药学学报, 2021, 56(4): 924-938
引用本文:
刘颖, 于海波, 孔庆飞. 癫痫的治疗和药物发现现状[J]. 药学学报, 2021, 56(4): 924-938.
LIU Ying, YU Hai-bo, KONG Qing-fei. Current status of treatment and drug discovery for epilepsy[J]. Acta Pharmaceutica Sinica, 2021, 56(4): 924-938.

癫痫的治疗和药物发现现状
刘颖1,2, 于海波2*, 孔庆飞1*
1. 哈尔滨医科大学神经生物学教研室, 黑龙江 哈尔滨 150086;
2. 中国医学科学院、北京协和医学院药物研究所, 天然药物活性物质与功能国家重点实验室, 北京 100050
摘要:
癫痫是常见的神经系统疾病之一,以神经元异常放电导致短暂的脑功能障碍为特征,主要以药物治疗为主。尽管近年来抗癫痫药物开发有卓越的进展,但是对于难治性癫痫患者仍存在疗效差的现状。本综述主要阐述癫痫的发病机制、临床常用的经典抗癫痫药物(靶向钠离子通道、钙通道阻断剂、钾通道,以及调节γ-氨基丁酸/谷氨酸系统平衡),以及作用于新靶点的抗癫痫药物(突触囊泡糖蛋白2调节剂、雷帕霉素靶蛋白信号通路阻滞剂、碳酸酐酶抑制剂、大麻二酚或腺苷抑制剂的药物)的作用和机制等。
关键词:    癫痫      抗癫痫药物      耐药性癫痫      离子通道      G蛋白偶联受体     
Current status of treatment and drug discovery for epilepsy
LIU Ying1,2, YU Hai-bo2*, KONG Qing-fei1*
1. Department of Neurobiology, Harbin Medical University, Harbin 150086, China;
2. State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
Abstract:
Epilepsy is one of the most common neurological conditions, which is characterized by recurrent unprovoked seizures. Drug treatment is still the main method for the disease. Although remarkable progress has been made in the development of antiepileptic drugs in recent years, there is still a poor curative effect on patients with refractory epilepsy. This review will focus on the current status and pathogenesis of epilepsy, as well as the antiepileptic drugs (targeting sodium channels, calcium channels, potassium channels, and the balance of γ-aminobuyric acid/glutamate system, respectively) that have been developed based on classical epileptogenic mechanisms. Further the antiepileptic drugs acting on new targets (epigenetic interferers, synaptic vesicle glycoprotein 2A modulators, mammalian target of rapamycin signal pathway blockers, carbonic anhydrase inhibitors, cannabidiol and adenosine inhibitors) have also been discussed.
Key words:    epilepsy    antiepileptic drug    drug resistant epilepsy    ion channel    G-protein coupled receptor   
收稿日期: 2020-10-08
DOI: 10.16438/j.0513-4870.2020-1578
基金项目: 重大新药创制科技重大专项(2018ZX09711001-004-001);新药作用机制研究与药效评价北京市重点实验室(BZ0150).
通讯作者: 孔庆飞,Tel:86-10-83165742,E-mail:kqfangel@163.com;于海波,E-mail:haiboyu@imm.ac.cn
Email: kqfangel@163.com;haiboyu@imm.ac.cn
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参考文献:
[1] Fisher RS, Acevedo C, Arzimanoglou A, et al. ILAE official report:a practical clinical definition of epilepsy[J]. Epilepsia, 2014, 55:475-482.
[2] Sander JW. The epidemiology of epilepsy revisited[J]. Curr Opin Neurol, 2003, 16:165-170.
[3] Scheffer IE, Berkovic S, Capovilla G, et al. ILAE classification of the epilepsies:position paper of the ILAE Commission for classification and terminology[J]. Epilepsia, 2017, 58:512-521.
[4] Kalilani L, Sun X, Pelgrims B, et al. The epidemiology of drug-resistant epilepsy:a systematic review and meta-analysis[J]. Epilepsia, 2018, 59:2179-2193.
