, 46(4), 481-489.
[http://dx.doi.org/10.1111/j.0013-9580.2005.35304.x] [PMID: 15816941] 
[91] 
Matar, N.; Jin, W.; Wrubel, H.; Hescheler, J.; Schneider, T.; Weiergräber, M. Zonisamide block of cloned human T-type voltage-gated calcium channels. Epilepsy Res.,  2009, 83(2-3), 224-234.
[http://dx.doi.org/10.1016/j.eplepsyres.2008.11.010] [PMID: 19124225] 
[92] 
Guo, M.; Cui, C.; Song, X.; Jia, L.; Li, D.; Wang, X.; Dong, H.; Ma, Y.; Liu, Y.; Cui, Z.; Yi, L.; Li, Z.; Bi, Y.; Li, Y.; Liu, Y.; Duan, W.; Li, C. Deletion of FGF9 in GABAergic neurons causes epilepsy. Cell Death Dis.,  2021, 12(2), 196.
[http://dx.doi.org/10.1038/s41419-021-03478-1] [PMID: 33608505] 
[93] 
Rudolph, U.; Knoflach, F. Beyond classical benzodiazepines: novel therapeutic potential of GABAA receptor subtypes. Nat. Rev. Drug Discov.,  2011, 10(9), 685-697.
[http://dx.doi.org/10.1038/nrd3502] [PMID: 21799515] 
[94] 
Hernandez, C.C.; Macdonald, R.L. A structural look at GABAA receptor mutations linked to epilepsy syndromes. Brain Res.,  2019, 1714, 234-247.
[http://dx.doi.org/10.1016/j.brainres.2019.03.004] [PMID: 30851244] 
[95] 
Jacob, T.C.; Moss, S.J.; Jurd, R. GABA(A) receptor trafficking and its role in the dynamic modulation of neuronal inhibition. Nat. Rev. Neurosci.,  2008, 9(5), 331-343.
[http://dx.doi.org/10.1038/nrn2370] [PMID: 18382465] 
[96] 
Scott, S.; Aricescu, A.R. A structural perspective on GABAA receptor pharmacology. Curr. Opin. Struct. Biol.,  2019, 54, 189-197.
[http://dx.doi.org/10.1016/j.sbi.2019.03.023] [PMID: 31129381] 
[97] 
Olsen, R.W. GABAA receptor: Positive and negative allosteric modulators. Neuropharmacology,  2018, 136((Pt A)), 10-22.
[http://dx.doi.org/10.1016/j.neuropharm.2018.01.036] [PMID: 29407219] 
[98] 
Sigel, E.; Steinmann, M.E. Structure, function, and modulation of GABA(A) receptors. J. Biol. Chem.,  2012, 287(48), 40224-40231.
[http://dx.doi.org/10.1074/jbc.R112.386664] [PMID: 23038269] 
[99] 
Solomon, V.R.; Tallapragada, V.J.; Chebib, M.; Johnston, G.A.R.; Hanrahan, J.R. GABA allosteric modulators: An overview of recent developments in non-benzodiazepine modulators. Eur. J. Med. Chem.,  2019, 171, 434-461.
[http://dx.doi.org/10.1016/j.ejmech.2019.03.043] [PMID: 30928713] 
[100] 
Zhu, S.; Noviello, C.M.; Teng, J.; Walsh, R.M., Jr; Kim, J.J.; Hibbs, R.E. Structure of a human synaptic GABAA receptor. Nature,  2018, 559(7712), 67-72.
[http://dx.doi.org/10.1038/s41586-018-0255-3] [PMID: 29950725] 
[101] 
Han, W.; Shepard, R.D.; Lu, W. Regulation of GABAARs by transmembrane accessory proteins. Trends Neurosci.,  2021, 44(2), 152-165.
[http://dx.doi.org/10.1016/j.tins.2020.10.011] [PMID: 33234346] 
[102] 
Ochoa, J.G.; Kilgo, W.A. The role of benzodiazepines in the treatment of epilepsy. Curr. Treat. Options Neurol.,  2016, 18(4), 18.
[http://dx.doi.org/10.1007/s11940-016-0401-x] [PMID: 26923608] 
[103] 
Gauthier, A.C.; Mattson, R.H. Clobazam: A safe, efficacious, and newly rediscovered therapeutic for epilepsy. CNS Neurosci. Ther.,  2015, 21(7), 543-548.
[http://dx.doi.org/10.1111/cns.12399] [PMID: 25917225] 
[104] 
Sankar, R. GABA(A) receptor physiology and its relationship to the mechanism of action of the 1,5-benzodiazepine clobazam. CNS Drugs,  2012, 26(3), 229-244.
[http://dx.doi.org/10.2165/11599020-000000000-00000] [PMID: 22145708] 
[105] 
Giarratano, M.; Standley, K.; Benbadis, S.R. Clobazam for treatment of epilepsy. Expert Opin. Pharmacother.,  2012, 13(2), 227-233.
[http://dx.doi.org/10.1517/14656566.2012.647686] [PMID: 22242724] 
[106] 
Riss, J.; Cloyd, J.; Gates, J.; Collins, S. Benzodiazepines in epilepsy: Pharmacology and pharmacokinetics. Acta Neurol. Scand.,  2008, 118(2), 69-86.
[http://dx.doi.org/10.1111/j.1600-0404.2008.01004.x] [PMID: 18384456] 
[107] 
Yasiry, Z.; Shorvon, S.D. How phenobarbital revolutionized epilepsy therapy: The story of phenobarbital therapy in epilepsy in the last 100 years. Epilepsia,  2012, 53(s8)(Suppl. 8), 26-39.
[http://dx.doi.org/10.1111/epi.12026] [PMID: 23205960] 
[108] 
Kim, J.J.; Gharpure, A.; Teng, J.; Zhuang, Y.; Howard, R.J.; Zhu, S.; Noviello, C.M.; Walsh, R.M., Jr; Lindahl, E.; Hibbs, R.E. Shared structural mechanisms of general anaesthetics and benzodiazepines. Nature,  2020, 585(7824), 303-308.
[http://dx.doi.org/10.1038/s41586-020-2654-5] [PMID: 32879488] 
[109] 
Bialer, M. How did phenobarbital’s chemical structure affect the development of subsequent antiepileptic drugs (AEDs)? Epilepsia,  2012, 53(Suppl. 8), 3-11.
