基于红藻氨酸和劳拉西泮联合给药的新型人类获得性颞叶癫痫动物模型_Journal of Epilepsy

Authors：

 Kienzler-NorwoodF , CostardL , SadangiC , 李思思　译 , 熊维希　慕洁　审

Corresponding author：

Kienzler-NorwoodF, Email: braxton.norwood@gmail.com

Keywords：

非惊厥性癫痫持续状态; 苯二氮卓; 海马硬化

DOI：

10.7507/2096-0247.20190025

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红藻氨酸（Kainic acid，KA）是一种有效的谷氨酸类似物，用于诱导啮齿动物的神经退行性变和颞叶癫痫（TLE）。KA 可诱发严重的、持续的癫痫发作，即惊厥性癫痫持续状态（convulsive Status epilepticus，cSE），没有药物干预的情况下通常是致命的。在过去 30 年里，使用 KA 来建立人类癫痫动物模型毫无疑问被证明是有价值的，但显著的可变性和死亡率一直使结果变得不确定。这些问题很可能是 cSE 导致的，这是一种本质上可变且无法控制的全或无反应。然而，cSE 与人类疾病的相关性尚不确定，因为大多数癫痫患者从未经历过这种情况。该研究试图构建一种简单的、基于 KA 的 TLE 动物模型，以避免 cSE 及其混淆因素。成年雄性 Sprague-Dawley 大鼠分别接受皮下注射 KA（5 mg）和劳拉西泮（0.25 mg），剂量分别约为 15.0 mg/kg 和 0.75 mg/kg。持续的视频脑电图（VEEG）被用来监测急性癫痫的发作和检测自发性癫痫发作。免疫细胞化学、Fluoro-Jade B 染色和 Timm 染色被用来描述急性和慢性神经病理学改变。急性局灶海马癫痫发作在约 30 min 后开始并在几小时后自行终止。广泛的海马神经变性在 4 d 之后发现。在所有动物中自发性的局灶海马癫痫发作平均 12 d 之后开始。典型的海马硬化和苔藓纤维出芽的形成是长期神经病理学的特征。发病率和死亡率均为 0%。我们发现在联合注射低剂量苯二氮卓类药物时，KA 全身性给药的作用可局限于海马。这意味着劳拉西泮可以阻止痉挛性癫痫发作，而没有真正阻止癫痫电活动。这个创新的、无 cSE 的动物模型，可靠地模拟了获得性颞叶内侧癫痫所定义的特征：海马硬化和在长时间无癫痫发作后自发的海马起源的癫痫发作，并不伴显著的发病率、死亡率或无反应者。

Citation： Kienzler-NorwoodF, CostardL, SadangiC, 李思思　译, 熊维希　慕洁　审. 基于红藻氨酸和劳拉西泮联合给药的新型人类获得性颞叶癫痫动物模型. Journal of Epilepsy, 2019, 5(2): 140-147. doi: 10.7507/2096-0247.20190025 Copy

