耐藥癲癇動物模型的研究進展_Journal of Epilepsy

Authors：

劉錢坤 ,  陳陽美

重慶醫科大學附屬第二醫院神經內科（重慶 400010）;

Corresponding?author：

陳陽美, Email: chenym1997@cqmu.edu.cn

Keywords：

癲癇; 耐藥癲癇; 藥物篩選; 動物模型

DOI：

10.7507/2096-0247.202204006

Video：

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耐藥癲癇的治療依然是神經科重大難題。在研究耐藥癲癇病理生理改變及篩選抗癲癇發作藥物時，所選擇的癲癇模型起到十分重要的作用。本文就近年來國內外的耐藥癲癇模型研究進展作一比較，8種耐藥癲癇的依次為：3-巰基丙酸模型、海馬海人酸模型、鋰-匹羅卡品模型、角膜點燃模型、單純杏仁核點燃模型、抗苯妥英鈉杏仁核點燃模型、苯巴比妥耐藥癲癇模型、抗拉莫三嗪杏仁核點燃模型。這些模型中，前三種為單純化學點燃模型，之后兩種主要為單純電點燃模型，最后三種為化學刺激加電點燃模型。本文文從設備條件、造模過程、成功率、耐藥評估、海馬病理改變等多方面歸納對比，以便學者根據實驗室條件和實驗目的選用合適的耐藥癲癇模型。

Citation： 劉錢坤, 陳陽美. 耐藥癲癇動物模型的研究進展. Journal of Epilepsy, 2022, 8(4): 331-337. doi: 10.7507/2096-0247.202204006 Copy