[http://dx.doi.org/10.1111/epi.12024] [PMID: 23205958] 
[110] 
Lyons, J.B.; Liversedge, L.A. Primidone in the treatment of epilepsy. BMJ,  1954, 2(4888), 625-627.
[http://dx.doi.org/10.1136/bmj.2.4888.625] [PMID: 13190211] 
[111] 
Rahim, F.; Azizimalamiri, R.; Sayyah, M.; Malayeri, A. Experimental therapeutic strategies in epilepsies using anti-seizure medications. J. Exp. Pharmacol.,  2021, 13, 265-290.
[http://dx.doi.org/10.2147/JEP.S267029] [PMID: 33732031] 
[112] 
Seyfert, S.; Honé, A.; Holl, G. Primidone and essential tremor. J. Neurol.,  1988, 235(3), 168-170.
[http://dx.doi.org/10.1007/BF00314310] [PMID: 3367165] 
[113] 
Groves, J.O.; Guscott, M.R.; Hallett, D.J.; Rosahl, T.W.; Pike, A.; Davies, A.; Wafford, K.A.; Reynolds, D.S. The role of GABAbeta2 subunit-containing receptors in mediating the anticonvulsant and sedative effects of loreclezole. Eur. J. Neurosci.,  2006, 24(1), 167-174.
[http://dx.doi.org/10.1111/j.1460-9568.2006.04890.x] [PMID: 16882014] 
[114] 
Wingrove, P.B.; Wafford, K.A.; Bain, C.; Whiting, P.J. The modulatory action of loreclezole at the gamma-aminobutyric acid type A receptor is determined by a single amino acid in the beta 2 and beta 3 subunit. Proc. Natl. Acad. Sci. USA,  1994, 91(10), 4569-4573.
[http://dx.doi.org/10.1073/pnas.91.10.4569] [PMID: 8183949] 
[115] 
Greenfield, L.J., Jr. Molecular mechanisms of antiseizure drug activity at GABAA receptors. Seizure,  2013, 22(8), 589-600.
[http://dx.doi.org/10.1016/j.seizure.2013.04.015] [PMID: 23683707] 
[116] 
Hussain, S.A.; Asilnejad, B.; Heesch, J.; Navarro, M.; Ji, M.; Shrey, D.W.; Rajaraman, R.R.; Sankar, R. Felbamate in the treatment of refractory epileptic spasms. Epilepsy Res.,  2020, 161, 106284.
[http://dx.doi.org/10.1016/j.eplepsyres.2020.106284] [PMID: 32058261] 
[117] 
Simeone, T.A.; Otto, J.F.; Wilcox, K.S.; White, H.S. Felbamate is a subunit selective modulator of recombinant γ -aminobutyric acid type A receptors expressed in Xenopus oocytes. Eur. J. Pharmacol.,  2006, 552(1-3), 31-35.
[http://dx.doi.org/10.1016/j.ejphar.2006.09.002] [PMID: 17056029] 
[118] 
Chen, H.; He, H.; Xiao, Y.; Luo, M.; Luo, H.; Wang, J. Losigamone add-on therapy for focal epilepsy. Cochrane Database Syst. Rev.,  2019, 12(12), CD009324.
[http://dx.doi.org/10.1002/14651858.CD009324.pub5] [PMID: 31823350] 
[119] 
Dimpfel, W.; Chatterjee, S.S.; Nöldner, M.; Ticku, M.K. Effects of the anticonvulsant losigamone and its isomers on the GABAA receptor system. Epilepsia,  1995, 36(10), 983-989.
[http://dx.doi.org/10.1111/j.1528-1157.1995.tb00956.x] [PMID: 7555962] 
[120] 
Grosenbaugh, D.K.; Mott, D.D. Stiripentol is anticonvulsant by potentiating GABAergic transmission in a model of benzodiazepine-refractory status epilepticus. Neuropharmacology,  2013, 67, 136-143.
[http://dx.doi.org/10.1016/j.neuropharm.2012.11.002] [PMID: 23168114] 
[121] 
Fisher, J.L. The effects of stiripentol on GABA(A) receptors. Epilepsia,  2011, 52(Suppl. 2), 76-78.
[http://dx.doi.org/10.1111/j.1528-1167.2011.03008.x] [PMID: 21463286] 
[122] 
Fisher, J.L. The anti-convulsant stiripentol acts directly on the GABA(A) receptor as a positive allosteric modulator. Neuropharmacology,  2009, 56(1), 190-197.
[http://dx.doi.org/10.1016/j.neuropharm.2008.06.004] [PMID: 18585399] 
[123] 
Quilichini, P.P.; Chiron, C.; Ben-Ari, Y.; Gozlan, H. Stiripentol, a putative antiepileptic drug, enhances the duration of opening of GABA-A receptor channels. Epilepsia,  2006, 47(4), 704-716.
[http://dx.doi.org/10.1111/j.1528-1167.2006.00497.x] [PMID: 16650136] 
[124] 
Fisher, J.L. Interactions between modulators of the GABA(A) receptor: Stiripentol and benzodiazepines. Eur. J. Pharmacol.,  2011, 654(2), 160-165.
[http://dx.doi.org/10.1016/j.ejphar.2010.12.037] [PMID: 21237147] 
[125] 
Sada, N.; Lee, S.; Katsu, T.; Otsuki, T.; Inoue, T. Epilepsy treatment. Targeting LDH enzymes with a stiripentol analog to treat epilepsy. Science,  2015, 347(6228), 1362-1367.
[http://dx.doi.org/10.1126/science.aaa1299] [PMID: 25792327] 
[126] 
Ben-Menachem, E. Mechanism of action of vigabatrin: correcting misperceptions. Acta Neurol. Scand. Suppl.,  2011, 124(192), 5-15.
[http://dx.doi.org/10.1111/j.1600-0404.2011.01596.x] [PMID: 22061176] 
[127] 
Chiron, C. Stiripentol and vigabatrin current roles in the treatment of epilepsy. Expert Opin. Pharmacother.,  2016, 17(8), 1091-1101.
[http://dx.doi.org/10.1517/14656566.2016.1161026] [PMID: 26933940] 
[128] 
Ben-Ari, Y. NKCC1 chloride importer antagonists attenuate many neurological and psychiatric disorders. Trends Neurosci.,  2017, 40(9), 536-554.
