How to Find Candidate Drug-targets for Antiepileptogenic Therapy?

Nian       Yu; Xing-jian       Lin; Qing       Di
Abstract

Although over 25 antiepileptic drugs (AEDs) have become currently available for clinical use, the incidence of epilepsy worldwide and the proportions of drug-resistant epilepsy among them are not significantly reduced during the past decades. Traditional screens for AEDs have been mainly focused on their anti-ictogenic roles, and their efficacies primarily depend on suppressing neuronal excitability or enhancing inhibitory neuronal activity, almost without the influence on the epileptogenesis or with inconsistent results from different studies. Epileptogenesis refers to the pathological process of a brain from its normal status to the alterations with the continuous prone of unprovoked spontaneous seizures after brain insults, such as stroke, traumatic brain injury, CNS infectious, and autoimmune disorders, and even some specific inherited conditions. Recently growing experimental and clinical studies have discovered the underlying mechanisms for epileptogenesis, which are multi-aspect and multistep. These findings provide us a number of interesting sites for antiepileptogenic drugs (AEGDs). AEGDs have been evidenced as significantly roles of postponing or completely blocking the development of epilepsy in experimental models. The present review will introduce potential novel candidate drug-targets for AEGDs based on the published studies.
Keywords: Epileptogenesis, antiepileptogenesis, anti-epileptogenic drugs, drug targets, immunomodulators, precipitating epileptogenic events.
« Previous Next »
Graphical Abstract

[1] 
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] 
[2] 
Rho, J.M.; White, H.S. Brief history of anti-seizure drug development. Epilepsia Open,  2018, 3(Suppl. 2), 114-119.
[http://dx.doi.org/10.1002/epi4.12268] [PMID: 30564769] 
[3] 
Santulli, L.; Coppola, A.; Balestrini, S.; Striano, S. The challenges of treating epilepsy with 25 antiepileptic drugs. Pharmacol. Res.,  2016, 107, 211-219.
[http://dx.doi.org/10.1016/j.phrs.2016.03.016] [PMID: 26995307] 
[4] 
Chen, Z.; Brodie, M.J.; Liew, D.; Kwan, P. Treatment outcomes in patients with newly diagnosed epilepsy treated with established and new antiepileptic drugs: a 30-year longitudinal cohort study. JAMA Neurol.,  2018, 75(3), 279-286.
[http://dx.doi.org/10.1001/jamaneurol.2017.3949] [PMID: 29279892] 
[5] 
Janmohamed, M.; Brodie, M.J.; Kwan, P. Pharmacoresistance - Epidemiology, mechanisms, and impact on epilepsy treatment. Neuropharmacology,  2020, 168107790
[http://dx.doi.org/10.1016/j.neuropharm.2019.107790] [PMID: 31560910] 
[6] 
Beghi, E. Addressing the burden of epilepsy: Many unmet needs. Pharmacol. Res.,  2016, 107, 79-84.
[http://dx.doi.org/10.1016/j.phrs.2016.03.003] [PMID: 26952026] 
[7] 
van den Berg, L.; de Weerd, A.W.; Reuvekamp, H.F.; van der Meere, J.J. The burden of parenting children with frontal lobe epilepsy. Epilepsy Behav.,  2019, 97, 269-274.
[http://dx.doi.org/10.1016/j.yebeh.2019.05.034] [PMID: 31254848] 
[8] 
Sankaraneni, R.; Lachhwani, D. Antiepileptic drugs--a review. Pediatr. Ann.,  2015, 44(2), e36-e42.
[http://dx.doi.org/10.3928/00904481-20150203-10] [PMID: 25658217] 
[9] 
Kobayashi, K.; Endoh, F.; Ohmori, I.; Akiyama, T. Action of antiepileptic drugs on neurons. Brain Dev.,  2020, 42(1), 2-5.
[10] 
Clossen, B.L.; Reddy, D.S. Novel therapeutic approaches for disease-modification of epileptogenesis for curing epilepsy. Biochim. Biophys. Acta Mol. Basis Dis.,  2017, 1863(6), 1519-1538.
[http://dx.doi.org/10.1016/j.bbadis.2017.02.003] [PMID: 28179120] 
[11] 
Mani, R.; Pollard, J.; Dichter, M.A. Human clinical trails in antiepileptogenesis. Neurosci. Lett.,  2011, 497(3), 251-256.
[http://dx.doi.org/10.1016/j.neulet.2011.03.010] [PMID: 21439351] 
[12] 
Wang, J.Z.; Vyas, M.V.; Saposnik, G.; Burneo, J.G. Incidence and management of seizures after ischemic stroke: Systematic review and meta-analysis. Neurology,  2017, 89(12), 1220-1228.
[http://dx.doi.org/10.1212/WNL.0000000000004407] [PMID: 28835405] 
[13] 
Wilson, C.D.; Burks, J.D.; Rodgers, R.B.; Evans, R.M.; Bakare, A.A.; Safavi-Abbasi, S. Early and late posttraumatic epilepsy in the setting of traumatic brain injury: a meta-analysis and review of antiepileptic management. World Neurosurg.,  2018, 110, e901-e906.
[http://dx.doi.org/10.1016/j.wneu.2017.11.116] [PMID: 29196247] 
[14] 
Spoelhof, B.; Sanchez-Bautista, J.; Zorrilla-Vaca, A.; Kaplan, P.W.; Farrokh, S.; Mirski, M.; Freund, B.; Rivera-Lara, L. Impact of antiepileptic drugs for seizure prophylaxis on short and long-term functional outcomes in patients with acute intracerebral hemorrhage: A meta-analysis and systematic review. Seizure,  2019, 69, 140-146.
[http://dx.doi.org/10.1016/j.seizure.2019.04.017] [PMID: 31048270] 
[15] 
Turnbull, D.; Singatullina, N.; Reilly, C. A systematic appraisal of neurosurgical seizure prophylaxis: Guidance for critical care management. J. Neurosurg. Anesthesiol.,  2016, 28(3), 233-249.
[PMID: 26192247] 
[16] 
Won, S.Y.; Dubinski, D.; Herrmann, E.; Cuca, C.; Strzelczyk, A.; Seifert, V.; Konczalla, J.; Freiman, T.M. Epileptic seizures in patients following surgical treatment of acute subdural hematoma-incidence, risk factors, patient outcome, and development of new scoring system for prophylactic antiepileptic treatment (GATE-24 score). World Neurosurg.,  2017, 101, 416-424.
[http://dx.doi.org/10.1016/j.wneu.2017.02.024] [PMID: 28213197] 
[17] 
Schmidt, D.; Sillanpää, M. Prevention of epilepsy: issues and innovations. Curr. Neurol. Neurosci. Rep.,  2016, 16(11), 95.
[http://dx.doi.org/10.1007/s11910-016-0695-9] [PMID: 27628962] 
[18] 
Terrone, G.; Pauletti, A.; Pascente, R.; Vezzani, A. Preventing epileptogenesis: A realistic goal? Pharmacol. Res.,  2016, 110, 96-100.