1.	Fisher RS, Acevedo C, Arzimanoglou A, et al. ILAE official report: a practical clinical definition of epilepsy. Epilepsia, 2014, 55(4): 475-482.
2.	Chang BS, Lowenstein DH. Epilepsy. N Engl J Med, 2003, 349(13): 1257-1266.
3.	Margerison JH, Corsellis JA. Epilepsy and the temporal lobes. A clinical, electroencephalographic and neuropathological study of the brain in epilepsy, with particular reference to the temporal lobes. Brain, 1966, 89(3): 499-530.
4.	Thurman DJ, Beghi E, Begley CE, et al. Standards for epidemiologic studies and surveillance of epilepsy. Epilepsia, 2011, 52(Suppl 7): 2-26.
5.	De Lanerolle NC, Kim JH, Williamson A, et al. A retrospective analysis of hippocampal pathology in human temporal lobe epilepsy: evidence for distinctive patient subcategories. Epilepsia, 2003, 44(5): 677-687.
6.	Spencer SS, Spencer DD. Entorhinal‐hippocampal interactions in medial temporal lobe epilepsy. Epilepsia, 1994, 35(4): 721-727.
7.	Lévesque M, Avoli M. The kainic acid model of temporal lobe epilepsy. Neurosci Biobehav Rev, 2013, 37(10 Pt2): 2887-2899.
8.	Murakami S, Takemoto T. On the effective principles of digenea‐simplex aq. 1. Separation of the effective fraction by liquid chromatography. Yakugaku, 1953.
9.	Watkins JC, Evans RH. Excitatory amino acid transmitters. Annu Rev Pharmacol Toxicol, 1981, 21: 165-204.
10.	Ben‐Ari Y, Lagowska J. Epileptogenic action of intra‐amygdaloid injection of kainic acid. C R Acad Sci Hebd Seances Acad Sci D, 1978, 287(8): 813-816.
11.	Ben‐Ari Y, Lagowska J, Tremblay E, et al. A new model of focal status epilepticus: intra‐amygdaloid application of kainic acid elicits repetitive secondarily generalized convulsive seizures. Brain Res, 1979, 163(1): 176-179.
12.	Lévesque M, Avoli M, Bernard C. Animal models of temporal lobe epilepsy following systemic chemoconvulsant administration. J Neurosci Methods, 2015, 260: 45-52.
13.	Hellier JL, Dudek FE. Chemoconvulsant model of chronic spontaneous seizures. Curr Protoc Neurosci, 2005.
14.	Alldredge BK, Gelb AM, Isaacs SM, et al. A comparison of lorazepam, diazepam, and placebo for the treatment of out‐of‐hospital status epilepticus. N Engl J Med, 2001, 345(9): 631-637.
15.	Norwood BA, Bumanglag AV, Osculati F, et al. Classic hippocampal sclerosis and hippocampal‐onset epilepsy produced by a single " cryptic” episode of focal hippocampal excitation in awake rats. J Comp Neurol, 2010, 518(16): 3381-3407.
16.	Harvey BD, Sloviter RS. Hippocampal granule cell activity and c‐Fos expression during spontaneous seizures in awake, chronically epileptic, pilocarpine‐treated rats: implications for hippocampal epileptogenesis. J Comp Neurol, 2005, 488(4): 442-463.
17.	Racine RJ. Modification of seizure activity by electrical stimulation: III. Motor seizure. Electroencephalogr. Clin Neurophysiol, 1972, 32(3): 281-294.
