婴儿痉挛症动物模型研究进展及其评价_Journal of Epilepsy

Authors：

刘雨田 ¹ ,  邹丽萍 ^1,2

1. ;
2. ;

Corresponding author：

邹丽萍, Email: zouliping21@hotmail.com

Keywords：

癫痫; 婴儿痉挛症; 动物模型; 机制

DOI：

10.7507/2096-0247.20190023

Video：

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婴儿痉挛症（Infantile spasm，IS）是一种婴幼儿期难治性癫痫性脑病，临床表现是点头抱团样痉挛发作，脑电图（EEG）呈发作间期高度失律以及精神运动发育落后。大多数患儿促肾上腺皮质激素（Adrenocorticotropic Hormone，ACTH）和氨己烯酸（Vigabatrin，VGB）治疗有效，对普通抗癫痫药物效果不佳。婴儿痉挛症的病因有 200 多种，但至今发病机制不明。本文总结了 7 个有关婴儿痉挛症典型的动物模型。ARX 基因突变小鼠模型对雌二醇治疗有效，且提出了中间神经元致病学说。唐氏综合症小鼠模型由氨基丁酸 B 受体（GABA_BR）激动剂诱发痉挛，对托肽品 Q 治疗有效。N-甲基-D-天冬氨酸（NMDA）可以诱导大、小鼠痉挛发作，在产前给予倍他米松或是产前游泳模拟产前压力解释了 ACTH 治疗有效性的原理。多重打击大鼠模型模拟大脑皮层受损导致的癫痫，做出了耐药模型。河豚毒大鼠模型是唯一有 EEG 发作间期高度失律的模型，并且和“发作不同步学说”相一致。本文回顾学习 7 个婴儿痉挛症不同动物模型的特点和局限性，探讨婴儿痉挛症的发病机制，以及部分模型的新药研究。

Citation： 刘雨田, 邹丽萍. 婴儿痉挛症动物模型研究进展及其评价. Journal of Epilepsy, 2019, 5(2): 125-129. doi: 10.7507/2096-0247.20190023 Copy