[http://dx.doi.org/10.1016/j.phrs.2016.05.009] [PMID: 27173399] 
[19] 
Becker, A.J. Review: Animal models of acquired epilepsy: insights into mechanisms of human epileptogenesis. Neuropathol. Appl. Neurobiol.,  2018, 44(1), 112-129.
[http://dx.doi.org/10.1111/nan.12451] [PMID: 29130506] 
[20] 
Maguire, J. Epileptogenesis: More than just the latent period. Epilepsy Curr.,  2016, 16(1), 31-33.
[http://dx.doi.org/10.5698/1535-7597-16.1.31] [PMID: 26900375] 
[21] 
Patel, D.C.; Wilcox, K.S.; Metcalf, C.S. Novel targets for developing antiseizure and, potentially, antiepileptogenic drugs. Epilepsy Curr.,  2017, 17(5), 293-298.
[http://dx.doi.org/10.5698/1535-7597.17.5.293] [PMID: 29225544] 
[22] 
Kaminski, R.M.; Rogawski, M.A.; Klitgaard, H. The potential of antiseizure drugs and agents that act on novel molecular targets as antiepileptogenic treatments. Neurotherapeutics,  2014, 11(2), 385-400.
[http://dx.doi.org/10.1007/s13311-014-0266-1] [PMID: 24671870] 
[23] 
Vespa, P.M.; Shrestha, V.; Abend, N.; Agoston, D.; Au, A.; Bell, M.J.; Bleck, T.P.; Blanco, M.B.; Claassen, J.; Diaz-Arrastia, R.; Duncan, D.; Ellingson, B.; Foreman, B.; Gilmore, E.J.; Hirsch, L.; Hunn, M.; Kamnaksh, A.; McArthur, D.; Morokoff, A.; O’Brien, T.; O’Phelan, K.; Robertson, C.L.; Rosenthal, E.; Staba, R.; Toga, A.; Willyerd, F.A.; Zimmermann, L.; Yam, E.; Martinez, S.; Real, C.; Engel, J., Jr The epilepsy bioinformatics study for anti-epileptogenic therapy (EpiBioS4Rx) clinical biomarker: Study design and protocol. Neurobiol. Dis.,  2019, 123, 110-114.
[http://dx.doi.org/10.1016/j.nbd.2018.07.025] [PMID: 30048805] 
[24] 
Tomari, S.; Tanaka, T.; Ihara, M.; Matsuki, T.; Fukuma, K.; Matsubara, S.; Nagatsuka, K.; Toyoda, K. Risk factors for post-stroke seizure recurrence after the first episode. Seizure,  2017, 52, 22-26.
[http://dx.doi.org/10.1016/j.seizure.2017.09.007] [PMID: 28957721] 
[25] 
Chen, F.; He, X.; Luan, G.; Li, T. Role of DNA methylation and adenosine in ketogenic diet for pharmacoresistant epilepsy: focus on epileptogenesis and associated comorbidities. Front. Neurol.,  2019, 10, 119.
[http://dx.doi.org/10.3389/fneur.2019.00119] [PMID: 30863356] 
[26] 
Jehi, L.E.; Vezzani, A. Novel concepts in epileptogenesis and its prevention. Neurotherapeutics,  2014, 11(2), 229-230.
[http://dx.doi.org/10.1007/s13311-014-0268-z] [PMID: 24652605] 
[27] 
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] 
[28] 
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] 
[29] 
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] 
[30] 
Pitkänen, A.; Lukasiuk, K. Mechanisms of epileptogenesis and potential treatment targets. Lancet Neurol.,  2011, 10(2), 173-186.
[http://dx.doi.org/10.1016/S1474-4422(10)70310-0] [PMID: 21256455] 
[31] 
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] 
[32] 
Pitkänen, A.; Kharatishvili, I.; Karhunen, H.; Lukasiuk, K.; Immonen, R.; Nairismägi, J.; Gröhn, O.; Nissinen, J. Epileptogenesis in experimental models. Epilepsia,  2007, 48(Suppl. 2), 13-20.
[33] 
Jayalakshmi, S.; Vooturi, S.; Sahu, S.; Yada, P.K.; Mohandas, S. Causes and outcomes of new onset status epilepticus and predictors of refractoriness to therapy. J. Clin. Neurosci.,  2016, 26, 89-94.
[34] 
Chakraborty, T.; Hocker, S. The clinical spectrum of new-onset status epilepticus. Crit. Care Med.,  2019, 47(7), 970-974.
[http://dx.doi.org/10.1097/CCM.0000000000003776] [PMID: 30985452] 
[35] 
Anjum, S.M.M.; Käufer, C.; Hopfengärtner, R.; Waltl, I.; Bröer, S.; Löscher, W. Automated quantification of EEG spikes and spike clusters as a new read out in Theiler’s virus mouse model of encephalitis-induced epilepsy. Epilepsy Behav.,  2018, 88, 189-204.
[http://dx.doi.org/10.1016/j.yebeh.2018.09.016] [PMID: 30292054] 
[36] 
Smith, Z.Z.; Benison, A.M.; Bercum, F.M.; Dudek, F.E.; Barth, D.S. Progression of convulsive and nonconvulsive seizures during epileptogenesis after pilocarpine-induced status epilepticus. J. Neurophysiol.,  2018, 119(5), 1818-1835.
[http://dx.doi.org/10.1152/jn.00721.2017] [PMID: 29442558] 
[37] 
Williams, P.A.; White, A.M.; Clark, S.; Ferraro, D.J.; Swiercz, W.; Staley, K.J.; Dudek, F.E. Development of spontaneous recurrent seizures after kainate-induced status epilepticus. J. Neurosci.,  2009, 29(7), 2103-2112.
[http://dx.doi.org/10.1523/JNEUROSCI.0980-08.2009] [PMID: 19228963] 
[38] 
Bertram, E.H.; Cornett, J.F. The evolution of a rat model of chronic spontaneous limbic seizures. Brain Res.,  1994, 661(1-2), 157-162.
[http://dx.doi.org/10.1016/0006-8993(94)91192-4] [PMID: 7834366] 
[39] 
Çarçak, N.; Yavuz, M.; Eryiğit Karamahmutoğlu, T.; Kurt, A.H.; Urhan Küçük, M.; Onat, F.Y.; Büyükafsar, K. Suppressive effect of Rho-kinase inhibitors Y-27632 and fasudil on spike-and-wave discharges in genetic absence epilepsy rats from Strasbourg (GAERS). Naunyn Schmiedebergs Arch. Pharmacol.,  2018, 391(11), 1275-1283.
[http://dx.doi.org/10.1007/s00210-018-1546-9] [PMID: 30073384] 
[40] 
Bekenstein, U.; Mishra, N.; Milikovsky, D.Z.; Hanin, G.; Zelig, D.; Sheintuch, L.; Berson, A.; Greenberg, D.S.; Friedman, A.; Soreq, H. Dynamic changes in murine forebrain miR-211 expression associate with cholinergic imbalances and epileptiform activity. Proc. Natl. Acad. Sci. USA,  2017, 114(25), E4996-E5005.