[5] Brodie MJ, Zuberi SM, Scheffer IE, et al. The 2017 ILAE classification of seizure types and the epilepsies:what do people with epilepsy and their caregivers need to know?[J]. Epileptic Disord, 2018, 20:77-87.
[6] Oyrer J, Maljevic S, Scheffer IE, et al. Ion channels in genetic epilepsy:from genes and mechanisms to disease-targeted therapies[J]. Pharmacol Rev, 2018, 70:142-173.
[7] Chow CY, Chin YKY, Ma L, et al. A selective Na(V) 1.1 activator with potential for treatment of dravet syndrome epilepsy[J]. Biochem Pharmacol, 2020, 181:113991.
[8] Brunklaus A, Lal D. Sodium channel epilepsies and neurodevelopmental disorders:from disease mechanisms to clinical application[J]. Dev Med Child Neurol, 2020, 62:784-792.
[9] Lim CX, Ricos MG, Dibbens LM, et al. KCNT1 mutations in seizure disorders:the phenotypic spectrum and functional effects[J]. J Med Genet, 2016, 53:217-225.
[10] Castaldo P, del Giudice EM, Coppola G, et al. Benign familial neonatal convulsions caused by altered gating of KCNQ2/KCNQ3 potassium channels[J]. J Neurosci, 2002, 22:Rc199.
[11] Soldovieri MV, Castaldo P, Iodice L, et al. Decreased subunit stability as a novel mechanism for potassium current impairment by a KCNQ2 C terminus mutation causing benign familial neonatal convulsions[J]. J Biol Chem, 2006, 281:418-428.
[12] Catterall WA. Structure and regulation of voltage-gated Ca2+ channels[J]. Annu Rev Cell Dev Biol, 2000, 16:521-555.
[13] Weiss N, Zamponi GW. T-type channel druggability at a crossroads[J]. ACS Chem Neurosci, 2019, 10:1124-1126.
[14] Rajakulendran S, Graves TD, Labrum RW, et al. Genetic and functional characterisation of the P/Q calcium channel in episodic ataxia with epilepsy[J]. J Physiol, 2010, 588:1905-1913.
[15] Valbuena S, Lerma J. Non-canonical signaling, the hidden life of ligand-gated ion channels[J]. Neuron, 2016, 92:316-329.
[16] Mihály A. The reactive plasticity of hippocampal ionotropic glutamate receptors in animal epilepsies[J]. Int J Mol Sci, 2019, 20:1030.
[17] Celli R, Santolini I, Van Luijtelaar G, et al. Targeting metabotropic glutamate receptors in the treatment of epilepsy:rationale and current status[J]. Expert Opin Ther Targets, 2019, 23:341-351.
[18] David Y, Cacheaux LP, Ivens S, et al. Astrocytic dysfunction in epileptogenesis:consequence of altered potassium and glutamate homeostasis?[J]. J Neurosci, 2009, 29:10588-10599.
[19] Vezzani A, Friedman A, Dingledine RJ. The role of inflammation in epileptogenesis[J]. Neuropharmacology, 2013, 69:16-24.
[20] Varvel NH, Neher JJ, Bosch A, et al. Infiltrating monocytes promote brain inflammation and exacerbate neuronal damage after status epilepticus[J]. Proc Natl Acad Sci U S A, 2016, 113:E5665-E5674.
[21] Roseti C, van Vliet EA, Cifelli P, et al. GABAA currents are decreased by IL-1β in epileptogenic tissue of patients with temporal lobe epilepsy:implications for ictogenesis[J]. Neurobiol Dis, 2015, 82:311-320.
[22] Vezzani A, Viviani B. Neuromodulatory properties of inflammatory cytokines and their impact on neuronal excitability[J]. Neuropharmacology, 2015, 96:70-82.
[23] Ravizza T, Terrone G, Salamone A, et al. High mobility group box 1 is a novel pathogenic factor and a mechanistic biomarker for epilepsy[J]. Brain Behav Immun, 2018, 72:14-21.
[24] Vezzani A, Maroso M, Balosso S, et al. IL-1 receptor/Toll-like receptor signaling in infection, inflammation, stress and neurodegeneration couples hyperexcitability and seizures[J]. Brain Behav Immun, 2011, 25:1281-1289.