18.	Blümcke I, Thom M, Aronica E, et al. International consensus classification of hippocampal sclerosis in temporal lobe epilepsy: a Task Force report from the ILAE Commission on Diagnostic Methods. Epilepsia, 2013, 54(7): 1315-1329.
19.	Trinka E, Cock H, Hesdorffer D, et al. A definition and classification of status epilepticus - report of the ILAE Task Force on Classification of Status Epilepticus. Epilepsia, 2015, 56(10): 1515-1523.
20.	Williams PA, White AM, Clark S, et al. Development of spontaneous recurrent seizures after kainate‐induced status epilepticus. J Neurosci, 2009, 29(7): 2103-2112.
21.	Deller T, Frotscher M, Nitsch R. Morphological evidence for the sprouting of inhibitory commissural fibers in response to the lesion of the excitatory entorhinal input to the rat dentate gyrus. J Neurosci, 1995, 15(10): 6868-6878.
22.	Elger CE, Schmidt D. Modern management of epilepsy: a practical approach. Epilepsy Behav, 2008, 12(4): 501-539.
23.	Löscher W, Schmidt D. Modern antiepileptic drug development has failed to deliver: ways out of the current dilemma. Epilepsia, 2011, 52(4): 657-678.
24.	Arabadzisz D, Antal K, Parpan F, et al. Epileptogenesis and chronic seizures in a mouse model of temporal lobe epilepsy are associated with distinct EEG patterns and selective neurochemical alterations in the contralateral hippocampus. Exp Neurol, 2005, 194(1): 76-90.
25.	Carriero G, Arcieri S, Cattalini A, et al. A guinea pig model of mesial temporal lobe epilepsy following nonconvulsive status epilepticus induced by unilateral intrahippocampal injection of kainic acid. Epilepsia, 2012, 53(11): 1917-1927.
26.	Daniels WMU, Jaffer A, Engelbrecht AH, et al. The effect of intrahippocampal injection of kainic acid on corticosterone release in rats. Neurochem Res, 1990, 15(5): 495-499.
27.	Victor Nadler J, Cuthbertson GJ. Kainic acid neurotoxicity toward hippocampal formation: dependence on specific excitatory pathways. Brain Res, 1980, 195(1): 47-56.
28.	Raedt R, Van Dycke A, Van Melkebeke D, et al. Seizures in the intrahippocampal kainic acid epilepsy model: characterization using long‐term video‐EEG monitoring in the rat. Acta Neurol Scand, 2009, 119(5): 293-303.
29.	Araki T, Simon RP, Taki W, et al. Characterization of neuronal death induced by focally evoked limbic seizures in the C57BL/6 mouse. J Neurosci Res, 2002, 69(5): 614-621.
30.	Ben‐Ari Y, Tremblay E, Ottersen OP. Injections of kainic acid into the amygdaloid complex of the rat: an electrographic, clinical and histological study in relation to the pathology of epilepsy. Neuroscience, 1980, 5(3): 515-528.
31.	Cavalheiro EA, Riche DA, Le Gal La Salle G. Long‐term effects of intrahippocampal kainic acid injection in rats: a method for inducing spontaneous recurrent seizures. Electroencephalogr Clin Neurophysiol, 1982, 53(6): 581-589.
32.	Dunleavy M, Shinoda S, Schindler C, et al. Experimental neonatal status epilepticus and the development of temporal lobe epilepsy with unilateral hippocampal sclerosis. Am J Pathol, 2010, 176(1): 330-342.