[http://dx.doi.org/10.1016/j.tins.2017.07.001] [PMID: 28818303] 
[129] 
Auer, T.; Schreppel, P.; Erker, T.; Schwarzer, C. Functional characterization of novel bumetanide derivatives for epilepsy treatment. Neuropharmacology,  2020, 162, 107754.
[http://dx.doi.org/10.1016/j.neuropharm.2019.107754] [PMID: 31476353] 
[130] 
Gharaylou, Z.; Tafakhori, A.; Agah, E.; Aghamollaii, V.; Kebriaeezadeh, A.; Hadjighassem, M. A preliminary study evaluating the safety and efficacy of bumetanide, an NKCC1 inhibitor, in patients with drug-resistant epilepsy. CNS Drugs,  2019, 33(3), 283-291.
[http://dx.doi.org/10.1007/s40263-019-00607-5] [PMID: 30784026] 
[131] 
Gonzalez-Burgos, G. GABA transporter GAT1: A crucial determinant of GABAB receptor activation in cortical circuits? Adv. Pharmacol.,  2010, 58, 175-204.
[http://dx.doi.org/10.1016/S1054-3589(10)58008-6] [PMID: 20655483] 
[132] 
Zafar, S.; Jabeen, I. Molecular dynamic simulations to probe stereoselectivity of tiagabine binding with human GAT1. Molecules,  2020, 25(20), 4745.
[http://dx.doi.org/10.3390/molecules25204745] [PMID: 33081136] 
[133] 
Richerson, G.B.; Wu, Y. Role of the GABA transporter in epilepsy. Adv. Exp. Med. Biol.,  2004, 548, 76-91.
[http://dx.doi.org/10.1007/978-1-4757-6376-8_6] [PMID: 15250587] 
[134] 
Simeone, T.A.; Wilcox, K.S.; White, H.S. Topiramate modulation of β(1)- and β(3)-homomeric GABA(A) receptors. Pharmacol. Res.,  2011, 64(1), 44-52.
[http://dx.doi.org/10.1016/j.phrs.2011.03.004] [PMID: 21421049] 
[135] 
Yu, J.; Wang, D-S.; Bonin, R.P.; Penna, A.; Alavian-Ghavanini, A.; Zurek, A.A.; Rauw, G.; Baker, G.B.; Orser, B.A. Gabapentin increases expression of δ subunit-containing GABAA receptors. EBioMedicine,  2019, 42, 203-213.
[http://dx.doi.org/10.1016/j.ebiom.2019.03.008] [PMID: 30878595] 
[136] 
Rundfeldt, C.; Netzer, R. Investigations into the mechanism of action of the new anticonvulsant retigabine. Interaction with GABAergic and glutamatergic neurotransmission and with voltage gated ion channels. Arzneimittelforschung,  2000, 50(12), 1063-1070.
[http://dx.doi.org/10.1055/s-0031-1300346] [PMID: 11190770] 
[137] 
van Rijn, C.M.; Willems-van Bree, E. Synergy between retigabine and GABA in modulating the convulsant site of the GABAA receptor complex. Eur. J. Pharmacol.,  2003, 464(2-3), 95-100.
[http://dx.doi.org/10.1016/S0014-2999(03)01426-2] [PMID: 12620500] 
[138] 
Pinheiro, P.S.; Mulle, C. Presynaptic glutamate receptors: physiological functions and mechanisms of action. Nat. Rev. Neurosci.,  2008, 9(6), 423-436.
[http://dx.doi.org/10.1038/nrn2379] [PMID: 18464791] 
[139] 
Traynelis, S.F.; Wollmuth, L.P.; McBain, C.J.; Menniti, F.S.; Vance, K.M.; Ogden, K.K.; Hansen, K.B.; Yuan, H.; Myers, S.J.; Dingledine, R. Glutamate receptor ion channels: structure, regulation, and function. Pharmacol. Rev.,  2010, 62(3), 405-496.
[http://dx.doi.org/10.1124/pr.109.002451] [PMID: 20716669] 
[140] 
Zhu, S.J.; Gouaux, E. Structure and symmetry inform gating principles of ionotropic glutamate receptors. Neuropharmacology,  2017, 112(Pt A), 11-15.
[http://dx.doi.org/10.1016/j.neuropharm.2016.08.034] [PMID: 27663701] 
[141] 
Henley, J.M.; Wilkinson, K.A. Synaptic AMPA receptor composition in development, plasticity and disease. Nat. Rev. Neurosci.,  2016, 17(6), 337-350.
[http://dx.doi.org/10.1038/nrn.2016.37] [PMID: 27080385] 
[142] 
Fleming, J.J.; England, P.M. AMPA receptors and synaptic plasticity: A chemist’s perspective. Nat. Chem. Biol.,  2010, 6(2), 89-97.
[http://dx.doi.org/10.1038/nchembio.298] [PMID: 20081822] 
[143] 
Twomey, E.C.; Yelshanskaya, M.V.; Grassucci, R.A.; Frank, J.; Sobolevsky, A.I. Channel opening and gating mechanism in AMPA-subtype glutamate receptors. Nature,  2017, 549(7670), 60-65.
[http://dx.doi.org/10.1038/nature23479] [PMID: 28737760] 
[144] 
Sobolevsky, A.I.; Rosconi, M.P.; Gouaux, E. X-ray structure, symmetry and mechanism of an AMPA-subtype glutamate receptor. Nature,  2009, 462(7274), 745-756.
[http://dx.doi.org/10.1038/nature08624] [PMID: 19946266] 
[145] 
Paoletti, P.; Bellone, C.; Zhou, Q. NMDA receptor subunit diversity: Impact on receptor properties, synaptic plasticity and disease. Nat. Rev. Neurosci.,  2013, 14(6), 383-400.
[http://dx.doi.org/10.1038/nrn3504] [PMID: 23686171] 
[146] 
Iacobucci, G.J.; Popescu, G.K. NMDA receptors: Linking physiological output to biophysical operation. Nat. Rev. Neurosci.,  2017, 18(4), 236-249.
[http://dx.doi.org/10.1038/nrn.2017.24] [PMID: 28303017] 
[147] 
Reiner, A.; Levitz, J. Glutamatergic signaling in the central nervous system: Ionotropic and metabotropic receptors in concert. Neuron,  2018, 98(6), 1080-1098.