[http://dx.doi.org/10.1073/pnas.1701201114] [PMID: 28584127] 
[41] 
Yu, N.; Liu, H.; Zhang, Y.F.; Su, L.Y.; Liu, X.H.; Li, L.C.; Hao, J.B.; Huang, X.J.; Di, Q. Effects of brain IKKβ gene silencing by small interfering RNA on P-glycoprotein expression and brain damage in the rat kainic acid-induced seizure model. CNS Neurol. Disord. Drug Targets,  2014, 13(4), 661-672.
[http://dx.doi.org/10.2174/18715273113129990106] [PMID: 24040792] 
[42] 
Yu, N.; Zhang, Y.F.; Zhang, K.; Cheng, Y.F.; Ma, H.Y.; Di, Q.; Pregnane, X. Pregnane X receptor not nuclear factor-kappa b up-regulates p-glycoprotein expression in the brain of chronic epileptic rats induced by kainic acid. Neurochem. Res.,  2017, 42(8), 2167-2177.
[http://dx.doi.org/10.1007/s11064-017-2224-x] [PMID: 28303499] 
[43] 
Löscher, W. The holy grail of epilepsy prevention: Preclinical approaches to antiepileptogenic treatments. Neuropharmacology,  2020, 167107605
[44] 
Fernandes, M.J.; Carneiro, J.E.; Amorim, R.P.; Araujo, M.G.; Nehlig, A. Neuroprotective agents and modulation of temporal lobe epilepsy. Front. Biosci. (Elite Ed.),  2015, 7, 79-93.
[http://dx.doi.org/10.2741/e719] [PMID: 25553365] 
[45] 
Chen, M.; Arumugam, T.V.; Leanage, G.; Tieng, Q.M.; Yadav, A.; Ullmann, J.F.; She, D.T.; Truong, V.; Ruitenberg, M.J.; Reutens, D.C. Disease-modifying effect of intravenous immunoglobulin in an experimental model of epilepsy. Sci. Rep.,  2017, 7, 40528.
[http://dx.doi.org/10.1038/srep40528] [PMID: 28074934] 
[46] 
Stables, J.P.; Bertram, E.; Dudek, F.E.; Holmes, G.; Mathern, G.; Pitkanen, A.; White, H.S. Therapy discovery for pharmacoresistant epilepsy and for disease-modifying therapeutics: summary of the NIH/NINDS/AES models II workshop. Epilepsia,  2003, 44(12), 1472-1478.
[http://dx.doi.org/10.1111/j.0013-9580.2003.32803.x] [PMID: 14636315] 
[47] 
Kwon, Y.S.; Pineda, E.; Auvin, S.; Shin, D.; Mazarati, A.; Sankar, R. Neuroprotective and antiepileptogenic effects of combination of anti-inflammatory drugs in the immature brain. J. Neuroinflammation,  2013, 10, 30.
[http://dx.doi.org/10.1186/1742-2094-10-30] [PMID: 23442201] 
[48] 
Krumholz, A.; Wiebe, S.; Gronseth, G.S.; Gloss, D.S.; Sanchez, A.M.; Kabir, A.A.; Liferidge, A.T.; Martello, J.P.; Kanner, A.M.; Shinnar, S.; Hopp, J.L.; French, J.A. Evidence-based guideline: management of an unprovoked first seizure in adults: report of the guideline development subcommittee of the american academy of neurology and the american epilepsy society. Epilepsy Curr.,  2015, 15(3), 144-152.
[http://dx.doi.org/10.5698/1535-7597-15.3.144] [PMID: 26316856] 
[49] 
Klein, P.; Dingledine, R.; Aronica, E.; Bernard, C.; Blümcke, I.; Boison, D.; Brodie, M.J.; Brooks-Kayal, A.R.; Engel, J., Jr; Forcelli, P.A.; Hirsch, L.J.; Kaminski, R.M.; Klitgaard, H.; Kobow, K.; Lowenstein, D.H.; Pearl, P.L.; Pitkänen, A.; Puhakka, N.; Rogawski, M.A.; Schmidt, D.; Sillanpää, M.; Sloviter, R.S.; Steinhäuser, C.; Vezzani, A.; Walker, M.C.; Löscher, W. Commonalities in epileptogenic processes from different acute brain insults: Do they translate? Epilepsia,  2018, 59(1), 37-66.
[http://dx.doi.org/10.1111/epi.13965] [PMID: 29247482] 
[50] 
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] 
[51] 
Citraro, R.; Leo, A.; Constanti, A.; Russo, E.; De Sarro, G. mTOR pathway inhibition as a new therapeutic strategy in epilepsy and epileptogenesis. Pharmacol. Res.,  2016, 107, 333-343.
[http://dx.doi.org/10.1016/j.phrs.2016.03.039] [PMID: 27049136] 
[52] 
Yu, N.; Liu, H.; Di, Q. Modulation of immunity and the inflammatory response: a new target for treating drug-resistant epilepsy. Curr. Neuropharmacol.,  2013, 11(1), 114-127.
[PMID: 23814544] 
[53] 
Thomas, R.H.; Berkovic, S.F. The hidden genetics of epilepsy-a clinically important new paradigm. Nat. Rev. Neurol.,  2014, 10(5), 283-292.
[http://dx.doi.org/10.1038/nrneurol.2014.62] [PMID: 24733163] 
[54] 
Pitkänen, A.; Bolkvadze, T.; Immonen, R. Anti-epileptogenesis in rodent post-traumatic epilepsy models. Neurosci. Lett.,  2011, 497(3), 163-171.
[http://dx.doi.org/10.1016/j.neulet.2011.02.033] [PMID: 21402123] 
[55] 
Patel, DC; Wallis, G; Dahle, EJ; McElroy, PB; Thomson, KE; Tesi, RJ; Szymkowski, DE; West, PJ; Smeal, RM; Patel, M; Fujinami, RS; White, HS; Wilcox, KS Hippocampal TNFα signaling contributes to seizure generation in an infection-induced mouse model of limbic epilepsy. eNeuro,,  2017, 4(2) pii: ENEURO,  , 0105-17.
[56] 
Ali, T.; Kaitha, S.; Mahmood, S.; Ftesi, A.; Stone, J.; Bronze, M.S. Clinical use of anti-TNF therapy and increased risk of infections. Drug Healthc. Patient Saf.,  2013, 5, 79-99.
[http://dx.doi.org/10.2147/DHPS.S28801] [PMID: 23569399] 
[57] 
Zeng, L.H.; Rensing, N.R.; Wong, M. developing antiepileptogenic drugs for acquired epilepsy: targeting the mammalian target of rapamycin (mtor) pathway. Mol. Cell. Pharmacol.,  2009, 1(3), 124-129.
[http://dx.doi.org/10.4255/mcpharmacol.09.16] [PMID: 20419051] 
[58] 
Kim, S.Y.; Buckwalter, M.; Soreq, H.; Vezzani, A.; Kaufer, D. Blood-brain barrier dysfunction-induced inflammatory signaling in brain pathology and epileptogenesis. Epilepsia,  2012, 53(Suppl. 6), 37-44.