1.	Riikonen R. Epidemiological data of west syndrome in Finland. Brain Dev, 2001, 23(7): 539-541.
2.	Shields WD. Infantile spasms: little seizures, BIG consequences. Epilepsy Curr, 2006, 6(3): 63-69.
3.	Frost JD Jr, Hrachovy RA. Pathogenesis of infantile spasms: a model based on developmental desynchronization. J Clin Neurophysiol, 2005, 22(1): 25-36.
4.	Hrachovy RA. West’s syndrome (infantile spasms). Clinical description and diagnosis. Adv Exp Med Biol, 2002, 497: 33-50.
5.	Dulac O, Soufflet C, Chiron C, et al. What is West syndrome? Int Rev Neurobiol, 2002, 49: 1-22.
6.	Kellaway P, Hrachovy RA, Frost JD Jr, et al. Precise characterization and quantification of infantile spasms. Ann Neurol, 1979, 6(3): 214-218.
7.	Baram TZ. Pathophysiology of massive infantile spasms: perspective on the putative role of the brain adrenal axis. Ann Neurol, 1993, 33(3): 231-236.
8.	Scheffer IE, French J, Hirsch E, et al. Classification of the epilepsies: New concepts for discussion and debate—Special report of the ILAE Classification Task Force of the Commission for Classification and Terminology. Epilepsia Open, 2016, 1(1-2): 37-44.
9.	Sorel L, Dusaucy-Bauloye A. Findings in 21 cases of Gibbs’ hypsarrhythmia; spectacular effectiveness of ACTH. Acta Neurol Psychiatr Belg, 1958, 58(2): 130-141.
10.	Hrachovy RA, Frost JD Jr, Kellaway P, et al. Double-blind study of ACTH vs prednisone therapy in infantile spasms. J Pediatr, 1983, 103(4): 641-645.
11.	Hrachovy RA, Frost JD Jr, Glaze DG. High-dose, long-duration versus low-dose, short-duration corticotropin therapy for infantile spasms. J Pediatr, 1994, 124(5 Pt 1): 803-836.
12.	Baram TZ, Mitchell WG, Tournay A, et al. High-dose corticotropin (ACTH) versus prednisone for infantile spasms: a prospective, randomized, blinded study. Pediatrics, 1996, 97(3): 375-379.
13.	Lux AL, Edwards SW, Hancock E, et al. The united kingdom infantile spasms study comparing vigabatrin with prednisolone or tetracosactide at 14 days: a multicentre, randomised controlled trial. Lancet, 2004, 364(9447): 1773-1778.
14.	Chu-Shore CJ, Major P, Camposano S, et al. The natural history of epilepsy in tuberous sclerosis complex. Epilepsia, 2010, 51(7): 1236-1241.
15.	Zeng LH, Xu L, Gutmann DH, et al. Rapamycin prevents epilepsy in a mouse model of tuberous sclerosis complex. Ann Neurol, 2008, 63(4): 444-453.
16.	Meikle L, Pollizzi K, Egnor A, et al. Response of a neuronal model of tuberous sclerosis to mammalian target of rapamycin (mTOR) inhibitors: effects on mTORC1 and Akt signaling lead to improved survival and function. J Neurosci, 2008, 28(21): 5422-5432.
17.	Stafstrom CE, Moshe SL, Swann JW, et al. Models of pediatric epilepsies: strategies and opportunities. Epilepsia, 2006, 47(8): 1407-1414.
18.	Stafstrom CE. Infantile spasms: a critical review of emerging animal models. Epilepsy Curr, 2009, 9(3): 75-81.
19.	Marsh ED, Golden JA. Developing an animal model for infantile spasms: pathogenesis, problems and progress. Dis Model Mech, 2009, 2(7-8): 329-335.
20.	Stafstrom CE, Holmes GL. Infantile spasms: criteria for an animal model. Int Rev Neurobiol, 2002, 49: 391-411.
21.	Stromme P, Mangelsdorf ME, Scheffer IE, et al. Infantile spasms, dystonia, and other X-linked phenotypes caused by mutations in Aristaless related homeobox gene, ARX. Brain Dev, 2002, 24(5): 266-268.
22.	Stromme P, Mangelsdorf ME, Shaw MA, et al. Mutations in the human ortholog of aristaless cause x-linked mental retardation and epilepsy. Nat Genet, 2002, 30(4): 441-445.