33.	Gurbanova AA, Aker RG, Sirvanci S, et al. Intra‐amygdaloid injection of kainic acid in rats with genetic absence epilepsy: the relationship of typical absence epilepsy and temporal lobe epilepsy. J Neurosci, 2008, 28(31): 7828-7836.
34.	Jimenez‐Mateos EM, Engel T, Merino‐Serrais P, et al. Silencing microRNA‐134 produces neuroprotective and prolonged seizure‐suppressive effects. Nat Med, 2012, 18: 1087-1094.
35.	Mouri G, Jimenez‐Mateos E, Engel T, et al. Unilateral hippocampal CA3‐predominant damage and short latency epileptogenesis after intra‐amygdala microinjection of kainic acid in mice. Brain Res, 2008, 1213: 140-151.
36.	Represa A, Tremblay E, Ben‐Ari Y. Kainate binding sites in the hippocampal mossy fibers: localization and plasticity. Neuroscience, 1987, 20(3): 739-748.
37.	Drexel M, Preidt AP, Sperk G. Sequel of spontaneous seizures after kainic acid‐induced status epilepticus and associated neuropathological changes in the subiculum and entorhinal cortex. Neuropharmacology, 2012, 63(5): 806-817.
38.	Haas KZ, Sperber EF, Opanashuk LA, et al. Resistance of immature hippocampus to morphologic and physiologic alterations following status epilepticus or kindling. Hippocampus, 2001, 11(6): 615-625.
39.	Heggli DE, Malthesorenssen D. Systemic injection of kainic acid ‐ effect on neurotransmitter markers in piriform cortex, amygdaloid complex and hippocampus and protection by cortical lesioning and anticonvulsants. Neuroscience, 1982, 7(5): 1257-1264.
40.	Kar S, Seto D, Doré S, et al. Systemic administration of kainic acid induces selective time dependent decrease in[¹²⁵I]insulin‐like growth factor I, [¹²⁵I]insulin‐like growth factor II and[125I]insulin receptor binding sites in adult rat hippocampal formation. Neuroscience, 1997, 80(4): 1041-1055.
41.	Sperk G, Lassmann H, Baran H, et al. Kainic acid‐induced seizures − dose‐relationship of behavioral, neurochemical and histopathological changes. Brain Res, 1985, 338: 289-295.
42.	Sloviter RS, Damiano BP. Sustained electrical stimulation of the perforant path duplicates kainate‐induced electrophysiological effects and hippocampal damage in rats. Neurosci Lett, 1981, 24(3): 279-284.
43.	Strain SM, Tasker R. Hippocampal damage produced by systemic injections of domoic acid in mice. Neuroscience, 1991, 44(2): 343-352.
44.	Suarez LM, Cid E, Gal B, et al. Systemic injection of kainic acid differently affects LTP magnitude depending on its epileptogenic efficiency. PLoS ONE, 2012, 7(10): e48128.
45.	Zhang X, Cui SS, Wallace AE, et al. Relations between brain pathology and temporal lobe epilepsy. J Neurosci, 2002, 22(14): 6052-6061.
46.	Hellier JL, Patrylo PR, Buckmaster PS, et al. Recurrent spontaneous motor seizures after repeated low‐dose systemic treatment with kainate: assessment of a rat model of temporal lobe epilepsy. Epilepsy Res, 1998, 31(1): 73-84.