[http://dx.doi.org/10.1111/j.1528-1167.2012.03701.x] [PMID: 23134494] 
[59] 
Jin, M.; Sheng, W.; Han, L.; He, Q.; Ji, X.; Liu, K. Activation of BDNF-TrkB signaling pathway-regulated brain inflammation in pentylenetetrazole-induced seizures in zebrafish. Fish Shellfish Immunol.,  2018, 83, 26-36.
[http://dx.doi.org/10.1016/j.fsi.2018.09.010] [PMID: 30195910] 
[60] 
Rana, A.; Musto, A.E. The role of inflammation in the development of epilepsy. J. Neuroinflammation,  2018, 15(1), 144.
[http://dx.doi.org/10.1186/s12974-018-1192-7] [PMID: 29764485] 
[61] 
Choi, J.; Choi, S.A.; Kim, S.Y.; Kim, H.; Lim, B.C.; Hwang, H.; Chae, J.H.; Kim, K.J.; Oh, S.; Kim, E.Y.; Shin, J.S. Association analysis of interleukin-1β, interleukin-6, and hmgb1 variants with postictal serum cytokine levels in children with febrile seizure and generalized epilepsy with febrile seizure plus. J. Clin. Neurol.,  2019, 15(4), 555-563.
[http://dx.doi.org/10.3988/jcn.2019.15.4.555] [PMID: 31591845] 
[62] 
Barbalho, P.G.; Carvalho, B.S.; Lopes-Cendes, I.; Maurer-Morelli, C.V. Cyclooxygenase-1 as a potential therapeutic target for seizure suppression: evidences from zebrafish pentylenetetrazole-seizure model. Front. Neurol.,  2016, 7, 200.
[http://dx.doi.org/10.3389/fneur.2016.00200] [PMID: 27895618] 
[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] 
Dupuis, N.; Mazarati, A.; Desnous, B.; Chhor, V.; Fleiss, B.; Le Charpentier, T.; Lebon, S.; Csaba, Z.; Gressens, P.; Dournaud, P.; Auvin, S. Pro-epileptogenic effects of viral-like inflammation in both mature and immature brains. J. Neuroinflammation,  2016, 13(1), 307.
[http://dx.doi.org/10.1186/s12974-016-0773-6] [PMID: 27955671] 
[65] 
Linnoila, J.; Pulli, B.; Armangué, T.; Planagumà, J.; Narsimhan, R.; Schob, S.; Zeller, M.W.G.; Dalmau, J.; Chen, J. Mouse model of anti-NMDA receptor post-herpes simplex encephalitis. Neurol. Neuroimmunol. Neuroinflamm.,  2018, 6(2) e529
[http://dx.doi.org/10.1212/NXI.0000000000000529] [PMID: 30697582] 
[66] 
Geis, C.; Planagumà, J.; Carreño, M.; Graus, F.; Dalmau, J. Autoimmune seizures and epilepsy. J. Clin. Invest.,  2019, 129(3), 926-940.
[http://dx.doi.org/10.1172/JCI125178] [PMID: 30714986] 
[67] 
Ahmed, N.; Aljuhani, N.; Al-Hujaili, H.S.; Al-Hujaili, M.A.; Elkablawy, M.A.; Noah, M.M.; Abo-Haded, H.; El-Agamy, D.S. Agmatine protects against sodium valproate-induced hepatic injury in mice via modulation of nuclear factor-κB/inducible nitric oxide synthetase pathway. J. Biochem. Mol. Toxicol.,  2018, 32(12)e22227
[http://dx.doi.org/10.1002/jbt.22227] [PMID: 30273971] 
[68] 
Arena, A.; Zimmer, T.S.; van Scheppingen, J.; Korotkov, A.; Anink, J.J.; Mühlebner, A.; Jansen, F.E.; van Hecke, W.; Spliet, W.G.; van Rijen, P.C.; Vezzani, A.; Baayen, J.C.; Idema, S.; Iyer, A.M.; Perluigi, M.; Mills, J.D.; van Vliet, E.A.; Aronica, E. Oxidative stress and inflammation in a spectrum of epileptogenic cortical malformations: molecular insights into their interdependence. Brain Pathol.,  2019, 29(3), 351-365.
[http://dx.doi.org/10.1111/bpa.12661] [PMID: 30303592] 
[69] 
Sedaghat, R.; Taab, Y.; Kiasalari, Z.; Afshin-Majd, S.; Baluchnejadmojarad, T.; Roghani, M. Berberine ameliorates intrahippocampal kainate-induced status epilepticus and consequent epileptogenic process in the rat: Underlying mechanisms. Biomed. Pharmacother.,  2017, 87, 200-208.
[http://dx.doi.org/10.1016/j.biopha.2016.12.109] [PMID: 28061403] 
[70] 
Jiang, Z.; Guo, M.; Shi, C.; Wang, H.; Yao, L.; Liu, L.; Xie, C.; Pu, S.; LaChaud, G.; Shen, J.; Zhu, M. Protection against cognitive impairment and modification of epileptogenesis with curcumin in a post-status epilepticus model of temporal lobe epilepsy. Neuroscience,  2015, 310, 362-371.
[PMID: 30152292] 
[71] 
Deng, X.; Xie, Y.; Chen, Y. Effect of neuroinflammation on ABC transporters: possible contribution to refractory epilepsy. CNS Neurol. Disord. Drug Targets,  2018, 17(10), 728-735.
[PMID: 30152292] 
[72] 
Abraham, J.; Fox, P.D.; Condello, C.; Bartolini, A.; Koh, S. Minocycline attenuates microglia activation and blocks the long-term epileptogenic effects of early-life seizures. Neurobiol. Dis.,  2012, 46(2), 425-430.
[http://dx.doi.org/10.1016/j.nbd.2012.02.006] [PMID: 22366182] 
[73] 
Paudel, Y.N.; Semple, B.D.; Jones, N.C.; Othman, I.; Shaikh, M.F. High mobility group box 1 (HMGB1) as a novel frontier in epileptogenesis: from pathogenesis to therapeutic approaches. J. Neurochem.,  2019, 151(5), 542-557.
[http://dx.doi.org/10.1111/jnc.14663] [PMID: 30644560] 
[74] 
Pauletti, A.; Terrone, G.; Shekh-Ahmad, T.; Salamone, A.; Ravizza, T.; Rizzi, M.; Pastore, A.; Pascente, R.; Liang, L.P.; Villa, B.R.; Balosso, S.; Abramov, A.Y.; van Vliet, E.A.; Del Giudice, E.; Aronica, E.; Patel, M.; Walker, M.C.; Vezzani, A. Targeting oxidative stress improves disease outcomes in a rat model of acquired epilepsy. Brain,  2019, 142(7)e39
[http://dx.doi.org/10.1093/brain/awz130] [PMID: 31145451] 
[75] 
Li, J.; Jiang, G.; Chen, Y.; Chen, L.; Li, Z.; Wang, Z.; Wang, X. Altered expression of hypoxia-Inducible factor-1α participates in the epileptogenesis in animal models. Synapse,  2014, 68(9), 402-409.