[25] Rojas A, Jiang J, Ganesh T, et al. Cyclooxygenase-2 in epilepsy[J]. Epilepsia, 2014, 55:17-25.
[26] Jiang J, Yang MS, Quan Y, et al. Therapeutic window for cyclooxygenase-2 related anti-inflammatory therapy after status epilepticus[J]. Neurobiol Dis, 2015, 76:126-136.
[27] Ivens S, Kaufer D, Flores LP, et al. TGF-beta receptor-mediated albumin uptake into astrocytes is involved in neocortical epileptogenesis[J]. Brain, 2007, 130:535-547.
[28] Panday A, Sahoo MK, Osorio D, et al. NADPH oxidases:an overview from structure to innate immunity-associated pathologies[J]. Cell Mol Immunol, 2015, 12:5-23.
[29] Debanne D, Thompson SM, Gähwiler BH. A brief period of epileptiform activity strengthens excitatory synapses in the rat hippocampus in vitro[J]. Epilepsia, 2006, 47:247-256.
[30] Lubin FD, Ren Y, Xu X, et al. Nuclear factor-kappa B regulates seizure threshold and gene transcription following convulsant stimulation[J]. J Neurochem, 2007, 103:1381-1395.
[31] Raper JA. Semaphorins and their receptors in vertebrates and invertebrates[J]. Curr Opin Neurobiol, 2000, 10:88-94.
[32] Lai KO, Ip NY. Synapse development and plasticity:roles of ephrin/Eph receptor signaling[J]. Curr Opin Neurobiol, 2009, 19:275-283.
[33] Nadler JV. The recurrent mossy fiber pathway of the epileptic brain[J]. Neurochem Res, 2003, 28:1649-1658.
[34] Botterill JJ, Lu YL, LaFrancois JJ, et al. An excitatory and epileptogenic effect of dentate gyrus mossy cells in a mouse model of epilepsy[J]. Cell Rep, 2019, 29:2875-2889.e6.
[35] Schmeiser B, Zentner J, Prinz M, et al. Extent of mossy fiber sprouting in patients with mesiotemporal lobe epilepsy correlates with neuronal cell loss and granule cell dispersion[J]. Epilepsy Res, 2017, 129:51-58.
[36] Richichi C, Lin EJ, Stefanin D, et al. Anticonvulsant and antiepileptogenic effects mediated by adeno-associated virus vector neuropeptide Y expression in the rat hippocampus[J]. J Neurosci, 2004, 24:3051-3059.
[37] Nateri AS, Raivich G, Gebhardt C, et al. ERK activation causes epilepsy by stimulating NMDA receptor activity[J]. EMBO J, 2007, 26:4891-4901.
[38] Tang F, Hartz AMS, Bauer B. Drug-resistant epilepsy:multiple hypotheses, few answers[J]. Front Neurol, 2017, 8:301.
[39] Ufer M, Mosyagin I, Muhle H, et al. Non-response to antiepileptic pharmacotherapy is associated with the ABCC2-24C>T polymorphism in young and adult patients with epilepsy[J]. Pharmacogenet Genomics, 2009, 19:353-362.
[40] Kwan P, Poon WS, Ng HK, et al. Multidrug resistance in epilepsy and polymorphisms in the voltage-gated sodium channel genes SCN1A, SCN2A, and SCN3A:correlation among phenotype, genotype, and mRNA expression[J]. Pharmacogenet Genomics, 2008, 18:989-998.
[41] Lazarowski A, Czornyj L, Lubienieki F, et al. ABC transporters during epilepsy and mechanisms underlying multidrug resistance in refractory epilepsy[J]. Epilepsia, 2007, 48 Suppl 5:140-149.
[42] Volk HA, Löscher W. Multidrug resistance in epilepsy:rats with drug-resistant seizures exhibit enhanced brain expression of P-glycoprotein compared with rats with drug-responsive seizures[J]. Brain, 2005, 128:1358-1368.