1. Fisher RS, Acevedo C, Arzimanoglou A, et al. ILAE official report: a practical clinical definition of epilepsy. Epilepsia, 2014, 55(4): 475-482.
2. Chang BS, Lowenstein DH. Epilepsy. N Engl J Med, 2003, 349(13): 1257-1266.
3. Margerison JH, Corsellis JA. Epilepsy and the temporal lobes. A clinical, electroencephalographic and neuropathological study of the brain in epilepsy, with particular reference to the temporal lobes. Brain, 1966, 89(3): 499-530.
4. Thurman DJ, Beghi E, Begley CE, et al. Standards for epidemiologic studies and surveillance of epilepsy. Epilepsia, 2011, 52(Suppl 7): 2-26.
5. De Lanerolle NC, Kim JH, Williamson A, et al. A retrospective analysis of hippocampal pathology in human temporal lobe epilepsy: evidence for distinctive patient subcategories. Epilepsia, 2003, 44(5): 677-687.
6. Spencer SS, Spencer DD. Entorhinal‐hippocampal interactions in medial temporal lobe epilepsy. Epilepsia, 1994, 35(4): 721-727.
7. Lévesque M, Avoli M. The kainic acid model of temporal lobe epilepsy. Neurosci Biobehav Rev, 2013, 37(10 Pt2): 2887-2899.
8. Murakami S, Takemoto T. On the effective principles of digenea‐simplex aq. 1. Separation of the effective fraction by liquid chromatography. Yakugaku, 1953.
9. Watkins JC, Evans RH. Excitatory amino acid transmitters. Annu Rev Pharmacol Toxicol, 1981, 21: 165-204.
10. Ben‐Ari Y, Lagowska J. Epileptogenic action of intra‐amygdaloid injection of kainic acid. C R Acad Sci Hebd Seances Acad Sci D, 1978, 287(8): 813-816.
11. Ben‐Ari Y, Lagowska J, Tremblay E, et al. A new model of focal status epilepticus: intra‐amygdaloid application of kainic acid elicits repetitive secondarily generalized convulsive seizures. Brain Res, 1979, 163(1): 176-179.
12. Lévesque M, Avoli M, Bernard C. Animal models of temporal lobe epilepsy following systemic chemoconvulsant administration. J Neurosci Methods, 2015, 260: 45-52.
13. Hellier JL, Dudek FE. Chemoconvulsant model of chronic spontaneous seizures. Curr Protoc Neurosci, 2005.
14. Alldredge BK, Gelb AM, Isaacs SM, et al. A comparison of lorazepam, diazepam, and placebo for the treatment of out‐of‐hospital status epilepticus. N Engl J Med, 2001, 345(9): 631-637.
15. Norwood BA, Bumanglag AV, Osculati F, et al. Classic hippocampal sclerosis and hippocampal‐onset epilepsy produced by a single " cryptic” episode of focal hippocampal excitation in awake rats. J Comp Neurol, 2010, 518(16): 3381-3407.
16. Harvey BD, Sloviter RS. Hippocampal granule cell activity and c‐Fos expression during spontaneous seizures in awake, chronically epileptic, pilocarpine‐treated rats: implications for hippocampal epileptogenesis. J Comp Neurol, 2005, 488(4): 442-463.
17. Racine RJ. Modification of seizure activity by electrical stimulation: III. Motor seizure. Electroencephalogr. Clin Neurophysiol, 1972, 32(3): 281-294.
18. Blümcke I, Thom M, Aronica E, et al. International consensus classification of hippocampal sclerosis in temporal lobe epilepsy: a Task Force report from the ILAE Commission on Diagnostic Methods. Epilepsia, 2013, 54(7): 1315-1329.
19. Trinka E, Cock H, Hesdorffer D, et al. A definition and classification of status epilepticus - report of the ILAE Task Force on Classification of Status Epilepticus. Epilepsia, 2015, 56(10): 1515-1523.
20. Williams PA, White AM, Clark S, et al. Development of spontaneous recurrent seizures after kainate‐induced status epilepticus. J Neurosci, 2009, 29(7): 2103-2112.
21. Deller T, Frotscher M, Nitsch R. Morphological evidence for the sprouting of inhibitory commissural fibers in response to the lesion of the excitatory entorhinal input to the rat dentate gyrus. J Neurosci, 1995, 15(10): 6868-6878.
22. Elger CE, Schmidt D. Modern management of epilepsy: a practical approach. Epilepsy Behav, 2008, 12(4): 501-539.
23. Löscher W, Schmidt D. Modern antiepileptic drug development has failed to deliver: ways out of the current dilemma. Epilepsia, 2011, 52(4): 657-678.
24. Arabadzisz D, Antal K, Parpan F, et al. Epileptogenesis and chronic seizures in a mouse model of temporal lobe epilepsy are associated with distinct EEG patterns and selective neurochemical alterations in the contralateral hippocampus. Exp Neurol, 2005, 194(1): 76-90.
25. Carriero G, Arcieri S, Cattalini A, et al. A guinea pig model of mesial temporal lobe epilepsy following nonconvulsive status epilepticus induced by unilateral intrahippocampal injection of kainic acid. Epilepsia, 2012, 53(11): 1917-1927.