[http://dx.doi.org/10.1002/syn.21752] [PMID: 24889205] 
[76] 
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] 
[77] 
Noe, F.M.; Polascheck, N.; Frigerio, F.; Bankstahl, M.; Ravizza, T.; Marchini, S.; Beltrame, L.; Banderó, C.R.; Löscher, W.; Vezzani, A. Pharmacological blockade of IL-1β/IL-1 receptor type 1 axis during epileptogenesis provides neuroprotection in two rat models of temporal lobe epilepsy. Neurobiol. Dis.,  2013, 59, 183-193.
[http://dx.doi.org/10.1016/j.nbd.2013.07.015] [PMID: 23938763] 
[78] 
Wang, Y.; Wang, Y.; Sun, R.; Wu, X.; Chu, X.; Zhou, S.; Hu, X.; Gao, L.; Kong, Q. The treatment value of IL-1β monoclonal antibody under the targeting location of alpha-methyl-L-tryptophan and superparamagnetic iron oxide nanoparticles in an acute temporal lobe epilepsy model. J. Transl. Med.,  2018, 16(1), 337.
[http://dx.doi.org/10.1186/s12967-018-1712-3] [PMID: 30514296] 
[79] 
Holtman, L.; van Vliet, E.A.; van Schaik, R.; Queiroz, C.M.; Aronica, E.; Gorter, J.A. Effects of SC58236, a selective COX-2 inhibitor, on epileptogenesis and spontaneous seizures in a rat model for temporal lobe epilepsy. Epilepsy Res.,  2009, 84(1), 56-66.
[http://dx.doi.org/10.1016/j.eplepsyres.2008.12.006] [PMID: 19186029] 
[80] 
Polascheck, N.; Bankstahl, M.; Löscher, W. The COX-2 inhibitor parecoxib is neuroprotective but not antiepileptogenic in the pilocarpine model of temporal lobe epilepsy. Exp. Neurol.,  2010, 224(1), 219-233.
[http://dx.doi.org/10.1016/j.expneurol.2010.03.014] [PMID: 20353773] 
[81] 
Jun, J.S.; Lee, S.T.; Kim, R.; Chu, K.; Lee, S.K. Tocilizumab treatment for new onset refractory status epilepticus. Ann. Neurol.,  2018, 84(6), 940-945.
[http://dx.doi.org/10.1002/ana.25374] [PMID: 30408233] 
[82] 
Ke, X.J.; Cheng, Y.F.; Yu, N.; Di, Q. Effects of carbamazepine on the P-gp and CYP3A expression correlated with PXR or NF-κB activity in the bEnd.3 cells. Neurosci. Lett.,  2019, 690, 48-55.
[http://dx.doi.org/10.1016/j.neulet.2018.10.016] [PMID: 30312753] 
[83] 
Ben-Sahra, I.; Manning, B.D. mTORC1 signaling and the metabolic control of cell growth. Curr. Opin. Cell Biol.,  2017, 45, 72-82.
[http://dx.doi.org/10.1016/j.ceb.2017.02.012] [PMID: 28411448] 
[84] 
Yoshida, S; Hong, S; Suzuki, T; Nada, S; Mannan, AM; Wang, J; Okada, M; Guan, KL; Inoki, K Redox regulates mammalian target of rapamycin complex 1 (mTORC1) activity by modulating the TSC1/TSC2-Rheb GTPase pathway. J Biol Chem, 201, 286(37), 32651-32660.
[85] 
Tee, A.R.; Sampson, J.R.; Pal, D.K.; Bateman, J.M. The role of mTOR signalling in neurogenesis, insights from tuberous sclerosis complex. Semin. Cell Dev. Biol.,  2016, 52, 12-20.
[http://dx.doi.org/10.1016/j.semcdb.2016.01.040] [PMID: 26849906] 
[86] 
Wong, M. Mammalian target of rapamycin (mTOR) pathways in neurological diseases. Biomed. J.,  2013, 36(2), 40-50.
[http://dx.doi.org/10.4103/2319-4170.110365] [PMID: 23644232] 
[87] 
Wong, M. Mammalian target of rapamycin (mTOR) activation in focal cortical dysplasia and related focal cortical malformations. Exp. Neurol.,  2013, 244, 22-26.
[http://dx.doi.org/10.1016/j.expneurol.2011.10.002] [PMID: 22015915] 
[88] 
Wang, F.; Chen, F.; Wang, G.; Wei, S.; Fang, F.; Kang, D.; Lin, Y. Rapamycin provides anti-epileptogenic effect in a rat model of post-traumatic epilepsy via deactivation of mTOR signaling pathway. Exp. Ther. Med.,  2018, 15(6), 4763-4770.
[http://dx.doi.org/10.3892/etm.2018.6004] [PMID: 29904395] 
[89] 
Yang, X; Hei, C; Liu, P; Li, PA Prevention of post-ischemic seizure by rapamycin is associated with deactivation of mTOR and ERK1/2 pathways in hyperglycemic rats. Biochem. Biophys. Res. Commun. 2019. pii, S0006-291X(19)31826-1., 
[http://dx.doi.org/10.1016/j.bbrc.2019.09.096] 
[90] 
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] 
[91] 
van Vliet, E.A.; Forte, G.; Holtman, L.; den Burger, J.C.; Sinjewel, A.; de Vries, H.E.; Aronica, E.; Gorter, J.A. Inhibition of mammalian target of rapamycin reduces epileptogenesis and blood-brain barrier leakage but not microglia activation. Epilepsia,  2012, 53(7), 1254-1263.
[http://dx.doi.org/10.1111/j.1528-1167.2012.03513.x] [PMID: 22612226] 
[92] 
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] 
[93] 
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] 
[94] 
Jozwiak, S.; Słowińska, M.; Borkowska, J.; Sadowski, K.; Łojszczyk, B.; Domańska-Pakieła, D.; Chmielewski, D.; Kaczorowska-Frontczak, M.; Głowacka, J.; Sijko, K.; Kotulska, K. Preventive antiepileptic treatment in tuberous sclerosis complex: a long-term, prospective trial. Pediatr. Neurol.,  2019, 101, 18-25.
[95] 
Santos, D.; Giudetti, G.; Micera, S.; Navarro, X.; Del Valle, J.; Domańska-Pakieła, D.; Chmielewski, D.; Kaczorowska-Frontczak, M.; Głowacka, J.; Sijko, K.; Kotulska, K. Focal release of neurotrophic factors by biodegradable microspheres enhance motor and sensory axonal regeneration in vitro and in vivo. Brain Res.,  2016, 1636, 93-106.
[96] 
Nafissi, N.; Foldvari, M. Neuroprotective therapies in glaucoma: I. Neurotrophic factor delivery. Wiley Interdiscip. Rev. Nanomed. Nanobiotechnol.,  2016, 8(2), 240-254.