[http://dx.doi.org/10.1016/j.neuron.2018.05.018] [PMID: 29953871] 
[148] 
Willard, S.S.; Koochekpour, S. Glutamate, glutamate receptors, and downstream signaling pathways. Int. J. Biol. Sci.,  2013, 9(9), 948-959.
[http://dx.doi.org/10.7150/ijbs.6426] [PMID: 24155668] 
[149] 
Madden, D.R. The structure and function of glutamate receptor ion channels. Nat. Rev. Neurosci.,  2002, 3(2), 91-101.
[http://dx.doi.org/10.1038/nrn725] [PMID: 11836517] 
[150] 
Hanada, T. Ionotropic glutamate receptors in epilepsy: A review focusing on AMPA and NMDA receptors. Biomolecules,  2020, 10(3), 464.
[http://dx.doi.org/10.3390/biom10030464] [PMID: 32197322] 
[151] 
Fukushima, K.; Hatanaka, K.; Sagane, K.; Ido, K. Inhibitory effect of anti-seizure medications on ionotropic glutamate receptors: special focus on AMPA receptor subunits. Epilepsy Res.,  2020, 167, 106452.
[http://dx.doi.org/10.1016/j.eplepsyres.2020.106452] [PMID: 32911258] 
[152] 
Potschka, H.; Trinka, E. Perampanel: Does it have broad-spectrum potential? Epilepsia,  2019, 60(Suppl. 1), 22-36.
[http://dx.doi.org/10.1111/epi.14456] [PMID: 29953584] 
[153] 
Di Bonaventura, C.; Labate, A.; Maschio, M.; Meletti, S.; Russo, E. AMPA receptors and perampanel behind selected epilepsies: Current evidence and future perspectives. Expert Opin. Pharmacother.,  2017, 18(16), 1751-1764.
[http://dx.doi.org/10.1080/14656566.2017.1392509] [PMID: 29023170] 
[154] 
Yelshanskaya, M.V.; Singh, A.K.; Sampson, J.M.; Narangoda, C.; Kurnikova, M.; Sobolevsky, A.I. Structural bases of noncompetitive inhibition of AMPA-subtype ionotropic glutamate receptors by antiepileptic drugs. Neuron,  2016, 91(6), 1305-1315.
[http://dx.doi.org/10.1016/j.neuron.2016.08.012] [PMID: 27618672] 
[155] 
Palmer, G.C.; Murray, R.J.; Wilson, T.C.; Eisman, M.S.; Ray, R.K.; Griffith, R.C.; Napier, J.J.; Fedorchuk, M.; Stagnitto, M.L.; Garske, G.E. Biological profile of the metabolites and potential metabolites of the anticonvulsant remacemide. Epilepsy Res.,  1992, 12(1), 9-20.
[http://dx.doi.org/10.1016/0920-1211(92)90086-9] [PMID: 1388119] 
[156] 
Małek, R.; Borowicz, K.K.; Kimber-Trojnar, Z.; Sobieszek, G.; Piskorska, B.; Czuczwar, S.J. Remacemide-a novel potential antiepileptic drug. Pol. J. Pharmacol.,  2003, 55(5), 691-698.
[PMID: 14704464] 
[157] 
Ghasemi, M.; Schachter, S.C. The NMDA receptor complex as a therapeutic target in epilepsy: A review. Epilepsy Behav.,  2011, 22(4), 617-640.
[http://dx.doi.org/10.1016/j.yebeh.2011.07.024] [PMID: 22056342] 
[158] 
Lynch, B.A.; Lambeng, N.; Nocka, K.; Kensel-Hammes, P.; Bajjalieh, S.M.; Matagne, A.; Fuks, B. The synaptic vesicle protein SV2A is the binding site for the antiepileptic drug levetiracetam. Proc. Natl. Acad. Sci. USA,  2004, 101(26), 9861-9866.
[http://dx.doi.org/10.1073/pnas.0308208101] [PMID: 15210974] 
[159] 
Mendoza-Torreblanca, J.G.; Vanoye-Carlo, A.; Phillips-Farfán, B.V.; Carmona-Aparicio, L.; Gómez-Lira, G. Synaptic vesicle protein 2A: Basic facts and role in synaptic function. Eur. J. Neurosci.,  2013, 38(11), 3529-3539.
[http://dx.doi.org/10.1111/ejn.12360] [PMID: 24102679] 
[160] 
Tokudome, K.; Okumura, T.; Shimizu, S.; Mashimo, T.; Takizawa, A.; Serikawa, T.; Terada, R.; Ishihara, S.; Kunisawa, N.; Sasa, M.; Ohno, Y. Synaptic vesicle glycoprotein 2A (SV2A) regulates kindling epileptogenesis via GABAergic neurotransmission. Sci. Rep.,  2016, 6, 27420.
[http://dx.doi.org/10.1038/srep27420] [PMID: 27265781] 
[161] 
Correa-Basurto, J.; Cuevas-Hernández, R.I.; Phillips-Farfán, B.V.; Martínez-Archundia, M.; Romo-Mancillas, A.; Ramírez-Salinas, G.L.; Pérez-González, O.A.; Trujillo-Ferrara, J.; Mendoza-Torreblanca, J.G. Identification of the antiepileptic racetam binding site in the synaptic vesicle protein 2A by molecular dynamics and docking simulations. Front. Cell. Neurosci.,  2015, 9, 125.
[http://dx.doi.org/10.3389/fncel.2015.00125] [PMID: 25914622] 
[162] 
Tokudome, K.; Okumura, T.; Terada, R.; Shimizu, S.; Kunisawa, N.; Mashimo, T.; Serikawa, T.; Sasa, M.; Ohno, Y. A missense mutation of the gene encoding synaptic vesicle glycoprotein 2A (SV2A) confers seizure susceptibility by disrupting amygdalar synaptic GABA release. Front. Pharmacol.,  2016, 7, 210.
[http://dx.doi.org/10.3389/fphar.2016.00210] [PMID: 27471467] 
[163] 
Lyseng-Williamson, K.A. Spotlight on levetiracetam in epilepsy. CNS Drugs,  2011, 25(10), 901-905.
[http://dx.doi.org/10.2165/11208340-000000000-00000] [PMID: 21936590] 
[164] 
Lyseng-Williamson, K.A. Levetiracetam: A review of its use in epilepsy. Drugs,  2011, 71(4), 489-514.