26. Daniels WMU, Jaffer A, Engelbrecht AH, et al. The effect of intrahippocampal injection of kainic acid on corticosterone release in rats. Neurochem Res, 1990, 15(5): 495-499.
27. Victor Nadler J, Cuthbertson GJ. Kainic acid neurotoxicity toward hippocampal formation: dependence on specific excitatory pathways. Brain Res, 1980, 195(1): 47-56.
28. Raedt R, Van Dycke A, Van Melkebeke D, et al. Seizures in the intrahippocampal kainic acid epilepsy model: characterization using long‐term video‐EEG monitoring in the rat. Acta Neurol Scand, 2009, 119(5): 293-303.
29. Araki T, Simon RP, Taki W, et al. Characterization of neuronal death induced by focally evoked limbic seizures in the C57BL/6 mouse. J Neurosci Res, 2002, 69(5): 614-621.
30. Ben‐Ari Y, Tremblay E, Ottersen OP. Injections of kainic acid into the amygdaloid complex of the rat: an electrographic, clinical and histological study in relation to the pathology of epilepsy. Neuroscience, 1980, 5(3): 515-528.
31. Cavalheiro EA, Riche DA, Le Gal La Salle G. Long‐term effects of intrahippocampal kainic acid injection in rats: a method for inducing spontaneous recurrent seizures. Electroencephalogr Clin Neurophysiol, 1982, 53(6): 581-589.
32. Dunleavy M, Shinoda S, Schindler C, et al. Experimental neonatal status epilepticus and the development of temporal lobe epilepsy with unilateral hippocampal sclerosis. Am J Pathol, 2010, 176(1): 330-342.
33. Gurbanova AA, Aker RG, Sirvanci S, et al. Intra‐amygdaloid injection of kainic acid in rats with genetic absence epilepsy: the relationship of typical absence epilepsy and temporal lobe epilepsy. J Neurosci, 2008, 28(31): 7828-7836.
34. Jimenez‐Mateos EM, Engel T, Merino‐Serrais P, et al. Silencing microRNA‐134 produces neuroprotective and prolonged seizure‐suppressive effects. Nat Med, 2012, 18: 1087-1094.
35. Mouri G, Jimenez‐Mateos E, Engel T, et al. Unilateral hippocampal CA3‐predominant damage and short latency epileptogenesis after intra‐amygdala microinjection of kainic acid in mice. Brain Res, 2008, 1213: 140-151.
36. Represa A, Tremblay E, Ben‐Ari Y. Kainate binding sites in the hippocampal mossy fibers: localization and plasticity. Neuroscience, 1987, 20(3): 739-748.
37. Drexel M, Preidt AP, Sperk G. Sequel of spontaneous seizures after kainic acid‐induced status epilepticus and associated neuropathological changes in the subiculum and entorhinal cortex. Neuropharmacology, 2012, 63(5): 806-817.
38. Haas KZ, Sperber EF, Opanashuk LA, et al. Resistance of immature hippocampus to morphologic and physiologic alterations following status epilepticus or kindling. Hippocampus, 2001, 11(6): 615-625.
39. Heggli DE, Malthesorenssen D. Systemic injection of kainic acid ‐ effect on neurotransmitter markers in piriform cortex, amygdaloid complex and hippocampus and protection by cortical lesioning and anticonvulsants. Neuroscience, 1982, 7(5): 1257-1264.
40. Kar S, Seto D, Doré S, et al. Systemic administration of kainic acid induces selective time dependent decrease in[¹²⁵I]insulin‐like growth factor I, [¹²⁵I]insulin‐like growth factor II and[125I]insulin receptor binding sites in adult rat hippocampal formation. Neuroscience, 1997, 80(4): 1041-1055.
41. Sperk G, Lassmann H, Baran H, et al. Kainic acid‐induced seizures − dose‐relationship of behavioral, neurochemical and histopathological changes. Brain Res, 1985, 338: 289-295.
42. Sloviter RS, Damiano BP. Sustained electrical stimulation of the perforant path duplicates kainate‐induced electrophysiological effects and hippocampal damage in rats. Neurosci Lett, 1981, 24(3): 279-284.
43. Strain SM, Tasker R. Hippocampal damage produced by systemic injections of domoic acid in mice. Neuroscience, 1991, 44(2): 343-352.
44. Suarez LM, Cid E, Gal B, et al. Systemic injection of kainic acid differently affects LTP magnitude depending on its epileptogenic efficiency. PLoS ONE, 2012, 7(10): e48128.
45. Zhang X, Cui SS, Wallace AE, et al. Relations between brain pathology and temporal lobe epilepsy. J Neurosci, 2002, 22(14): 6052-6061.
46. Hellier JL, Patrylo PR, Buckmaster PS, et al. Recurrent spontaneous motor seizures after repeated low‐dose systemic treatment with kainate: assessment of a rat model of temporal lobe epilepsy. Epilepsy Res, 1998, 31(1): 73-84.

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基于红藻氨酸和劳拉西泮联合给药的新型人类获得性颞叶癫痫动物模型

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