[http://dx.doi.org/10.1002/wnan.1361] [PMID: 26306832] 
[97] 
Binder, D.K.; Croll, S.D.; Gall, C.M.; Scharfman, H.E. BDNF and epilepsy: too much of a good thing? Trends Neurosci.,  2001, 24(1), 47-53.
[http://dx.doi.org/10.1016/S0166-2236(00)01682-9] [PMID: 11163887] 
[98] 
He, X.P.; Kotloski, R.; Nef, S.; Luikart, B.W.; Parada, L.F.; McNamara, J.O. Conditional deletion of TrkB but not BDNF prevents epileptogenesis in the kindling model. Neuron,  2004, 43(1), 31-42.
[http://dx.doi.org/10.1016/j.neuron.2004.06.019] [PMID: 15233915] 
[99] 
Heinrich, C.; Lähteinen, S.; Suzuki, F.; Anne-Marie, L.; Huber, S.; Häussler, U.; Haas, C.; Larmet, Y.; Castren, E.; Depaulis, A. Increase in BDNF-mediated TrkB signaling promotes epileptogenesis in a mouse model of mesial temporal lobe epilepsy. Neurobiol. Dis.,  2011, 42(1), 35-47.
[http://dx.doi.org/10.1016/j.nbd.2011.01.001] [PMID: 21220014] 
[100] 
Lin, T.W.; Harward, S.C.; Huang, Y.Z.; McNamara, J.O. Targeting BDNF/TrkB pathways for preventing or suppressing epilepsy. Neuropharmacology,  2019, 107734107734 Epub ahead of print
[http://dx.doi.org/10.1016/j.neuropharm.2019.107734] [PMID: 31377199] 
[101] 
Bar-Klein, G.; Lublinsky, S.; Kamintsky, L.; Noyman, I.; Veksler, R.; Dalipaj, H.; Senatorov, V.V., Jr; Swissa, E.; Rosenbach, D.; Elazary, N.; Milikovsky, D.Z.; Milk, N.; Kassirer, M.; Rosman, Y.; Serlin, Y.; Eisenkraft, A.; Chassidim, Y.; Parmet, Y.; Kaufer, D.; Friedman, A. Imaging blood-brain barrier dysfunction as a biomarker for epileptogenesis. Brain,  2017, 140(6), 1692-1705.
[http://dx.doi.org/10.1093/brain/awx073] [PMID: 28444141] 
[102] 
Broekaart, D.W.M.; Anink, J.J.; Baayen, J.C.; Idema, S.; de Vries, H.E.; Aronica, E.; Gorter, J.A.; van Vliet, E.A. Activation of the innate immune system is evident throughout epileptogenesis and is associated with blood-brain barrier dysfunction and seizure progression. Epilepsia,  2018, 59(10), 1931-1944.
[http://dx.doi.org/10.1111/epi.14550] [PMID: 30194729] 
[103] 
Weissberg, I.; Wood, L.; Kamintsky, L.; Vazquez, O.; Milikovsky, D.Z.; Alexander, A.; Oppenheim, H.; Ardizzone, C.; Becker, A.; Frigerio, F.; Vezzani, A.; Buckwalter, M.S.; Huguenard, J.R.; Friedman, A.; Kaufer, D. Albumin induces excitatory synaptogenesis through astrocytic TGF-β/ALK5 signaling in a model of acquired epilepsy following blood-brain barrier dysfunction. Neurobiol. Dis.,  2015, 78, 115-125.
[http://dx.doi.org/10.1016/j.nbd.2015.02.029] [PMID: 25836421] 
[104] 
Bar-Klein, G.; Cacheaux, L.P.; Kamintsky, L.; Prager, O.; Weissberg, I.; Schoknecht, K.; Cheng, P.; Kim, S.Y.; Wood, L.; Heinemann, U.; Kaufer, D.; Friedman, A. Losartan prevents acquired epilepsy via TGF-β signaling suppression. Ann. Neurol.,  2014, 75(6), 864-875.
[http://dx.doi.org/10.1002/ana.24147] [PMID: 24659129] 
[105] 
González, O.C.; Krishnan, G.P.; Chauvette, S.; Timofeev, I.; Sejnowski, T.; Bazhenov, M. Modeling of age-dependent epileptogenesis by differential homeostatic synaptic scaling. J. Neurosci.,  2015, 35(39), 13448-13462.
[http://dx.doi.org/10.1523/JNEUROSCI.5038-14.2015] [PMID: 26424890] 
[106] 
Vendramin P, M.; Meier, L.; Loureiro, S.; Ganzella, M.; Junges, B.; Barbieri C, L.; Umpierrez A, A.; Koeller, D.M.; Goodman, S.; Woontner, M.; Gomes de Souza, D.O.; Wajner, M.; Calcagnotto, M.E. Impairment of GABAergic system contributes to epileptogenesis in glutaric acidemia type I. Epilepsia,  2017, 58(10), 1771-1781.
[http://dx.doi.org/10.1111/epi.13862] [PMID: 28762469] 
[107] 
Zubareva, O.E.; Kovalenko, A.A.; Kalemenev, S.V.; Schwarz, A.P.; Karyakin, V.B.; Zaitsev, A.V. Alterations in mRNA expression of glutamate receptor subunits and excitatory amino acid transporters following pilocarpine-induced seizures in rats. Neurosci. Lett.,  2018, 686, 94-100.
[http://dx.doi.org/10.1016/j.neulet.2018.08.047] [PMID: 30189229] 
[108] 
Zhao, W.; Chuang, S.C.; Young, S.R.; Bianchi, R.; Wong, R.K. Extracellular glutamate exposure facilitates group I mGluR-mediated epileptogenesis in the hippocampus. J. Neurosci.,  2015, 35(1), 308-315.
[http://dx.doi.org/10.1523/JNEUROSCI.1944-14.2015] [PMID: 25568123] 
[109] 
McNamara, J.O.; Russell, R.D.; Rigsbee, L.; Bonhaus, D.W. Anticonvulsant and antiepileptogenic actions of MK-801 in the kindling and electroshock models. Neuropharmacology,  1988, 27(6), 563-568.
[http://dx.doi.org/10.1016/0028-3908(88)90176-1] [PMID: 2843782] 
[110] 
Hong, S.; Li, T.; Luo, Y.; Li, W.; Tang, X.; Ye, Y.; Wu, P.; Hu, Q.; Cheng, L.; Chen, H.; Jiang, L. Dynamic changes of astrocytes and adenosine signaling in rat hippocampus in post-status epilepticus model of epileptogenesis. Cell. Mol. Neurobiol.,  2018, 38(6), 1227-1234.
[http://dx.doi.org/10.1007/s10571-018-0590-9] [PMID: 29770956] 
[111] 
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] 
[112] 
Serajee, F.J.; Huq, A.M. Homozygous mutation in synaptic vesicle glycoprotein 2A gene results in intractable epilepsy, involuntary movements, microcephaly, and developmental and growth retardation. Pediatr. Neurol.,  2015, 52(6), 642-6.e1.