1.	Sander JW, Shorvon SD. Epidemiology of the epilepsies. Journal of Neurology Neurosurgery & Psychiatry, 1996, 61(5): 433-443.
2.	Fisher RS, Acevedo C, Arzimanoglou A, et al. ILAE official report: a practical clinical definition of epilepsy. Epilepsia, 2014, 55(4): 475-482.
3.	Kalilani L, Sun X, Pelgrims B, et al. The epidemiology of drug-resistant epilepsy: a systematic review and meta-analysis. Epilepsia, 2018, 59(12): 2179-2193.
4.	Jr engel J. The current place of epilepsy surgery. Curr Opin Neurol, 2018, 31(2): 192-197.
5.	Maguire MJ, Jackson CF, Marson AG, et al. Treatments for the prevention of Sudden Unexpected Death in Epilepsy (SUDEP). Cochrane Database Syst Rev, 2016, 7(7).
6.	Kanner AM. Management of psychiatric and neurological comorbidities in epilepsy. Nat Rev Neurol, 2016, 12(2): 106-116.
7.	Stables JP, Bertram E, Dudek FE, et al. Therapy discovery for pharmacoresistant epilepsy and for disease-modifying therapeutics: summary of the Nih/ninds/aes Models Ii Workshop. Epilepsia, 2010, 44(12): 1472-1478.
8.	Enrique A, Goicoechea S, Castao R, et al. New model of pharmacoresistant seizures induced by 3-mercaptopropionic acid in mice. Epilepsy Research, 2017, 129: 8-16.
9.	Riban V, Bouilleret V, Pham-lê BT, et al. Evolution of hippocampal epileptic activity during the development of hippocampal sclerosis in a mouse model of temporal lobe epilepsy. Neuroscience, 2002, 112(1): 101-111.
10.	方子妍, 吳逢春, 陳樹達, 等. 苯妥英鈉耐藥性顳葉內側癲癇大鼠模型的構建. 癲癇雜志, 2019, 5(1): 21-25.
11.	許蘭, 王麗琨, 周鑫, 等. 兩種耐藥性顳葉癲癇模型海馬硬化及苔蘚纖維發芽的對比. 貴州醫科大學學報, 2019, 44(10): 1145-1150.
12.	唐太峰, 伍國鋒. 耐苯巴比妥鈉及苯妥英鈉杏仁核點燃大鼠癲癇模型的制作. 貴州醫科大學學報, 2016, 41(6): 671-674.
13.	陸海美, 謝美娟, 李姍, 等. 6 Hz角膜點燃耐藥癲癇小鼠模型改良及3種中藥方劑的作用. 藥學學報, 2018, 53(7): 1048-1053.
14.	Jiang W, Du B, Chi Z, et al. Preliminary explorations of the role of mitochondrial proteins in refractory epilepsy: some findings from comparative proteomics. Journal of Neuroscience Research, 2007, 85(14): 3160-3170.
15.	Rocha L. Effects of high frequency electrical stimulation and r-verapamil on seizure susceptibility and glutamate and gaba release in a model of phenytoin-resistant seizures. Neuropharmacology, 2011, 61(4): 807-814.
16.	Zeng K, Wang X, Wang Y, et al. Enhanced synaptic vesicle traffic in hippocampus of phenytoin-resistant kindled rats. Neurochemical Research, 2009, 34(5): 899-904.
17.	Potschka H, Volk HA, L?scher W. Pharmacoresistance and expression of multidrug transporter P-glycoprotein in kindled rats. Neuroreport, 2004, (10): 1657-1661.
18.	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. Brain, 2005, 128(Pt 6): 1358-1368.
19.	Bethmann K, Fritschy JM, Brandt C, et al. Antiepileptic drug resistant rats differ from drug responsive rats in GABA A receptor subunit expression in a model of temporal lobe epilepsy. Neurobiol Dis, 2008, 31(2): 169-187.
20.	Volk HA, Arabadzisz D, Fritschy JM, et al. Antiepileptic drug-resistant rats differ from drug-responsive rats in hippocampal neurodegeneration and GABA(A) receptor ligand binding in a model of temporal lobe epilepsy. Neurobiol Dis, 2006, 2(3): 633-646.
21.	Metcalf CS, Huff J, Thomson KE, et al. Evaluation of antiseizure drug efficacy and tolerability in the rat lamotrigine-resistant amygdala kindling model. Epilepsia Open, 2019, 4(3): 452-463.
22.	Zhang C, Zuo Z, Kwan P, et al. In vitro transport profile of carbamazepine, oxcarbazepine, eslicarbazepine acetate, and their active metabolites by human p-glycoprotein. Epilepsia, 2011, 52(10): 1894-1904.