[43] Remy S, Gabriel S, Urban BW, et al. A novel mechanism underlying drug resistance in chronic epilepsy[J]. Ann Neurol, 2003, 53:469-479.
[44] Töllner K, Wolf S, Löscher W, et al. The anticonvulsant response to valproate in kindled rats is correlated with its effect on neuronal firing in the substantia nigra pars reticulata:a new mechanism of pharmacoresistance[J]. J Neurosci, 2011, 31:16423-16434.
[45] Xu C, Wang Y, Zhang S, et al. Subicular pyramidal neurons gate drug resistance in temporal lobe epilepsy[J]. Ann Neurol, 2019, 86:626-640.
[46] Ali R, Khan MA, Siddiqui N. Past, present and future of antiepileptic drug therapy-finding a place for heterocyclics[J]. Mini Rev Med Chem, 2015, 15:1024-1050.
[47] Sankaraneni R, Lachhwani D. Antiepileptic drugs——a review[J]. Pediatr Ann, 2015, 44:e36-e42.
[48] Lu Y, Xiao Z, Yu W, et al. Efficacy and safety of adjunctive zonisamide in adult patients with refractory partial-onset epilepsy:a randomized, double-blind, placebo-controlled trial[J]. Clin Drug Investig, 2011, 31:221-229.
[49] Nakamura M, Cho JH, Shin H, et al. Effects of cenobamate (YKP3089), a newly developed anti-epileptic drug, on voltage-gated sodium channels in rat hippocampal CA3 neurons[J]. Eur J Pharmacol, 2019, 855:175-182.
[50] Pasierski M, Szulczyk B. Capsaicin inhibits sodium currents and epileptiform activity in prefrontal cortex pyramidal neurons[J]. Neurochem Int, 2020, 135:104709.
[51] Flor-Hirsch H, Heyman E, Livneh A, et al. Lacosamide for SCN2A-related intractable neonatal and infantile seizures[J]. Epileptic Disord, 2018, 20:440-446.
[52] Balagura G, Riva A, Marchese F, et al. Adjunctive rufinamide in children with Lennox-Gastaut syndrome:a literature review[J]. Neuropsychiatr Dis Treat, 2020, 16:369-379.
[53] Grunnet M, Strobaek D, Hougaard C, et al. Kv7 channels as targets for anti-epileptic and psychiatric drug-development[J]. Eur J Pharmacol, 2014, 726:133-137.
[54] Prakash C, Mishra M, Kumar P, et al. Response of voltage-gated sodium and calcium channels subtypes on dehydroepiandrosterone treatment in iron-induced epilepsy[J]. Cell Mol Neurobiol, 2020. DOI:10.1007/s10571-020-00851-0.
[55] Gomora JC, Daud AN, Weiergräber M, et al. Block of cloned human T-type calcium channels by succinimide antiepileptic drugs[J]. Mol Pharmacol, 2001, 60:1121-1132.
[56] Zhu S, Noviello CM, Teng J, et al. Structure of a human synaptic GABA(A) receptor[J]. Nature, 2018, 559:67-72.
[57] Zolkowska D, Wu CY, Rogawski MA. Intramuscular allopregnanolone and ganaxolone in a mouse model of treatment-resistant status epilepticus[J]. Epilepsia, 2018, 59 Suppl 2:220-227.
[58] Sharma R, Nakamura M, Neupane C, et al. Positive allosteric modulation of GABA(A) receptors by a novel antiepileptic drug cenobamate[J]. Eur J Pharmacol, 2020, 879:173117.
[59] Quilichini PP, Chiron C, Ben-Ari Y, et al. Stiripentol, a putative antiepileptic drug, enhances the duration of opening of GABA-A receptor channels[J]. Epilepsia, 2006, 47:704-716.
[60] Czapiński P, Blaszczyk B, Czuczwar SJ. Mechanisms of action of antiepileptic drugs[J]. Curr Top Med Chem, 2005, 5:3-14.
[61] Madsen KK, White HS, Schousboe A. Neuronal and non-neuronal GABA transporters as targets for antiepileptic drugs[J]. Pharmacol Ther, 2010, 125:394-401.