[http://dx.doi.org/10.2165/11204490-000000000-00000] [PMID: 21395360] 
[165] 
Deshpande, L.S.; Delorenzo, R.J. Mechanisms of levetiracetam in the control of status epilepticus and epilepsy. Front. Neurol.,  2014, 5, 11.
[http://dx.doi.org/10.3389/fneur.2014.00011] [PMID: 24550884] 
[166] 
Steinhoff, B.J.; Staack, A.M. Levetiracetam and brivaracetam: A review of evidence from clinical trials and clinical experience. Ther. Adv. Neurol. Disord.,  2019, 12, 1756286419873518.
[http://dx.doi.org/10.1177/1756286419873518] [PMID: 31523280] 
[167] 
Kaur, H.; Kumar, B.; Medhi, B. Antiepileptic drugs in development pipeline: A recent update. eNeurologicalSci,  2016, 4, 42-51.
[http://dx.doi.org/10.1016/j.ensci.2016.06.003] [PMID: 29430548] 
[168] 
Golyala, A.; Kwan, P. Drug development for refractory epilepsy: The past 25 years and beyond. Seizure,  2017, 44, 147-156.
[http://dx.doi.org/10.1016/j.seizure.2016.11.022] [PMID: 28017578] 
[169] 
Zaccara, G.; Schmidt, D. Do traditional anti-seizure drugs have a future? A review of potential anti-seizure drugs in clinical development. Pharmacol. Res.,  2016, 104, 38-48.
[http://dx.doi.org/10.1016/j.phrs.2015.12.011] [PMID: 26689774] 
[170] 
Bialer, M.; Johannessen, S.I.; Koepp, M.J.; Levy, R.H.; Perucca, E.; Perucca, P.; Tomson, T.; White, H.S. Progress report on new antiepileptic drugs: A summary of the Fifteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XV). I. Drugs in preclinical and early clinical development. Epilepsia,  2020, 61(11), 2340-2364.
[http://dx.doi.org/10.1111/epi.16725] [PMID: 33190243] 
[171] 
Bialer, M.; Johannessen, S.I.; Koepp, M.J.; Levy, R.H.; Perucca, E.; Tomson, T.; White, H.S. Progress report on new antiepileptic drugs: A summary of the Fourteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XIV). I. Drugs in preclinical and early clinical development. Epilepsia,  2018, 59(10), 1811-1841.
[http://dx.doi.org/10.1111/epi.14557] [PMID: 30368792] 
[172] 
Younus, I.; Reddy, D.S. A resurging boom in new drugs for epilepsy and brain disorders. Expert Rev. Clin. Pharmacol.,  2018, 11(1), 27-45.
[http://dx.doi.org/10.1080/17512433.2018.1386553] [PMID: 28956955] 
[173] 
Keam, S.J. Cenobamate: First Approval. Drugs,  2020, 80(1), 73-78.
[http://dx.doi.org/10.1007/s40265-019-01250-6] [PMID: 31933170] 
[174] 
Nakamura, M.; Cho, J-H.; Shin, H.; Jang, I-S. Effects of cenobamate (YKP3089), a newly developed anti-epileptic drug, on voltage-gated sodium channels in rat hippocampal CA3 neurons. Eur. J. Pharmacol.,  2019, 855, 175-182.
[http://dx.doi.org/10.1016/j.ejphar.2019.05.007] [PMID: 31063770] 
[175] 
Sharma, R.; Nakamura, M.; Neupane, C.; Jeon, B.H.; Shin, H.; Melnick, S.M.; Glenn, K.J.; Jang, I-S.; Park, J.B. Positive allosteric modulation of GABAA receptors by a novel antiepileptic drug cenobamate. Eur. J. Pharmacol.,  2020, 879, 173117.
[http://dx.doi.org/10.1016/j.ejphar.2020.173117] [PMID: 32325146] 
[176] 
Arnold, S. Cenobamate: new hope for treatment-resistant epilepsy. Lancet Neurol.,  2020, 19(1), 23-24.
[http://dx.doi.org/10.1016/S1474-4422(19)30434-X] [PMID: 31734104] 
[177] 
Owen, R.M.; Blakemore, D.; Cao, L.; Flanagan, N.; Fish, R.; Gibson, K.R.; Gurrell, R.; Huh, C.W.; Kammonen, J.; Mortimer-Cassen, E.; Nickolls, S.A.; Omoto, K.; Owen, D.; Pike, A.; Pryde, D.C.; Reynolds, D.S.; Roeloffs, R.; Rose, C.; Stead, C.; Takeuchi, M.; Warmus, J.S.; Watson, C. Design and identification of a novel, functionally subtype selective GABAA positive allosteric modulator (PF-06372865). J. Med. Chem.,  2019, 62(12), 5773-5796.
[http://dx.doi.org/10.1021/acs.jmedchem.9b00322] [PMID: 30964988] 
[178] 
Bialer, M.; Johannessen, S.I.; Koepp, M.J.; Levy, R.H.; Perucca, E.; Perucca, P.; Tomson, T.; White, H.S. Progress report on new antiepileptic drugs: A summary of the Fifteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XV). II. Drugs in more advanced clinical development. Epilepsia,  2020, 61(11), 2365-2385.
[http://dx.doi.org/10.1111/epi.16726] [PMID: 33165915] 
[179] 
Nickolls, S.A.; Gurrell, R.; van Amerongen, G.; Kammonen, J.; Cao, L.; Brown, A.R.; Stead, C.; Mead, A.; Watson, C.; Hsu, C.; Owen, R.M.; Pike, A.; Fish, R.L.; Chen, L.; Qiu, R.; Morris, E.D.; Feng, G.; Whitlock, M.; Gorman, D.; van Gerven, J.; Reynolds, D.S.; Dua, P.; Butt, R.P. Pharmacology in translation: the preclinical and early clinical profile of the novel α2/3 functionally selective GABAA receptor positive allosteric modulator PF-06372865. Br. J. Pharmacol.,  2018, 175(4), 708-725.
[http://dx.doi.org/10.1111/bph.14119] [PMID: 29214652] 
[180] 
Hosie, A.M.; Wilkins, M.E.; da Silva, H.M.; Smart, T.G.; Smart, T.G. Endogenous neurosteroids regulate GABAA receptors through two discrete transmembrane sites. Nature,  2006, 444(7118), 486-489.