23.	Chen C, Zhou H, Guan C, et al. Applicability of free drug hypothesis to drugs with good membrane permeability that are not efflux transporter substrates: a microdialysis study in rats. Pharmacology Research & Perspectives, 2020, 8(2): e00575.
24.	Nagaya Y, Nozaki Y, Takenaka O, et al. Investigation of utility of cerebrospinal fluid drug concentration as a surrogate for interstitial fluid concentration using microdialysis coupled with cisternal cerebrospinal fluid sampling in wild-type and mdr1a(-/-) rats. Drug Metabolism and Pharmacokinetics, 2016, (1): 57-66.
25.	Baraban SC, Löscher W. What new modeling approaches will help us identify promising drug treatments? Adv Exp Med Biol, 2014, 813: 283-294.
26.	Guillemain I, Kahane P, Depaulis A. Animal models to study aetiopathology of epilepsy: what are the features to model? Epileptic Disord, 2012, 14(3): 217-225.
27.	Klein S, Bankstahl M, L?scher W. Inter-individual variation in the effect of antiepileptic drugs in the intrahippocampal kainate model of mesial temporal lobe epilepsy in mice. Neuropharmacology, 2015, 9: 53-62.
28.	Wang L, Shi J, Wu G, et al. Hippocampal low-frequency stimulation increased SV2A expression and inhibited the seizure degree in pharmacoresistant amygdala-kindling epileptic rats. Epilepsy Res, 2014, (9): 1483-1491.
29.	Toman JEP. Neuropharmacologic considerations in psychic seizures. Neurology, 1951, 1(6): 444-460.
30.	L?scher W. Critical review of current animal models of seizures and epilepsy used in the discovery and development of new antiepileptic drugs. Seizure, 2011, 20(5): 359-368.
31.	Albertini G, Walrave L, Demuyser T, et al. 6hz corneal kindling in mice triggers neurobehavioral comorbidities accompanied by relevant changes in c‐fos immunoreactivity throughout the brain. Epilepsia, 2018, 59(1): 67-78.
32.	Florek-luszczki M, Wlaz A, Kondrat-wrobel MW, et al. Effects of win 55, 212-2 (a non-selective cannabinoid cb1 and cb2 receptor agonist) on the protective action of various classical antiepileptic drugs in the mouse 6hz psychomotor seizure model. Journal of Neural Transmission, 2014, (7): 707-715.
33.	Matagne A, Klitgaard H. Validation of corneally kindled mice: a sensitive screening model for partial epilepsy in man. Epilepsy Res, 1998, 31(1): 59-71.
34.	Leclercq K, Matagne A, Kaminski RM. Low potency and limited efficacy of antiepileptic drugs in the mouse 6 Hz corneal kindling model. Epilepsy Res, 2014, 108(4): 675-683.
35.	Rowley NM, White HS. Comparative anticonvulsant efficacy in the corneal kindled mouse model of partial epilepsy: correlation with other seizure and epilepsy models. Epilepsy Res, 2010, 92(2): 163-169.
36.	Barker-haliski ML, Vanegas F, Mau MJ, et al. Acute cognitive impact of antiseizure drugs in naive rodents and corneal-kindled mice. Epilepsia, 2016, 57(9): 1386-1397.
37.	Barker-haliski ML, Johnson K, Billingsley P, et al. Validation of a preclinical drug screening platform for pharmacoresistant epilepsy. Neurochem Res, 2017, 42(7): 1904-1918.
38.	Remigio GJ, Loewen JL, Heuston S, et al. Corneal kindled C57BL/6 mice exhibit saturated dentate gyrus long-term potentiation and associated memory deficits in the absence of overt neuron loss. Neurobiol Dis, 2017, 105: 221-234.
39.	Loewen JL, Barker-haliski ML, Dahle EJ, et al. Neuronal injury, gliosis, and glial proliferation in two models of temporal lobe epilepsy. J Neuropathol Exp Neurol, 2016, 75(4): 366-378.