[62] Bröer S, Backofen-Wehrhahn B, Bankstahl M, et al. Vigabatrin for focal drug delivery in epilepsy:bilateral microinfusion into the subthalamic nucleus is more effective than intranigral or systemic administration in a rat seizure model[J]. Neurobiol Dis, 2012, 46:362-376.
[63] de Grazia U, DʼUrso A, Ranzato F, et al. A liquid chromatography-mass spectrometry assay for determination of perampanel and concomitant antiepileptic drugs in the plasma of patients with epilepsy compared with a fluorescent HPLC assay[J]. Ther Drug Monit, 2018, 40:477-485.
[64] Prüss H, Holtkamp M. Ketamine successfully terminates malignant status epilepticus[J]. Epilepsy Res, 2008, 82:219-222.
[65] Lynch JM, Tate SK, Kinirons P, et al. No major role of common SV2A variation for predisposition or levetiracetam response in epilepsy[J]. Epilepsy Res, 2009, 83:44-51.
[66] Lynch BA, Lambeng N, Nocka K, et al. The synaptic vesicle protein SV2A is the binding site for the antiepileptic drug levetiracetam[J]. Proc Natl Acad Sci U S A, 2004, 101:9861-9866.
[67] Niespodziany I, Rigo JM, Moonen G, et al. Brivaracetam does not modulate ionotropic channels activated by glutamate, γ-aminobutyric acid, and glycine in hippocampal neurons[J]. Epilepsia, 2017, 58:e157-e161.
[68] Wood M, Daniels V, Provins L, et al. Pharmacological profile of the novel antiepileptic drug candidate padsevonil:interactions with synaptic vesicle 2 proteins and the GABA(A) receptor[J]. J Pharmacol Exp Ther, 2020, 372:1-10.
[69] Hamidi S, Avoli M. Carbonic anhydrase inhibition by acetazolamide reduces in vitro epileptiform synchronization[J]. Neuropharmacology, 2015, 95:377-387.
[70] Leniger T, Wiemann M, Bingmann D, et al. Carbonic anhydrase inhibitor sulthiame reduces intracellular pH and epileptiform activity of hippocampal CA3 neurons[J]. Epilepsia, 2002, 43:469-474.
[71] Wang X, Li T. Role of adenosine kinase inhibitor in adenosine augmentation therapy for epilepsy:a potential novel drug for epilepsy[J]. Curr Drug Targets, 2020, 21:252-257.
[72] MacKeigan JP, Krueger DA. Differentiating the mTOR inhibitors everolimus and sirolimus in the treatment of tuberous sclerosis complex[J]. Neuro Oncol, 2015, 17:1550-1559.
[73] He W, Chen J, Wang YY, et al. Sirolimus improves seizure control in pediatric patients with tuberous sclerosis:a prospective cohort study[J]. Seizure, 2020, 79:20-26.
[74] Dilena R, Mauri E, Aronica E, et al. Therapeutic effect of anakinra in the relapsing chronic phase of febrile infection-related epilepsy syndrome[J]. Epilepsia Open, 2019, 4:344-350.
[75] Godfred RM, Parikh MS, Haltiner AM, et al. Does aspirin use make it harder to collect seizures during elective video-EEG telemetry?[J]. Epilepsy Behav, 2013, 27:115-117.
[76] Romoli M, Mazzocchetti P, D'Alonzo R, et al. Valproic acid and epilepsy:from molecular mechanisms to clinical evidences[J]. Curr Neuropharmacol, 2019, 17:926-946.
[77] Guerrini R. Valproate as a mainstay of therapy for pediatric epilepsy[J]. Paediatr Drugs, 2006, 8:113-129.
[78] Dodgson SJ, Shank RP, Maryanoff BE. Topiramate as an inhibitor of carbonic anhydrase isoenzymes[J]. Epilepsia, 2000, 41 Suppl 1:S35-S39.
[79] Shank RP, Gardocki JF, Streeter AJ, et al. An overview of the preclinical aspects of topiramate:pharmacology, pharmacokinetics, and mechanism of action[J]. Epilepsia, 2000, 41 Suppl 1:S3-S9.