[http://dx.doi.org/10.1038/nature05324] [PMID: 17108970] 
[181] 
Nohria, V.; Giller, E. Ganaxolone. Neurotherapeutics,  2007, 4(1), 102-105.
[http://dx.doi.org/10.1016/j.nurt.2006.11.003] [PMID: 17199022] 
[182] 
Monaghan, E.P.; McAuley, J.W.; Data, J.L. Ganaxolone: a novel positive allosteric modulator of the GABA(A) receptor complex for the treatment of epilepsy. Expert Opin. Investig. Drugs,  1999, 8(10), 1663-1671.
[http://dx.doi.org/10.1517/13543784.8.10.1663] [PMID: 11139818] 
[183] 
Yawno, T.; Miller, S.L.; Bennet, L.; Wong, F.; Hirst, J.J.; Fahey, M.; Walker, D.W. Ganaxolone: A new treatment for neonatal seizures. Front. Cell. Neurosci.,  2017, 11, 246.
[http://dx.doi.org/10.3389/fncel.2017.00246] [PMID: 28878622] 
[184] 
Carter, R.B.; Wood, P.L.; Wieland, S.; Hawkinson, J.E.; Belelli, D.; Lambert, J.J.; White, H.S.; Wolf, H.H.; Mirsadeghi, S.; Tahir, S.H.; Bolger, M.B.; Lan, N.C.; Gee, K.W. Characterization of the anticonvulsant properties of ganaxolone (CCD 1042; 3α-hydroxy-3β-methyl-5α-pregnan-20-one), a selective, high-affinity, steroid modulator of the γ-aminobutyric acid(A) receptor. J. Pharmacol. Exp. Ther.,  1997, 280(3), 1284-1295.
[PMID: 9067315] 
[185] 
Pan, Y.; Qiu, J.; Silverman, R.B. Design, synthesis, and biological activity of a difluoro-substituted, conformationally rigid vigabatrin analogue as a potent γ-aminobutyric acid aminotransferase inhibitor. J. Med. Chem.,  2003, 46(25), 5292-5293.
[http://dx.doi.org/10.1021/jm034162s] [PMID: 14640537] 
[186] 
Juncosa, J.I.; Takaya, K.; Le, H.V.; Moschitto, M.J.; Weerawarna, P.M.; Mascarenhas, R.; Liu, D.; Dewey, S.L.; Silverman, R.B. Design and mechanism of (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid, a highly potent γ-aminobutyric acid aminotransferase inactivator for the treatment of addiction. J. Am. Chem. Soc.,  2018, 140(6), 2151-2164.
[http://dx.doi.org/10.1021/jacs.7b10965] [PMID: 29381352] 
[187] 
Cid, J.M.; Tresadern, G.; Duvey, G.; Lütjens, R.; Finn, T.; Rocher, J-P.; Poli, S.; Vega, J.A.; de Lucas, A.I.; Matesanz, E.; Linares, M.L.; Andrés, J.I.; Alcazar, J.; Alonso, J.M.; Macdonald, G.J.; Oehlrich, D.; Lavreysen, H.; Ahnaou, A.; Drinkenburg, W.; Mackie, C.; Pype, S.; Gallacher, D.; Trabanco, A.A. Discovery of 1-butyl-3-chloro-4-(4-phenyl-1-piperidinyl)-(1H)-pyridone (JNJ-40411813): A novel positive allosteric modulator of the metabotropic glutamate 2 receptor. J. Med. Chem.,  2014, 57(15), 6495-6512.
[http://dx.doi.org/10.1021/jm500496m] [PMID: 25032784] 
[188] 
Metcalf, C.S.; Klein, B.D.; Smith, M.D.; Pruess, T.; Ceusters, M.; Lavreysen, H.; Pype, S.; Van Osselaer, N.; Twyman, R.; White, H.S. Efficacy of mGlu2 -positive allosteric modulators alone and in combination with levetiracetam in the mouse 6 Hz model of psychomotor seizures. Epilepsia,  2017, 58(3), 484-493.
[http://dx.doi.org/10.1111/epi.13659] [PMID: 28166368] 
[189] 
Metcalf, C.S.; Klein, B.D.; Smith, M.D.; Ceusters, M.; Lavreysen, H.; Pype, S.; Van Osselaer, N.; Twyman, R.; White, H.S. Potent and selective pharmacodynamic synergy between the metabotropic glutamate receptor subtype 2-positive allosteric modulator JNJ-46356479 and levetiracetam in the mouse 6-Hz (44-mA) model. Epilepsia,  2018, 59(3), 724-735.
[http://dx.doi.org/10.1111/epi.14005] [PMID: 29360159] 
[190] 
Straub, C.; Tomita, S. The regulation of glutamate receptor trafficking and function by TARPs and other transmembrane auxiliary subunits. Curr. Opin. Neurobiol.,  2012, 22(3), 488-495.
[http://dx.doi.org/10.1016/j.conb.2011.09.005] [PMID: 21993243] 
[191] 
Jackson, A.C.; Nicoll, R.A. The expanding social network of ionotropic glutamate receptors: TARPs and other transmembrane auxiliary subunits. Neuron,  2011, 70(2), 178-199.
[http://dx.doi.org/10.1016/j.neuron.2011.04.007] [PMID: 21521608] 
[192] 
Sumioka, A. Auxiliary subunits provide new insights into regulation of AMPA receptor trafficking. J. Biochem.,  2013, 153(4), 331-337.
[http://dx.doi.org/10.1093/jb/mvt015] [PMID: 23426437] 
[193] 
Maher, M.P.; Wu, N.; Ravula, S.; Ameriks, M.K.; Savall, B.M.; Liu, C.; Lord, B.; Wyatt, R.M.; Matta, J.A.; Dugovic, C.; Yun, S.; Ver Donck, L.; Steckler, T.; Wickenden, A.D.; Carruthers, N.I.; Lovenberg, T.W. Discovery and characterization of AMPA receptor modulators selective for TARP-γ8. J. Pharmacol. Exp. Ther.,  2016, 357(2), 394-414.
[http://dx.doi.org/10.1124/jpet.115.231712] [PMID: 26989142] 
[194] 
Dohrke, J-N.; Watson, J.F.; Birchall, K.; Greger, I.H. Characterizing the binding and function of TARP γ8-selective AMPA receptor modulators. J. Biol. Chem.,  2020, 295(43), 14565-14577.