23.	Olivetti PR, Maheshwari A, Noebels JL. Neonatal estradiol stimulation prevents epilepsy in arx model of x-linked infantile spasms syndrome. Sci Transl Med, 2014, 6(220): 220ra12.
24.	Stafstrom CE. Epilepsy in Down Syndrome: Clinical Aspects and Possible Mechanisms. Am J Ment Retard, 1993, 98(suppl): 12.
25.	Stafstrom CE, Konkol RJ. Infantile spasms in children with down syndrome. Dev Med Child Neurol, 1994, 36(7): 576-585.
26.	Joshi K, Shen L, Michaeli A, et al. Infantile spasms in down syndrome: Rescue by knockdown of the GIRK2 channel. Ann Neurol, 2016, 80(4): 511-521.
27.	Chachua T, Yum MS, Veliskova J, et al. Validation of the rat model of cryptogenic infantile spasms. Epilepsia, 2011, 52(9): 1666-1677.
28.	Yum MS, Chachua T, Veliskova J, et al. Prenatal stress promotes development of spasms in infant rats. Epilepsia, 2012, 53(3): e46-49.
29.	Tsuji M, Takahashi Y, Watabe AM, et al. Enhanced long-term potentiation in mature rats in a model of epileptic spasms with betamethasone-priming and postnatal N-methyl-D-aspartate administration. Epilepsia, 2016, 57(3): 495-505.
30.	Price MG, Yoo JW, Burgess DL, et al. A triplet repeat expansion genetic mouse model of infantile spasms syndrome, Arx(GCG)10+7, with interneuronopathy, spasms in infancy, persistent seizures, and adult cognitive and behavioral impairment. J Neurosci, 2009, 29(27): 8752-8763.
31.	Chachua T, Di Grazia P, Chern CR, et al. Estradiol does not affect spasms in the beta methasone-NMDA rat model of infantile spasms. Epilepsia, 2016, 57(8): 1326-1336.
32.	Shi XY, Yang XF, Tomonoh Y, et al. Development of a mouse model of infantile spasms induced by N-methyl-D-aspartate. Epilepsy Res, 2015, 118: 29-33.
33.	Shi XY, Ju J, Zou LP, et al. Increased precipitation of spasms in an animal model of infantile spasms by prenatal stress exposure. Life Sci, 2016, 152: 171-177.
34.	De Weerth C, Buitelaar JK. Physiological stress reactivity in human pregnancy--a review. Neurosci Biobehav Rev, 2005, 29(2): 295-312.
35.	Murphy BE, Clark SJ, Donald IR, et al. Conversion of maternal cortisol to cortisone during placental transfer to the human fetus. Am J Obstet Gynecol, 1974, 118(4): 538-541.
36.	Brunson KL, Avishai-Eliner S, Baram TZ. ACTH treatment of infantile spasms: mechanisms of its effects in modulation of neuronal excitability. Int Rev Neurobiol, 2002, 49: 185-197.
37.	Scantlebury MH, Galanopoulou AS, Chudomelova L, et al. A model of symptomatic infantile spasms syndrome. Neurobiol Dis, 2010, 37(3): 604-612.
38.	Galanopoulou AS, Mowrey WB, Liu W, et al. Preclinical Screening for treatments for infantile spasms in the multiple hit rat model of infantile spasms: An Update. Neurochem Res, 2017, 42(7): 1949-1961.
39.	Pellock JM, Hrachovy R, Shinnar S, et al. Infantile spasms: a U.S. consensus report. Epilepsia, 2010, 51(10): 2175-2189.
40.	Galvan CD, Hrachovy RA, Smith KL, et al. Blockade of neuronal activity during hippocampal development produces a chronic focal epilepsy in the rat. J Neurosci, 2000, 20(8): 2904-2916.
41.	Lee CL, Frost JD Jr, Swann JW, et al. A new animal model of infantile spasms with unprovoked persistent seizures. Epilepsia, 2008, 49(2): 298-307.
42.	Frost JD Jr, Le JT, Lee CL, et al. Vigabatrin therapy implicates neocortical high frequency oscillations in an animal model of infantile spasms. Neurobiol Dis, 2015, 82: 1-11.