[80] Dibué-Adjei M, Kamp MA, Alpdogan S, et al. Cav2.3(R-type) calcium channels are critical for mediating anticonvulsive and neuroprotective properties of lamotrigine in vivo[J]. Cell Physiol Biochem, 2017, 44:935-947.
[81] Abelaira HM, Réus GZ, Ribeiro KF, et al. Lamotrigine treatment reverses depressive-like behavior and alters BDNF levels in the brains of maternally deprived adult rats[J]. Pharmacol Biochem Behav, 2012, 101:348-353.
[82] Billakota S, Devinsky O, Marsh E. Cannabinoid therapy in epilepsy[J]. Curr Opin Neurol, 2019, 32:220-226.
[83] Kaplan DI, Isom LL, Petrou S. Role of sodium channels in epilepsy[J]. Cold Spring Harb Perspect Med, 2016, 6:a022814.
[84] Brodie MJ. Sodium channel blockers in the treatment of epilepsy[J]. CNS Drugs, 2017, 31:527-534.
[85] Kuo FS, Cleary CM, LoTurco JJ, et al. Disordered breathing in a mouse model of Dravet syndrome[J]. Elife, 2019, 26:43387.
[86] Richards KL, Milligan CJ, Richardson RJ, et al. Selective NaV1.1 activation rescues Dravet syndrome mice from seizures and premature death[J]. Proc Natl Acad Sci U S A, 2018, 115:E8077-E8085.
[87] Baker EM, Thompson CH, Hawkins NA, et al. The novel sodium channel modulator GS-458967(GS967) is an effective treatment in a mouse model of SCN8A encephalopathy[J]. Epilepsia, 2018, 59:1166-1176.
[88] Wengert ER, Saga AU, Panchal PS, et al. Prax330 reduces persistent and resurgent sodium channel currents and neuronal hyperexcitability of subiculum neurons in a mouse model of SCN8A epileptic encephalopathy[J]. Neuropharmacology, 2019, 158:107699.
[89] Asadi-Pooya AA. Lennox-Gastaut syndrome:a comprehensive review[J]. Neurol Sci, 2018, 39:403-414.
[90] Coetzee WA, Amarillo Y, Chiu J, et al. Molecular diversity of K+ channels[J]. Ann N Y Acad Sci, 1999, 868:233-285.
[91] Grunnet M, Strøbæk D, Hougaard C, et al. Kv7 channels as targets for anti-epileptic and psychiatric drug-development[J]. Eur J Pharmacol, 2014, 726:133-137.
[92] Surur AS, Bock C, Beirow K, et al. Flupirtine and retigabine as templates for ligand-based drug design of KV7.2/3 activators[J]. Org Biomol Chem, 2019, 17:4512-4522.
[93] Du J, Vegh V, Reutens DC. Persistent sodium current blockers can suppress seizures caused by loss of low-threshold D-type potassium currents:predictions from an in silico study of Kv1 channel disorders[J]. Epilepsia Open, 2020, 5:86-96.
[94] Zamponi GW, Striessnig J, Koschak A, et al. The physiology, pathology, and pharmacology of voltage-gated calcium channels and their future therapeutic potential[J]. Pharmacol Rev, 2015, 67:821-870.
[95] Huguenard JR. Block of T-type Ca2+ channels is an important action of succinimide antiabsence drugs[J]. Epilepsy Curr, 2002, 2:49-52.
[96] Yu Y, Nguyen DT, Jiang J. G protein-coupled receptors in acquired epilepsy:druggability and translatability[J]. Prog Neurobiol, 2019, 183:101682.
[97] Kew JN, Kemp JA. Ionotropic and metabotropic glutamate receptor structure and pharmacology[J]. Psychopharmacology (Berl), 2005, 179:4-29.
[98] Hanada T. Ionotropic glutamate receptors in epilepsy:a review focusing on AMPA and NMDA receptors[J]. Biomolecules, 2020, 10:464.
[99] Rogawski MA, Löscher W, Rho JM. Mechanisms of action of antiseizure drugs and the ketogenic diet[J]. Cold Spring Harb Perspect Med, 2016, 6:a022780.