[http://dx.doi.org/10.1016/j.pediatrneurol.2015.02.011] [PMID: 26002053] 
[113] 
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] 
[114] 
Ohno, Y.; Tokudome, K. Therapeutic role of synaptic vesicle glycoprotein 2A (SV2A) in modulating epileptogenesis. CNS Neurol. Disord. Drug Targets,  2017, 16(4), 463-471.
[http://dx.doi.org/10.2174/1871527316666170404115027] [PMID: 28393712] 
[115] 
Chaari, A.; Mohamed, A.S.; Abdelhakim, K.; Kauts, V.; Casey, W.F. Levetiracetam versus phenytoin for seizure prophylaxis in brain injured patients: a systematic review and meta-analysis. Int. J. Clin. Pharm.,  2017, 39(5), 998-1003.
[http://dx.doi.org/10.1007/s11096-017-0507-6] [PMID: 28780739] 
[116] 
Younus, I.; Reddy, D.S. Epigenetic interventions for epileptogenesis: A new frontier for curing epilepsy. Pharmacol. Ther.,  2017, 177, 108-122.
[http://dx.doi.org/10.1016/j.pharmthera.2017.03.002] [PMID: 28279785] 
[117] 
Lindhout, D. Somatic mosaicism as a basic epileptogenic mechanism? Brain,  2008, 131(Pt 4), 900-901.
[http://dx.doi.org/10.1093/brain/awn056] [PMID: 18339639] 
[118] 
Kobow, K.; Blümcke, I. The methylation hypothesis: do epigenetic chromatin modifications play a role in epileptogenesis? Epilepsia,  2011, 52(Suppl. 4), 15-19.
[http://dx.doi.org/10.1111/j.1528-1167.2011.03145.x] [PMID: 21732935] 
[119] 
Kobow, K.; Jeske, I.; Hildebrandt, M.; Hauke, J.; Hahnen, E.; Buslei, R.; Buchfelder, M.; Weigel, D.; Stefan, H.; Kasper, B.; Pauli, E.; Blümcke, I. Increased reelin promoter methylation is associated with granule cell dispersion in human temporal lobe epilepsy. J. Neuropathol. Exp. Neurol.,  2009, 68(4), 356-364.
[http://dx.doi.org/10.1097/NEN.0b013e31819ba737] [PMID: 19287316] 
[120] 
de Nijs, L.; Choe, K.; Steinbusch, H.; Schijns, O.E.M.G.; Dings, J.; van den Hove, D.L.A.; Rutten, B.P.F.; Hoogland, G. DNA methyltransferase isoforms expression in the temporal lobe of epilepsy patients with a history of febrile seizures. Clin. Epigenetics,  2019, 11(1), 118.
[http://dx.doi.org/10.1186/s13148-019-0721-2] [PMID: 31426844] 
[121] 
Reddy, S.D.; Clossen, B.L.; Reddy, D.S. Epigenetic histone deacetylation inhibition prevents the development and persistence of temporal lobe epilepsy. J. Pharmacol. Exp. Ther.,  2018, 364(1), 97-109.
[http://dx.doi.org/10.1124/jpet.117.244939] [PMID: 29101217] 
[122] 
Hoffmann, K.; Czapp, M.; Löscher, W. Increase in antiepileptic efficacy during prolonged treatment with valproic acid: role of inhibition of histone deacetylases? Epilepsy Res.,  2008, 81(2-3), 107-113.
[http://dx.doi.org/10.1016/j.eplepsyres.2008.04.019] [PMID: 18538545] 
[123] 
Rossetti, F.; de Araujo Furtado, M.; Pak, T.; Bailey, K.; Shields, M.; Chanda, S.; Addis, M.; Robertson, B.D.; Moffett, M.; Lumley, L.A.; Yourick, D.L. Combined diazepam and HDAC inhibitor treatment protects against seizures and neuronal damage caused by soman exposure. Neurotoxicology,  2012, 33(3), 500-511.
[PMID: 31038487] 
[124] 
Zandi, N.; Zaniani, N.R.; Moghimi, A.; Roohbakhsh, A. Protective effects of M8‑B, a TRPM8 antagonist, on febrile‑ and pentylenetetrazol‑induced seizures. Acta Neurobiol. Exp. (Warsz.),  2019, 79(1), 86-91.
[PMID: 31038487] 
[125] 
Koyama, R.; Tao, K.; Sasaki, T.; Ichikawa, J.; Miyamoto, D.; Muramatsu, R.; Matsuki, N.; Ikegaya, Y. GABAergic excitation after febrile seizures induces ectopic granule cells and adult epilepsy. Nat. Med.,  2012, 18(8), 1271-1278.
[http://dx.doi.org/10.1038/nm.2850] [PMID: 22797810] 
[126] 
Marguet, S.L.; Le-Schulte, V.T.; Merseburg, A.; Neu, A.; Eichler, R.; Jakovcevski, I.; Ivanov, A.; Hanganu-Opatz, I.L.; Bernard, C.; Morellini, F.; Isbrandt, D. Treatment during a vulnerable developmental period rescues a genetic epilepsy. Nat. Med.,  2015, 21(12), 1436-1444.
[http://dx.doi.org/10.1038/nm.3987] [PMID: 26594844] 
[127] 
Töllner, K.; Brandt, C.; Erker, T.; Löscher, W. Bumetanide is not capable of terminating status epilepticus but enhances phenobarbital efficacy in different rat models. Eur. J. Pharmacol.,  2015, 746, 78-88.
[http://dx.doi.org/10.1016/j.ejphar.2014.10.056] [PMID: 25445051] 
[128] 
Li, S.; Luo, Z.; Lu, B.; Xia, S.; Li, C.; Guan, X.; Zhang, J.; Huang, K.; Xian, F. Protective effects of lycopene on kainic acid-induced seizures. Epilepsy Res.,  2019, 151, 1-6.
[http://dx.doi.org/10.1016/j.eplepsyres.2019.01.010] [PMID: 30669043] 
[129] 
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] 
[130] 
Tse, K.; Hammond, D.; Simpson, D.; Beynon, R.J.; Beamer, E.; Tymianski, M.; Salter, M.W.; Sills, G.J.; Thippeswamy, T. The impact of postsynaptic density 95 blocking peptide (Tat-NR2B9c) and an iNOS inhibitor (1400W) on proteomic profile of the hippocampus in C57BL/6J mouse model of kainate-induced epileptogenesis. J. Neurosci. Res.,  2019, 97(11), 1378-1392.
[http://dx.doi.org/10.1002/jnr.24441] [PMID: 31090233] 
[131] 
Xia, J.; Li, C.Y.; Wang, H.; Zhang, Q.M.; Han, Z.M. Therapeutic effects of scoparone on pilocarpine (Pilo)-induced seizures in mice. Biomed. Pharmacother.,  2018, 97, 1501-1513.
[http://dx.doi.org/10.1016/j.biopha.2017.09.127] [PMID: 29793313] 
[132] 
Suemaru, K.; Yoshikawa, M.; Aso, H.; Watanabe, M. TRPV1 mediates the anticonvulsant effects of acetaminophen in mice. Epilepsy Res.,  2018, 145, 153-159.