1. Riikonen R. Epidemiological data of west syndrome in Finland. Brain Dev, 2001, 23(7): 539-541.
2. Shields WD. Infantile spasms: little seizures, BIG consequences. Epilepsy Curr, 2006, 6(3): 63-69.
3. Frost JD Jr, Hrachovy RA. Pathogenesis of infantile spasms: a model based on developmental desynchronization. J Clin Neurophysiol, 2005, 22(1): 25-36.
4. Hrachovy RA. West’s syndrome (infantile spasms). Clinical description and diagnosis. Adv Exp Med Biol, 2002, 497: 33-50.
5. Dulac O, Soufflet C, Chiron C, et al. What is West syndrome? Int Rev Neurobiol, 2002, 49: 1-22.
6. Kellaway P, Hrachovy RA, Frost JD Jr, et al. Precise characterization and quantification of infantile spasms. Ann Neurol, 1979, 6(3): 214-218.
7. Baram TZ. Pathophysiology of massive infantile spasms: perspective on the putative role of the brain adrenal axis. Ann Neurol, 1993, 33(3): 231-236.
8. Scheffer IE, French J, Hirsch E, et al. Classification of the epilepsies: New concepts for discussion and debate—Special report of the ILAE Classification Task Force of the Commission for Classification and Terminology. Epilepsia Open, 2016, 1(1-2): 37-44.
9. Sorel L, Dusaucy-Bauloye A. Findings in 21 cases of Gibbs’ hypsarrhythmia; spectacular effectiveness of ACTH. Acta Neurol Psychiatr Belg, 1958, 58(2): 130-141.
10. Hrachovy RA, Frost JD Jr, Kellaway P, et al. Double-blind study of ACTH vs prednisone therapy in infantile spasms. J Pediatr, 1983, 103(4): 641-645.
11. Hrachovy RA, Frost JD Jr, Glaze DG. High-dose, long-duration versus low-dose, short-duration corticotropin therapy for infantile spasms. J Pediatr, 1994, 124(5 Pt 1): 803-836.
12. Baram TZ, Mitchell WG, Tournay A, et al. High-dose corticotropin (ACTH) versus prednisone for infantile spasms: a prospective, randomized, blinded study. Pediatrics, 1996, 97(3): 375-379.
13. Lux AL, Edwards SW, Hancock E, et al. The united kingdom infantile spasms study comparing vigabatrin with prednisolone or tetracosactide at 14 days: a multicentre, randomised controlled trial. Lancet, 2004, 364(9447): 1773-1778.
14. Chu-Shore CJ, Major P, Camposano S, et al. The natural history of epilepsy in tuberous sclerosis complex. Epilepsia, 2010, 51(7): 1236-1241.
15. Zeng LH, Xu L, Gutmann DH, et al. Rapamycin prevents epilepsy in a mouse model of tuberous sclerosis complex. Ann Neurol, 2008, 63(4): 444-453.
16. Meikle L, Pollizzi K, Egnor A, et al. Response of a neuronal model of tuberous sclerosis to mammalian target of rapamycin (mTOR) inhibitors: effects on mTORC1 and Akt signaling lead to improved survival and function. J Neurosci, 2008, 28(21): 5422-5432.
17. Stafstrom CE, Moshe SL, Swann JW, et al. Models of pediatric epilepsies: strategies and opportunities. Epilepsia, 2006, 47(8): 1407-1414.
18. Stafstrom CE. Infantile spasms: a critical review of emerging animal models. Epilepsy Curr, 2009, 9(3): 75-81.
19. Marsh ED, Golden JA. Developing an animal model for infantile spasms: pathogenesis, problems and progress. Dis Model Mech, 2009, 2(7-8): 329-335.
20. Stafstrom CE, Holmes GL. Infantile spasms: criteria for an animal model. Int Rev Neurobiol, 2002, 49: 391-411.
21. Stromme P, Mangelsdorf ME, Scheffer IE, et al. Infantile spasms, dystonia, and other X-linked phenotypes caused by mutations in Aristaless related homeobox gene, ARX. Brain Dev, 2002, 24(5): 266-268.
22. Stromme P, Mangelsdorf ME, Shaw MA, et al. Mutations in the human ortholog of aristaless cause x-linked mental retardation and epilepsy. Nat Genet, 2002, 30(4): 441-445.
23. Olivetti PR, Maheshwari A, Noebels JL. Neonatal estradiol stimulation prevents epilepsy in arx model of x-linked infantile spasms syndrome. Sci Transl Med, 2014, 6(220): 220ra12.
24. Stafstrom CE. Epilepsy in Down Syndrome: Clinical Aspects and Possible Mechanisms. Am J Ment Retard, 1993, 98(suppl): 12.
25. Stafstrom CE, Konkol RJ. Infantile spasms in children with down syndrome. Dev Med Child Neurol, 1994, 36(7): 576-585.
26. Joshi K, Shen L, Michaeli A, et al. Infantile spasms in down syndrome: Rescue by knockdown of the GIRK2 channel. Ann Neurol, 2016, 80(4): 511-521.
27. Chachua T, Yum MS, Veliskova J, et al. Validation of the rat model of cryptogenic infantile spasms. Epilepsia, 2011, 52(9): 1666-1677.
28. Yum MS, Chachua T, Veliskova J, et al. Prenatal stress promotes development of spasms in infant rats. Epilepsia, 2012, 53(3): e46-49.
29. Tsuji M, Takahashi Y, Watabe AM, et al. Enhanced long-term potentiation in mature rats in a model of epileptic spasms with betamethasone-priming and postnatal N-methyl-D-aspartate administration. Epilepsia, 2016, 57(3): 495-505.
30. Price MG, Yoo JW, Burgess DL, et al. A triplet repeat expansion genetic mouse model of infantile spasms syndrome, Arx(GCG)10+7, with interneuronopathy, spasms in infancy, persistent seizures, and adult cognitive and behavioral impairment. J Neurosci, 2009, 29(27): 8752-8763.
31. Chachua T, Di Grazia P, Chern CR, et al. Estradiol does not affect spasms in the beta methasone-NMDA rat model of infantile spasms. Epilepsia, 2016, 57(8): 1326-1336.
32. Shi XY, Yang XF, Tomonoh Y, et al. Development of a mouse model of infantile spasms induced by N-methyl-D-aspartate. Epilepsy Res, 2015, 118: 29-33.
33. Shi XY, Ju J, Zou LP, et al. Increased precipitation of spasms in an animal model of infantile spasms by prenatal stress exposure. Life Sci, 2016, 152: 171-177.
34. De Weerth C, Buitelaar JK. Physiological stress reactivity in human pregnancy--a review. Neurosci Biobehav Rev, 2005, 29(2): 295-312.
35. Murphy BE, Clark SJ, Donald IR, et al. Conversion of maternal cortisol to cortisone during placental transfer to the human fetus. Am J Obstet Gynecol, 1974, 118(4): 538-541.
36. Brunson KL, Avishai-Eliner S, Baram TZ. ACTH treatment of infantile spasms: mechanisms of its effects in modulation of neuronal excitability. Int Rev Neurobiol, 2002, 49: 185-197.
37. Scantlebury MH, Galanopoulou AS, Chudomelova L, et al. A model of symptomatic infantile spasms syndrome. Neurobiol Dis, 2010, 37(3): 604-612.
38. Galanopoulou AS, Mowrey WB, Liu W, et al. Preclinical Screening for treatments for infantile spasms in the multiple hit rat model of infantile spasms: An Update. Neurochem Res, 2017, 42(7): 1949-1961.
39. Pellock JM, Hrachovy R, Shinnar S, et al. Infantile spasms: a U.S. consensus report. Epilepsia, 2010, 51(10): 2175-2189.
40. Galvan CD, Hrachovy RA, Smith KL, et al. Blockade of neuronal activity during hippocampal development produces a chronic focal epilepsy in the rat. J Neurosci, 2000, 20(8): 2904-2916.
41. Lee CL, Frost JD Jr, Swann JW, et al. A new animal model of infantile spasms with unprovoked persistent seizures. Epilepsia, 2008, 49(2): 298-307.
42. Frost JD Jr, Le JT, Lee CL, et al. Vigabatrin therapy implicates neocortical high frequency oscillations in an animal model of infantile spasms. Neurobiol Dis, 2015, 82: 1-11.

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