[100] Duan ML, Tan LL, Du J, et al. Structure based virtual screening of novel noncompetitive antagonist of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor[J]. J Biotechnol, 2019, 295:9-18.
[101] Yelshanskaya MV, Singh AK, Sampson JM, et al. Structural bases of noncompetitive inhibition of AMPA-subtype ionotropic glutamate receptors by antiepileptic drugs[J]. Neuron, 2016, 91:1305-1315.
[102] Twele F, Bankstahl M, Klein S, et al. The AMPA receptor antagonist NBQX exerts anti-seizure but not antiepileptogenic effects in the intrahippocampal kainate mouse model of mesial temporal lobe epilepsy[J]. Neuropharmacology, 2015, 95:234-242.
[103] Lee CY, Fu WM, Chen CC, et al. Lamotrigine inhibits postsynaptic AMPA receptor and glutamate release in the dentate gyrus[J]. Epilepsia, 2008, 49:888-897.
[104] Alexander GM, Godwin DW. Metabotropic glutamate receptors as a strategic target for the treatment of epilepsy[J]. Epilepsy Res, 2006, 71:1-22.
[105] Stout KA, Dunn AR, Hoffman C, et al. The synaptic vesicle glycoprotein 2:structure, function, and disease relevance[J]. ACS Chem Neurosci, 2019, 10:3927-3938.
[106] Löscher W, Gillard M, Sands ZA, et al. Synaptic vesicle glycoprotein 2A ligands in the treatment of epilepsy and beyond[J]. CNS Drugs, 2016, 30:1055-1077.
[107] Niespodziany I, Ghisdal P, Mullier B, et al. Functional characterization of the antiepileptic drug candidate, padsevonil, on GABA(A) receptors[J]. Epilepsia, 2020, 61:914-923.
[108] Thiry A, Rolin S, Vullo D, et al. Indanesulfonamides as carbonic anhydrase inhibitors and anticonvulsant agents:structure-activity relationship and pharmacological evaluation[J]. Eur J Med Chem, 2008, 43:2853-2860.
[109] Aggarwal M, Kondeti B, McKenna R. Anticonvulsant/antiepileptic carbonic anhydrase inhibitors:a patent review[J]. Expert Opin Ther Pat, 2013, 23:717-724.
[110] Dupont S, Stefan H. Zonisamide in clinical practice[J]. Acta Neurol Scand Suppl, 2012, (194):29-35.
[111] Boison D. Adenosine as a modulator of brain activity[J]. Drug News Perspect, 2007, 20:607-611.
[112] Paul S, Elsinga PH, Ishiwata K, et al. Adenosine A(1) receptors in the central nervous system:their functions in health and disease, and possible elucidation by PET imaging[J]. Curr Med Chem, 2011, 18:4820-4835.
[113] Boison D. Adenosine kinase, epilepsy and stroke:mechanisms and therapies[J]. Trends Pharmacol Sci, 2006, 27:652-658.
[114] Curatolo P, Jóźwiak S, Nabbout R. Management of epilepsy associated with tuberous sclerosis complex (TSC):clinical recommendations[J]. Eur J Paediatr Neurol, 2012, 16:582-586.
[115] Curatolo P, Aronica E, Jansen A, et al. Early onset epileptic encephalopathy or genetically determined encephalopathy with early onset epilepsy? Lessons learned from TSC[J]. Eur J Paediatr Neurol, 2016, 20:203-211.
[116] Krueger DA, Wilfong AA, Holland-Bouley K, et al. Everolimus treatment of refractory epilepsy in tuberous sclerosis complex[J]. Ann Neurol, 2013, 74:679-687.
[117] Vezzani A, Balosso S, Ravizza T. Neuroinflammatory pathways as treatment targets and biomarkers in epilepsy[J]. Nat Rev Neurol, 2019, 15:459-472.
[118] Hoffmann J, Akerman S, Goadsby PJ. Efficacy and mechanism of anticonvulsant drugs in migraine[J]. Expert Rev Clin Pharmacol, 2014, 7:191-201.