40.	Koneval Z, Knox KM, White HS, et al. Lamotrigine-resistant corneal-kindled mice: a model of pharmacoresistant partial epilepsy for moderate-throughput drug discovery. Epilepsia, 2018, 59(6): 1245-1256.
41.	Goddard GV, Mcintyre DC, Leech CK. A permanent change in brain function resulting from daily electrical stimulation. Exp Neurol, 1969, 25(3): 295-330.
42.	L?scher W. Animal models of drug-resistant epilepsy. Novartis Found Symp, 2002, 243: 149-166.
43.	L?scher Wr W. Animal models of intractable epilepsy. Prog Neurobiol, 1997, 53(2): 239-258.
44.	L?sche S, eds. Models of seizures and epilepsy. Elsevier, San Diego, 2006: 551-567.
45.	T?llner K, Wolf S, L?scher 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 Neurosci, 2011, 31(45): 16423-16434.
46.	Brandt C, Glien M, Potschka H, et al. Epileptogenesis and neuropathology after different types of status epilepticus induced by prolonged electrical stimulation of the basolateral amygdala in rats. Epilepsy Res, 2003, 50(1): 83-103.
47.	Brandt C, Volk HA, L?scher W. Striking differences in individual anticonvulsant response to phenobarbital in rats with spontaneous seizures after status epilepticus. Epilepsia, 2004, 45(12): 1488-1497.
48.	Bethmann K, Brandt C, L?scher W. Resistance to phenobarbital extends to phenytoin in a rat model of temporal lobe epilepsy. Epilepsia, 2007, 48(4): 816-826.
49.	Brandt C, L?scher W. Antiepileptic efficacy of lamotrigine in phenobarbital-resistant and -responsive epileptic rats: a pilot study. Epilepsy Res, 2014, 108(7): 1145-1157.
50.	L?scher W, Brandt C. High seizure frequency prior to antiepileptic treatment is a predictor of pharmacoresistant epilepsy in a rat model of temporal lobe epilepsy. Epilepsia, 2010, 51(1): 89-97.
51.	Rogawski MA. The intrinsic severity hypothesis of pharmacoresistance to antiepileptic drugs. Epilepsia, 2013, 54(s2): 33-40.
52.	Kwan P, Brodie MJ. Early identification of refractory epilepsy. The New England Journal of Medicine, 2000, 342(5): 314-319.
53.	Gastens AM, Brandt C, Bankstahl JP, et al. Predictors of pharmacoresistant epilepsy: pharmacoresistant rats differ from pharmacoresponsive rats in behavioral and cognitive abnormalities associated with experimentally induced epilepsy. Epilepsia, 2008, 49(10): 1759-1776.
54.	L?scher W. Fit for purpose application of currently existing animal models in the discovery of novel epilepsy therapies. Epilepsy Res, 2016, 126: 157-184.
55.	Rogawski MA, L?scher W. The neurobiology of antiepileptic drugs for the treatment of nonepileptic conditions. Nat Med, 2004, 10(7): 685-692.
56.	Racine RJ. Modification of seizure activity by electrical stimulation. II. Motor seizure. Electroencephalogr Clin Neurophysiol, 1972, 32(3): 281-294.
57.	Klitgaard H, Matagne A, Gobert J, et al. Evidence for a unique profile of levetiracetam in rodent models of seizures and epilepsy. European Journal of Pharmacology, 1998, 353(2): 191-206.
58.	Barton ME, White HS. The effect of CGX-1007 and CI-1041, novel NMDA receptor antagonists, on kindling acquisition and expression. Epilepsy Res, 2004, 59(1): 1-12.
59.	Klein BD, Jacobson CA, Metcalf CS, et al. Evaluation of cannabidiol in animal seizure models by the epilepsy therapy screening program (ETSP). Neurochem Res, 2017, 42(7): 1939-1948.
60.	Srivastava AK, Alex AB, Wilcox KS, et al. Rapid loss of efficacy to the antiseizure drugs lamotrigine and carbamazepine: a novel experimental model of pharmacoresistant epilepsy. Epilepsia, 2013, 54(7): 1186-1194.