[http://dx.doi.org/10.1016/j.eplepsyres.2018.06.016] [PMID: 30007240] 
[133] 
Fu, M.; Xie, Z.; Zuo, H. TRPV1: a potential target for antiepileptogenesis. Med. Hypotheses,  2009, 73(1), 100-102.
[http://dx.doi.org/10.1016/j.mehy.2009.01.005] [PMID: 19328632] 
[134] 
Valle-Dorado, M.G.; Santana-Gómez, C.E.; Orozco-Suárez, S.A.; Rocha, L. Sodium cromoglycate reduces short- and long-term consequences of status epilepticus in rats. Epilepsy Behav.,  2018, 87, 200-206.
[http://dx.doi.org/10.1016/j.yebeh.2018.06.021] [PMID: 30115604] 
[135] 
Nissinen, J.; Andrade, P.; Natunen, T.; Hiltunen, M.; Malm, T.; Kanninen, K.; Soares, J.I.; Shatillo, O.; Sallinen, J.; Ndode-Ekane, X.E.; Pitkänen, A. Disease-modifying effect of atipamezole in a model of post-traumatic epilepsy. Epilepsy Res.,  2017, 136, 18-34.
[http://dx.doi.org/10.1016/j.eplepsyres.2017.07.005] [PMID: 28753497] 
[136] 
Grabenstatter, H.L.; Del Angel, Y.C.; Carlsen, J.; Wempe, M.F.; White, A.M.; Cogswell, M.; Russek, S.J.; Brooks-Kayal, A.R. The effect of STAT3 inhibition on status epilepticus and subsequent spontaneous seizures in the pilocarpine model of acquired epilepsy. Neurobiol. Dis.,  2014, 62, 73-85.
[http://dx.doi.org/10.1016/j.nbd.2013.09.003] [PMID: 24051278] 
[137] 
Hsu, H.C.; Tang, N.Y.; Liu, C.H.; Hsieh, C.L. Antiepileptic effect of uncaria rhynchophylla and rhynchophylline involved in the initiation of c-jun n-terminal kinase phosphorylation of mapk signal pathways in acute seizures of kainic acid-treated rats. Evid. Based Complement. Alternat. Med.,  2013, 2013961289
[http://dx.doi.org/10.1155/2013/961289] [PMID: 24381640] 
[138] 
Seeger, N.; Zellinger, C.; Rode, A.; Roloff, F.; Bicker, G.; Russmann, V.; Fischborn, S.; Wendt, H.; Potschka, H. The erythropoietin-derived peptide mimetic pHBSP affects cellular and cognitive consequences in a rat post-status epilepticus model. Epilepsia,  2011, 52(12), 2333-2343.
[http://dx.doi.org/10.1111/j.1528-1167.2011.03302.x] [PMID: 22050420] 
[139] 
Lai, M.C.; Lin, K.M.; Yeh, P.S.; Wu, S.N.; Huang, C.W. The novel effect of immunomodulator-glatiramer acetate on epileptogenesis and epileptic seizures. Cell. Physiol. Biochem.,  2018, 50(1), 150-168.
[http://dx.doi.org/10.1159/000493965] [PMID: 30278465] 
[140] 
Citraro, R.; Chimirri, S.; Aiello, R.; Gallelli, L.; Trimboli, F.; Britti, D.; De Sarro, G.; Russo, E. Protective effects of some statins on epileptogenesis and depressive-like behavior in WAG/Rij rats, a genetic animal model of absence epilepsy. Epilepsia,  2014, 55(8), 1284-1291.
[http://dx.doi.org/10.1111/epi.12686] [PMID: 24962151] 
[141] 
Bar-Klein, G.; Klee, R.; Brandt, C.; Bankstahl, M.; Bascuñana, P.; Töllner, K.; Dalipaj, H.; Bankstahl, J.P.; Friedman, A.; Löscher, W. Isoflurane prevents acquired epilepsy in rat models of temporal lobe epilepsy. Ann. Neurol.,  2016, 80(6), 896-908.
[http://dx.doi.org/10.1002/ana.24804] [PMID: 27761920] 
[142] 
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, 233116686
[http://dx.doi.org/10.1016/j.lfs.2019.116686] [PMID: 31348946] 
[143] 
Wong, S.B.; Cheng, S.J.; Hung, W.C.; Lee, W.T.; Min, M.Y. Rosiglitazone suppresses In Vitro seizures in hippocampal slice by inhibiting presynaptic glutamate release in a model of temporal lobe epilepsy. PLoS One,  2015, 10(12)e0144806
[http://dx.doi.org/10.1371/journal.pone.0144806] [PMID: 26659605] 
[144] 
Rosenberg, EC; Patra, PH; Whalley, BJ Therapeutic effects of cannabinoids in animal models of seizures, epilepsy, epileptogenesis, and epilepsy-related neuroprotection. Epilepsy Behav,,  2017, 70(Pt B), 319-327.
[http://dx.doi.org/10.1016/j.yebeh.2016.11.006] 
[145] 
Pugh, M.J.; Knoefel, J.E.; Mortensen, E.M.; Amuan, M.E.; Berlowitz, D.R.; Van Cott, A.C. New-onset epilepsy risk factors in older veterans. J. Am. Geriatr. Soc.,  2009, 57(2), 237-242.
[http://dx.doi.org/10.1111/j.1532-5415.2008.02124.x] [PMID: 19207140] 
[146] 
Bumanglag, A.V.; Sloviter, R.S. No latency to dentate granule cell epileptogenesis in experimental temporal lobe epilepsy with hippocampal sclerosis. Epilepsia,  2018, 59(11), 2019-2034.
[http://dx.doi.org/10.1111/epi.14580] [PMID: 30338519] 
[147] 
Welzel, L.; Twele, F.; Schidlitzki, A.; Töllner, K.; Klein, P.; Löscher, W. Network pharmacology for antiepileptogenesis: Tolerability and neuroprotective effects of novel multitargeted combination treatments in nonepileptic vs. post-status epilepticus mice. Epilepsy Res.,  2019, 151, 48-66.
[http://dx.doi.org/10.1016/j.eplepsyres.2019.02.010] [PMID: 30831337] 
[148] 
Dey, A.; Kang, X.; Qiu, J.; Du, Y.; Jiang, J. Anti-inflammatory small molecules to treat seizures and epilepsy: from bench to bedside. Trends Pharmacol. Sci.,  2016, 37(6), 463-484.
[http://dx.doi.org/10.1016/j.tips.2016.03.001] [PMID: 27062228] 
Rights & Permissions Print Cite
Article Metrics
22
Journal Information
For Authors
For Editors
For Reviewers
Explore Articles
Open Access
Open Access Articles
For Visitors
DOI https://dx.doi.org/10.2174/1570159X18666200128124338	Print ISSN 1570-159X
Publisher Name Bentham Science Publisher	Online ISSN 1875-6190
Current Neuropharmacology

How to Find Candidate Drug-targets for Antiepileptogenic Therapy?

Abstract

Graphical Abstract

Related Journals

Related Books

Related Articles