[119] Musetti L, Tundo A, Benedetti A, et al. Lithium, valproate, and carbamazepine prescribing patterns for long-term treatment of bipolar I and Ⅱ disorders:a prospective study[J]. Hum Psychopharmacol, 2018, 33:e2676.
[120] Balagura G, Iapadre G, Verrotti A, et al. Moving beyond sodium valproate:choosing the right anti-epileptic drug in children[J]. Expert Opin Pharmacother, 2019, 20:1449-1456.
[121] Khalil NY, AlRabiah HK, Al Rashoud SS, et al. Topiramate:comprehensive profile[J]. Profiles Drug Subst Excip Relat Methodol, 2019, 44:333-378.
[122] Spritzer SD, Bravo TP, Drazkowski JF. Topiramate for treatment in patients with migraine and epilepsy[J]. Headache, 2016, 56:1081-1085.
[123] Lipkind GM, Fozzard HA. Molecular modeling of local anesthetic drug binding by voltage-gated sodium channels[J]. Mol Pharmacol, 2005, 68:1611-1622.
[124] Sekar K, Pack A. Epidiolex as adjunct therapy for treatment of refractory epilepsy:a comprehensive review with a focus on adverse effects[J]. F1000Res, 2019, 8:F1000Faculty Rev-234.
[125] Ghovanloo MR, Shuart NG, Mezeyova J, et al. Inhibitory effects of cannabidiol on voltage-dependent sodium currents[J]. J Biol Chem, 2018, 293:16546-16558.
[126] Khan AA, Shekh-Ahmad T, Khalil A, et al. Cannabidiol exerts antiepileptic effects by restoring hippocampal interneuron functions in a temporal lobe epilepsy model[J]. Br J Pharmacol, 2018, 175:2097-2115.
[127] Ibeas Bih C, Chen T, Nunn AV, et al. Molecular targets of cannabidiol in neurological disorders[J]. Neurotherapeutics, 2015, 12:699-730.
[128] Sylantyev S, Jensen TP, Ross RA, et al. Cannabinoid- and lysophosphatidylinositol-sensitive receptor GPR55 boosts neurotransmitter release at central synapses[J]. Proc Natl Acad Sci U S A, 2013, 110:5193-5198.
[129] Manjarrez-Marmolejo J, Franco-Pérez J. Gap junction blockers:an overview of their effects on induced seizures in animal models[J]. Curr Neuropharmacol, 2016, 14:759-771.
[130] Mehta P, Malik R. Discovery and identification of putative adenosine kinase inhibitors as potential anti-epileptic agents from structural insights[J]. J Biomol Struct Dyn, 2020, 38:5320-5337.
[131] Campos G, Fortuna A, Falcão A, et al. In vitro and in vivo experimental models employed in the discovery and development of antiepileptic drugs for pharmacoresistant epilepsy[J]. Epilepsy Res, 2018, 146:63-86.
[132] Loscher W. Animal models of seizures and epilepsy:past, present, and future role for the discovery of antiseizure drugs[J]. Neurochem Res, 2017, 42:1873-1888.
[133] Grone BP, Baraban SC. Animal models in epilepsy research:legacies and new directions[J]. Nat Neurosci, 2015, 18:339-343.
[134] Wilcox KS, West PJ, Metcalf CS. The current approach of the epilepsy therapy screening program contract site for identifying improved therapies for the treatment of pharmacoresistant seizures in epilepsy[J]. Neuropharmacology, 2020, 166:107811.
[135] Barker-Haliski ML, Johnson K, Billingsley P, et al. Validation of a preclinical drug screening platform for pharmacoresistant epilepsy[J]. Neurochem Res, 2017, 42:1904-1918.
[136] Bennewitz MF, Saltzman WM. Nanotechnology for delivery of drugs to the brain for epilepsy[J]. Neurotherapeutics, 2009, 6:323-336.
[137] Shah V, Kochar P. Brain cancer:implication to disease, therapeutic strategies and tumor targeted drug delivery approaches[J]. Recent Pat Anticancer Drug Discov, 2018, 13:70-85.
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