[http://dx.doi.org/10.1074/jbc.RA120.014135] [PMID: 32747446] 
[195] 
Ravula, S.; Savall, B.M.; Wu, N.; Lord, B.; Coe, K.; Wang, K.; Seierstad, M.; Swanson, D.M.; Ziff, J.; Nguyen, M.; Leung, P.; Rynberg, R.; La, D.; Pippel, D.J.; Koudriakova, T.; Lovenberg, T.W.; Carruthers, N.I.; Maher, M.P.; Ameriks, M.K. Lead optimization of 5-aryl benzimidazolone- and oxindole-based AMPA receptor modulators selective for TARP γ-8. ACS Med. Chem. Lett.,  2018, 9(8), 821-826.
[http://dx.doi.org/10.1021/acsmedchemlett.8b00215] [PMID: 30128074] 
[196] 
Kaminski, R.M.; Matagne, A.; Patsalos, P.N.; Klitgaard, H. Benefit of combination therapy in epilepsy: A review of the preclinical evidence with levetiracetam. Epilepsia,  2009, 50(3), 387-397.
[http://dx.doi.org/10.1111/j.1528-1167.2008.01713.x] [PMID: 18627416] 
[197] 
Leclercq, K.; Matagne, A.; Provins, L.; Klitgaard, H.; Kaminski, R.M. Pharmacological profile of the novel antiepileptic drug candidate padsevonil: Characterization in rodent seizure and epilepsy models. J. Pharmacol. Exp. Ther.,  2020, 372(1), 11-20.
[http://dx.doi.org/10.1124/jpet.119.261222] [PMID: 31619464] 
[198] 
Wood, M.; Daniels, V.; Provins, L.; Wolff, C.; Kaminski, R.M.; Gillard, M. Pharmacological profile of the novel antiepileptic drug candidate padsevonil: Interactions with synaptic vesicle 2 proteins and the GABAA receptor. J. Pharmacol. Exp. Ther.,  2020, 372(1), 1-10.
[http://dx.doi.org/10.1124/jpet.119.261149] [PMID: 31619465] 
[199] 
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] 
[200] 
Aronica, E.; Bauer, S.; Bozzi, Y.; Caleo, M.; Dingledine, R.; Gorter, J.A.; Henshall, D.C.; Kaufer, D.; Koh, S.; Löscher, W.; Louboutin, J-P.; Mishto, M.; Norwood, B.A.; Palma, E.; Poulter, M.O.; Terrone, G.; Vezzani, A.; Kaminski, R.M. Neuroinflammatory targets and treatments for epilepsy validated in experimental models. Epilepsia,  2017, 58(Suppl. 3), 27-38.
[http://dx.doi.org/10.1111/epi.13783] [PMID: 28675563] 
[201] 
Mukhtar, I. Inflammatory and immune mechanisms underlying epileptogenesis and epilepsy: From pathogenesis to treatment target. Seizure,  2020, 82, 65-79.
[http://dx.doi.org/10.1016/j.seizure.2020.09.015] [PMID: 33011590] 
[202] 
Maroso, M.; Balosso, S.; Ravizza, T.; Iori, V.; Wright, C.I.; French, J.; Vezzani, A. Interleukin-1β biosynthesis inhibition reduces acute seizures and drug resistant chronic epileptic activity in mice. Neurotherapeutics,  2011, 8(2), 304-315.
[http://dx.doi.org/10.1007/s13311-011-0039-z] [PMID: 21431948] 
[203] 
Kenney-Jung, D.L.; Vezzani, A.; Kahoud, R.J.; LaFrance-Corey, R.G.; Ho, M-L.; Muskardin, T.W.; Wirrell, E.C.; Howe, C.L.; Payne, E.T. Febrile infection-related epilepsy syndrome treated with anakinra. Ann. Neurol.,  2016, 80(6), 939-945.
[http://dx.doi.org/10.1002/ana.24806] [PMID: 27770579] 
[204] 
DeSena, A.D.; Do, T.; Schulert, G.S. Systemic autoinflammation with intractable epilepsy managed with interleukin-1 blockade. J. Neuroinflammation,  2018, 15(1), 38.
[http://dx.doi.org/10.1186/s12974-018-1063-2] [PMID: 29426321] 
[205] 
Lai, Y-C.; Muscal, E.; Wells, E.; Shukla, N.; Eschbach, K.; Hyeong Lee, K.; Kaliakatsos, M.; Desai, N.; Wickström, R.; Viri, M.; Freri, E.; Granata, T.; Nangia, S.; Dilena, R.; Brunklaus, A.; Wainwright, M.S.; Gorman, M.P.; Stredny, C.M.; Asiri, A.; Hundallah, K.; Doja, A.; Payne, E.; Wirrell, E.; Koh, S.; Carpenter, J.L.; Riviello, J. Anakinra usage in febrile infection related epilepsy syndrome: An international cohort. Ann. Clin. Transl. Neurol.,  2020, 7(12), 2467-2474.
[http://dx.doi.org/10.1002/acn3.51229] [PMID: 33506622] 
[206] 
Ravizza, T.; Noé, F.; Zardoni, D.; Vaghi, V.; Sifringer, M.; Vezzani, A. Interleukin Converting Enzyme inhibition impairs kindling epileptogenesis in rats by blocking astrocytic IL-1beta production. Neurobiol. Dis.,  2008, 31(3), 327-333.
[http://dx.doi.org/10.1016/j.nbd.2008.05.007] [PMID: 18632279] 
[207] 
Wong, M. Mammalian target of rapamycin (mTOR) inhibition as a potential antiepileptogenic therapy: From tuberous sclerosis to common acquired epilepsies. Epilepsia,  2010, 51(1), 27-36.
[http://dx.doi.org/10.1111/j.1528-1167.2009.02341.x] [PMID: 19817806] 
[208] 
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] 
[209] 
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] 
[210] 
Russo, E.; Citraro, R.; Donato, G.; Camastra, C.; Iuliano, R.; Cuzzocrea, S.; Constanti, A.; De Sarro, G. mTOR inhibition modulates epileptogenesis, seizures and depressive behavior in a genetic rat model of absence epilepsy. Neuropharmacology,  2013, 69, 25-36.