1. Sander JW, Shorvon SD. Epidemiology of the epilepsies. Journal of Neurology Neurosurgery & Psychiatry, 1996, 61(5): 433-443.
2. Fisher RS, Acevedo C, Arzimanoglou A, et al. ILAE official report: a practical clinical definition of epilepsy. Epilepsia, 2014, 55(4): 475-482.
3. Kalilani L, Sun X, Pelgrims B, et al. The epidemiology of drug-resistant epilepsy: a systematic review and meta-analysis. Epilepsia, 2018, 59(12): 2179-2193.
4. Jr engel J. The current place of epilepsy surgery. Curr Opin Neurol, 2018, 31(2): 192-197.
5. Maguire MJ, Jackson CF, Marson AG, et al. Treatments for the prevention of Sudden Unexpected Death in Epilepsy (SUDEP). Cochrane Database Syst Rev, 2016, 7(7).
6. Kanner AM. Management of psychiatric and neurological comorbidities in epilepsy. Nat Rev Neurol, 2016, 12(2): 106-116.
7. Stables JP, Bertram E, Dudek FE, et al. Therapy discovery for pharmacoresistant epilepsy and for disease-modifying therapeutics: summary of the Nih/ninds/aes Models Ii Workshop. Epilepsia, 2010, 44(12): 1472-1478.
8. Enrique A, Goicoechea S, Castao R, et al. New model of pharmacoresistant seizures induced by 3-mercaptopropionic acid in mice. Epilepsy Research, 2017, 129: 8-16.
9. Riban V, Bouilleret V, Pham-lê BT, et al. Evolution of hippocampal epileptic activity during the development of hippocampal sclerosis in a mouse model of temporal lobe epilepsy. Neuroscience, 2002, 112(1): 101-111.
10. 方子妍, 吳逢春, 陳樹達, 等. 苯妥英鈉耐藥性顳葉內側癲癇大鼠模型的構建. 癲癇雜志, 2019, 5(1): 21-25.
11. 許蘭, 王麗琨, 周鑫, 等. 兩種耐藥性顳葉癲癇模型海馬硬化及苔蘚纖維發芽的對比. 貴州醫科大學學報, 2019, 44(10): 1145-1150.
12. 唐太峰, 伍國鋒. 耐苯巴比妥鈉及苯妥英鈉杏仁核點燃大鼠癲癇模型的制作. 貴州醫科大學學報, 2016, 41(6): 671-674.
13. 陸海美, 謝美娟, 李姍, 等. 6 Hz角膜點燃耐藥癲癇小鼠模型改良及3種中藥方劑的作用. 藥學學報, 2018, 53(7): 1048-1053.
14. Jiang W, Du B, Chi Z, et al. Preliminary explorations of the role of mitochondrial proteins in refractory epilepsy: some findings from comparative proteomics. Journal of Neuroscience Research, 2007, 85(14): 3160-3170.
15. Rocha L. Effects of high frequency electrical stimulation and r-verapamil on seizure susceptibility and glutamate and gaba release in a model of phenytoin-resistant seizures. Neuropharmacology, 2011, 61(4): 807-814.
16. Zeng K, Wang X, Wang Y, et al. Enhanced synaptic vesicle traffic in hippocampus of phenytoin-resistant kindled rats. Neurochemical Research, 2009, 34(5): 899-904.
17. Potschka H, Volk HA, L?scher W. Pharmacoresistance and expression of multidrug transporter P-glycoprotein in kindled rats. Neuroreport, 2004, (10): 1657-1661.
18. 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. Brain, 2005, 128(Pt 6): 1358-1368.
19. Bethmann K, Fritschy JM, Brandt C, et al. Antiepileptic drug resistant rats differ from drug responsive rats in GABA A receptor subunit expression in a model of temporal lobe epilepsy. Neurobiol Dis, 2008, 31(2): 169-187.
20. Volk HA, Arabadzisz D, Fritschy JM, et al. Antiepileptic drug-resistant rats differ from drug-responsive rats in hippocampal neurodegeneration and GABA(A) receptor ligand binding in a model of temporal lobe epilepsy. Neurobiol Dis, 2006, 2(3): 633-646.
21. Metcalf CS, Huff J, Thomson KE, et al. Evaluation of antiseizure drug efficacy and tolerability in the rat lamotrigine-resistant amygdala kindling model. Epilepsia Open, 2019, 4(3): 452-463.
22. Zhang C, Zuo Z, Kwan P, et al. In vitro transport profile of carbamazepine, oxcarbazepine, eslicarbazepine acetate, and their active metabolites by human p-glycoprotein. Epilepsia, 2011, 52(10): 1894-1904.
23. Chen C, Zhou H, Guan C, et al. Applicability of free drug hypothesis to drugs with good membrane permeability that are not efflux transporter substrates: a microdialysis study in rats. Pharmacology Research & Perspectives, 2020, 8(2): e00575.
24. Nagaya Y, Nozaki Y, Takenaka O, et al. Investigation of utility of cerebrospinal fluid drug concentration as a surrogate for interstitial fluid concentration using microdialysis coupled with cisternal cerebrospinal fluid sampling in wild-type and mdr1a(-/-) rats. Drug Metabolism and Pharmacokinetics, 2016, (1): 57-66.
25. Baraban SC, Löscher W. What new modeling approaches will help us identify promising drug treatments? Adv Exp Med Biol, 2014, 813: 283-294.
26. Guillemain I, Kahane P, Depaulis A. Animal models to study aetiopathology of epilepsy: what are the features to model? Epileptic Disord, 2012, 14(3): 217-225.
27. Klein S, Bankstahl M, L?scher W. Inter-individual variation in the effect of antiepileptic drugs in the intrahippocampal kainate model of mesial temporal lobe epilepsy in mice. Neuropharmacology, 2015, 9: 53-62.
28. Wang L, Shi J, Wu G, et al. Hippocampal low-frequency stimulation increased SV2A expression and inhibited the seizure degree in pharmacoresistant amygdala-kindling epileptic rats. Epilepsy Res, 2014, (9): 1483-1491.
29. Toman JEP. Neuropharmacologic considerations in psychic seizures. Neurology, 1951, 1(6): 444-460.
30. L?scher W. Critical review of current animal models of seizures and epilepsy used in the discovery and development of new antiepileptic drugs. Seizure, 2011, 20(5): 359-368.
31. Albertini G, Walrave L, Demuyser T, et al. 6hz corneal kindling in mice triggers neurobehavioral comorbidities accompanied by relevant changes in c‐fos immunoreactivity throughout the brain. Epilepsia, 2018, 59(1): 67-78.