[http://dx.doi.org/10.1016/j.neuropharm.2012.09.019] [PMID: 23092918] 
[211] 
French, J.A.; Lawson, J.A.; Yapici, Z.; Ikeda, H.; Polster, T.; Nabbout, R.; Curatolo, P.; de Vries, P.J.; Dlugos, D.J.; Berkowitz, N.; Voi, M.; Peyrard, S.; Pelov, D.; Franz, D.N. Adjunctive everolimus therapy for treatment-resistant focal-onset seizures associated with tuberous sclerosis (EXIST-3): a phase 3, randomised, double-blind, placebo-controlled study. Lancet,  2016, 388(10056), 2153-2163.
[http://dx.doi.org/10.1016/S0140-6736(16)31419-2] [PMID: 27613521] 
[212] 
Williams-Karnesky, R.L.; Sandau, U.S.; Lusardi, T.A.; Lytle, N.K.; Farrell, J.M.; Pritchard, E.M.; Kaplan, D.L.; Boison, D. Epigenetic changes induced by adenosine augmentation therapy prevent epileptogenesis. J. Clin. Invest.,  2013, 123(8), 3552-3563.
[http://dx.doi.org/10.1172/JCI65636] [PMID: 23863710] 
[213] 
Aronica, E.; Zurolo, E.; Iyer, A.; de Groot, M.; Anink, J.; Carbonell, C.; van Vliet, E.A.; Baayen, J.C.; Boison, D.; Gorter, J.A. Upregulation of adenosine kinase in astrocytes in experimental and human temporal lobe epilepsy. Epilepsia,  2011, 52(9), 1645-1655.
[http://dx.doi.org/10.1111/j.1528-1167.2011.03115.x] [PMID: 21635241] 
[214] 
Sandau, U.S.; Yahya, M.; Bigej, R.; Friedman, J.L.; Saleumvong, B.; Boison, D. Transient use of a systemic adenosine kinase inhibitor attenuates epilepsy development in mice. Epilepsia,  2019, 60(4), 615-625.
[http://dx.doi.org/10.1111/epi.14674] [PMID: 30815855] 
[215] 
Toti, K.S.; Osborne, D.; Ciancetta, A.; Boison, D.; Jacobson, K.A. South (S)- and north (N)-methanocarba-7-deazaadenosine analogues as inhibitors of human adenosine kinase. J. Med. Chem.,  2016, 59(14), 6860-6877.
[http://dx.doi.org/10.1021/acs.jmedchem.6b00689] [PMID: 27410258] 
[216] 
Damar, U.; Gersner, R.; Johnstone, J.T.; Schachter, S.; Rotenberg, A. Huperzine A as a neuroprotective and antiepileptic drug: A review of preclinical research. Expert Rev. Neurother.,  2016, 16(6), 671-680.
[http://dx.doi.org/10.1080/14737175.2016.1175303] [PMID: 27086593] 
[217] 
Gersner, R.; Ekstein, D.; Dhamne, S.C.; Schachter, S.C.; Rotenberg, A. Huperzine A prophylaxis against pentylenetetrazole-induced seizures in rats is associated with increased cortical inhibition. Epilepsy Res.,  2015, 117, 97-103.
[http://dx.doi.org/10.1016/j.eplepsyres.2015.08.012] [PMID: 26432930] 
[218] 
Fuller, R.W.; Snoddy, H.D.; Robertson, D.W. Mechanisms of effects of d-fenfluramine on brain serotonin metabolism in rats: Uptake inhibition versus release. Pharmacol. Biochem. Behav.,  1988, 30(3), 715-721.
[http://dx.doi.org/10.1016/0091-3057(88)90089-5] [PMID: 2463643] 
[219] 
Gogou, M.; Cross, J.H. Fenfluramine as antiseizure medication for epilepsy. Dev. Med. Child Neurol.,  2021, 63(8), 899-907.
[http://dx.doi.org/10.1111/dmcn.14822] [PMID: 33565102] 
[220] 
Lagae, L.; Sullivan, J.; Knupp, K.; Laux, L.; Polster, T.; Nikanorova, M.; Devinsky, O.; Cross, J.H.; Guerrini, R.; Talwar, D.; Miller, I.; Farfel, G.; Galer, B.S.; Gammaitoni, A.; Mistry, A.; Morrison, G.; Lock, M.; Agarwal, A.; Lai, W.W.; Ceulemans, B. Fenfluramine hydrochloride for the treatment of seizures in Dravet syndrome: a randomised, double-blind, placebo-controlled trial. Lancet,  2019, 394(10216), 2243-2254.
[http://dx.doi.org/10.1016/S0140-6736(19)32500-0] [PMID: 31862249] 
[221] 
Martin, P.; de Witte, P.A.M.; Maurice, T.; Gammaitoni, A.; Farfel, G.; Galer, B. Fenfluramine acts as a positive modulator of sigma-1 receptors. Epilepsy Behav.,  2020, 105, 106989.
[http://dx.doi.org/10.1016/j.yebeh.2020.106989] [PMID: 32169824] 
[222] 
Garriga-Canut, M.; Schoenike, B.; Qazi, R.; Bergendahl, K.; Daley, T.J.; Pfender, R.M.; Morrison, J.F.; Ockuly, J.; Stafstrom, C.; Sutula, T.; Roopra, A. 2-Deoxy-D-glucose reduces epilepsy progression by NRSF-CtBP–dependent metabolic regulation of chromatin structure. Nat. Neurosci.,  2006, 9(11), 1382-1387.
[http://dx.doi.org/10.1038/nn1791] [PMID: 17041593] 
[223] 
Gasior, M.; Yankura, J.; Hartman, A.L.; French, A.; Rogawski, M.A. Anticonvulsant and proconvulsant actions of 2-deoxy-D-glucose. Epilepsia,  2010, 51(8), 1385-1394.
[http://dx.doi.org/10.1111/j.1528-1167.2010.02593.x] [PMID: 20491877] 
[224] 
Long, Y.; Zhuang, K.; Ji, Z.; Han, Y.; Fei, Y.; Zheng, W.; Song, Z.; Yang, H. 2-Deoxy-D-Glucose Exhibits Anti-seizure Effects by Mediating the Netrin-G1-KATP Signaling Pathway in Epilepsy. Neurochem. Res.,  2019, 44(4), 994-1004.
[http://dx.doi.org/10.1007/s11064-019-02734-3] [PMID: 30805800] 
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DOI https://dx.doi.org/10.2174/0929867328666210910124727	Print ISSN 0929-8673
Publisher Name Bentham Science Publisher	Online ISSN 1875-533X
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