32. Florek-luszczki M, Wlaz A, Kondrat-wrobel MW, et al. Effects of win 55, 212-2 (a non-selective cannabinoid cb1 and cb2 receptor agonist) on the protective action of various classical antiepileptic drugs in the mouse 6hz psychomotor seizure model. Journal of Neural Transmission, 2014, (7): 707-715.
33. Matagne A, Klitgaard H. Validation of corneally kindled mice: a sensitive screening model for partial epilepsy in man. Epilepsy Res, 1998, 31(1): 59-71.
34. Leclercq K, Matagne A, Kaminski RM. Low potency and limited efficacy of antiepileptic drugs in the mouse 6 Hz corneal kindling model. Epilepsy Res, 2014, 108(4): 675-683.
35. Rowley NM, White HS. Comparative anticonvulsant efficacy in the corneal kindled mouse model of partial epilepsy: correlation with other seizure and epilepsy models. Epilepsy Res, 2010, 92(2): 163-169.
36. Barker-haliski ML, Vanegas F, Mau MJ, et al. Acute cognitive impact of antiseizure drugs in naive rodents and corneal-kindled mice. Epilepsia, 2016, 57(9): 1386-1397.
37. Barker-haliski ML, Johnson K, Billingsley P, et al. Validation of a preclinical drug screening platform for pharmacoresistant epilepsy. Neurochem Res, 2017, 42(7): 1904-1918.
38. Remigio GJ, Loewen JL, Heuston S, et al. Corneal kindled C57BL/6 mice exhibit saturated dentate gyrus long-term potentiation and associated memory deficits in the absence of overt neuron loss. Neurobiol Dis, 2017, 105: 221-234.
39. Loewen JL, Barker-haliski ML, Dahle EJ, et al. Neuronal injury, gliosis, and glial proliferation in two models of temporal lobe epilepsy. J Neuropathol Exp Neurol, 2016, 75(4): 366-378.
40. Koneval Z, Knox KM, White HS, et al. Lamotrigine-resistant corneal-kindled mice: a model of pharmacoresistant partial epilepsy for moderate-throughput drug discovery. Epilepsia, 2018, 59(6): 1245-1256.
41. Goddard GV, Mcintyre DC, Leech CK. A permanent change in brain function resulting from daily electrical stimulation. Exp Neurol, 1969, 25(3): 295-330.
42. L?scher W. Animal models of drug-resistant epilepsy. Novartis Found Symp, 2002, 243: 149-166.
43. L?scher Wr W. Animal models of intractable epilepsy. Prog Neurobiol, 1997, 53(2): 239-258.
44. L?sche S, eds. Models of seizures and epilepsy. Elsevier, San Diego, 2006: 551-567.
45. T?llner K, Wolf S, L?scher 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 Neurosci, 2011, 31(45): 16423-16434.
46. Brandt C, Glien M, Potschka H, et al. Epileptogenesis and neuropathology after different types of status epilepticus induced by prolonged electrical stimulation of the basolateral amygdala in rats. Epilepsy Res, 2003, 50(1): 83-103.
47. Brandt C, Volk HA, L?scher W. Striking differences in individual anticonvulsant response to phenobarbital in rats with spontaneous seizures after status epilepticus. Epilepsia, 2004, 45(12): 1488-1497.
48. Bethmann K, Brandt C, L?scher W. Resistance to phenobarbital extends to phenytoin in a rat model of temporal lobe epilepsy. Epilepsia, 2007, 48(4): 816-826.
49. Brandt C, L?scher W. Antiepileptic efficacy of lamotrigine in phenobarbital-resistant and -responsive epileptic rats: a pilot study. Epilepsy Res, 2014, 108(7): 1145-1157.
50. L?scher W, Brandt C. High seizure frequency prior to antiepileptic treatment is a predictor of pharmacoresistant epilepsy in a rat model of temporal lobe epilepsy. Epilepsia, 2010, 51(1): 89-97.
51. Rogawski MA. The intrinsic severity hypothesis of pharmacoresistance to antiepileptic drugs. Epilepsia, 2013, 54(s2): 33-40.
52. Kwan P, Brodie MJ. Early identification of refractory epilepsy. The New England Journal of Medicine, 2000, 342(5): 314-319.
53. Gastens AM, Brandt C, Bankstahl JP, et al. Predictors of pharmacoresistant epilepsy: pharmacoresistant rats differ from pharmacoresponsive rats in behavioral and cognitive abnormalities associated with experimentally induced epilepsy. Epilepsia, 2008, 49(10): 1759-1776.
54. L?scher W. Fit for purpose application of currently existing animal models in the discovery of novel epilepsy therapies. Epilepsy Res, 2016, 126: 157-184.
55. Rogawski MA, L?scher W. The neurobiology of antiepileptic drugs for the treatment of nonepileptic conditions. Nat Med, 2004, 10(7): 685-692.
56. Racine RJ. Modification of seizure activity by electrical stimulation. II. Motor seizure. Electroencephalogr Clin Neurophysiol, 1972, 32(3): 281-294.
57. Klitgaard H, Matagne A, Gobert J, et al. Evidence for a unique profile of levetiracetam in rodent models of seizures and epilepsy. European Journal of Pharmacology, 1998, 353(2): 191-206.
58. Barton ME, White HS. The effect of CGX-1007 and CI-1041, novel NMDA receptor antagonists, on kindling acquisition and expression. Epilepsy Res, 2004, 59(1): 1-12.
59. Klein BD, Jacobson CA, Metcalf CS, et al. Evaluation of cannabidiol in animal seizure models by the epilepsy therapy screening program (ETSP). Neurochem Res, 2017, 42(7): 1939-1948.
60. Srivastava AK, Alex AB, Wilcox KS, et al. Rapid loss of efficacy to the antiseizure drugs lamotrigine and carbamazepine: a novel experimental model of pharmacoresistant epilepsy. Epilepsia, 2013, 54(7): 1186-1194.

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