癫痫细胞模型的建立及应用_Journal of Epilepsy

Authors：

李硕 ¹ ,  薛国芳 ²

1. ;
2. ;

Corresponding author：

薛国芳, Email: xueguofangty@163.com

Keywords：

癫痫; 细胞模型; 神经胶质细胞; 神经元

DOI：

10.7507/2096-0247.202204007

Video：

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癫痫是神经系统的第二大疾病，癫痫模型是癫痫相关研究的重要工具，其中细胞模型具有造模简单、干扰因素少、结果直观等优点，且从单细胞培养向多细胞共培养发展，以在维持其上述优点的同时更大程度上地还原其在体环境，也满足了不同的实验需求。在抗癫痫发作药物、癫痫病理生理学以及生物标志物等研究中有广泛的应用。癫痫细胞模型可初步筛选可能抗癫痫发作的药物，而已被证实的抗癫痫发作药物也可进一步探索其作用机制。癫痫病理生理学机制复杂，在细胞模型中可针对某种机制进行独立研究，排除其他因素的干扰。生物标志物对于疾病临床有极大意义，细胞模型可对癫痫的生物标志物进行初步筛选和验证。本文概述了常用癫痫细胞模型的细胞系、培养体系、诱导方法及应用，可作为选择癫痫模型时的参考依据。

Citation： 李硕, 薛国芳. 癫痫细胞模型的建立及应用. Journal of Epilepsy, 2022, 8(5): 448-452. doi: 10.7507/2096-0247.202204007 Copy

1.	Stern JM, Sankar R, Sperling M. Medication-resistant epilepsy: diagnosis and treatment. Cambridge University Press, 2020.
2.	顾友余, 陈文杰, 秦炯. 癫痫研究中常用的体外模型及啮齿类动物模型. 生理科学进展, 2019, 50(5): 375-380.
3.	Di Nunzio M, Di Sapia R, Sorrentino D, et al. Microglia proliferation plays distinct roles in acquired epilepsy depending on disease stages. Epilepsia, 2021, 62(8): 1931-1945.
4.	Aronica E, Bauer S, Bozzi Y, et al. Neuroinflammatory targets and treatments for epilepsy validated in experimental models . Epilepsia, 2017, 58(Suppl 3): 27-38.
5.	Robel S, Buckingham SC, Boni JL, et al. Reactive astrogliosis causes the development of spontaneous seizures. The Journal of Neuroscience, 2015, 35(8): 3330-3345.
6.	Zheng YF, Zhou X, Chang D, et al. A novel tri-culture model for neuroinflammation. Journal of neurochemistry, 2021, 156(2): 249-261.
7.	杨盛, 何然, 张飞燕, 等. 细胞共培养模型及其在中枢神经系统疾病研究中的应用. 药学学报, 2016, 51(3): 338-346.
8.	郭雅静, 薛国芳. 小胶质细胞和星形胶质细胞及其相互作用对癫痫发生影响的研究进展. 癫痫杂志, 2021, 7(3): 252-256.
9.	Faustmann TJ, Corvace F, Faustmann PM, et al. Effects of lamotrigine and topiramate on glial properties in an astrocyte-microglia co-culture model of inflammation. The International Journal of Neuropsychopharmacology, 2022, 25(3): 185-196.
10.	Deshpande LS, Delorenzo RJ, Churn SB, et al. Neuronal-specific inhibition of endoplasmic reticulum mg(2+)/ca(2+) atpase ca(2+) uptake in a mixed primary hippocampal culture model of status epilepticus. Brain Sciences, 2020, 10(7): 438.
11.	体外共培养癫痫细胞模型中沉默突触的转化及AMPA受体亚基的变化. 重庆医科大学, 硕士学位论文, 2014: 1-58.
12.	Yang MT, Lin YC, Ho WH, et al. Everolimus is better than rapamycin in attenuating neuroinflammation in kainic acid-induced seizures. Journal of Neuroinflammation, 2017, 14(1): 15.
13.	高茉菡. 匹鲁卡品诱导神经细胞铁死亡的发生及其机制研究. 河北师范大学, 硕士学位论文, 2021: 1-69.
14.	Delorenzo RJ, Sun DA, Blair RE, et al. An in vitro model of stroke-induced epilepsy: Elucidation of the roles of glutamate and calcium in the induction and maintenance of stroke-induced epileptogenesis. International Review of Neurobiology, 2007, 81: 59-84.
15.	Zhu X, Chen Y, Du Y, et al. Astragaloside iv attenuates penicillin-induced epilepsy via inhibiting activation of the mapk signaling pathway. Molecular Medicine Reports, 2018, 17(1): 643-647.
16.	Ostendorf AP, Wong M. Mtor inhibition in epilepsy: Rationale and clinical perspectives. CNS Drugs, 2015, 29(2): 91-99.
17.	Kaur T, Manchanda S, Saini V, et al. Efficacy of anti-epileptic drugs in the treatment of tumor and its associated epilepsy: An in vitro perspective. Annals of Neurosciences, 2016, 23(1): 33-43.
18.	Lyseng-Williamson KA. Levetiracetam: a review of its use in epilepsy. Drugs, 2011, 71(4): 489-514.
19.	Haghikia A, Ladage K, Hinkerohe D, et al. Implications of antiinflammatory properties of the anticonvulsant drug levetiracetam in astrocytes. Journal of Neuroscience Research, 2008, 86(8): 1781-1788.
20.	Stienen MN, Haghikia A, Dambach H, et al. Anti-inflammatory effects of the anticonvulsant drug levetiracetam on electrophysiological properties of astroglia are mediated via tgfβ1 regulation. British Journal of Pharmacology, 2011, 162(2): 491-507.
21.	Itoh K, Ishihara Y, Komori R, et al. Levetiracetam treatment influences blood-brain barrier failure associated with angiogenesis and inflammatory responses in the acute phase of epileptogenesis in post-status epilepticus mice. Brain Research, 2016, 1652: 1-13.
22.	Itoh K, Taniguchi R, Matsuo T, et al. Suppressive effects of levetiracetam on neuroinflammation and phagocytic microglia: a comparative study of levetiracetam, valproate and carbamazepine. Neuroscience Letters, 2019, 708: 134363.
23.	Niidome K, Taniguchi R, Yamazaki T, et al. Fosl1 is a novel target of levetiracetam for suppressing the microglial inflammatory reaction . Int J Mol Sci, 2021, 22(20):.
24.	Zhang XM, Zhu J. Kainic acid-induced neurotoxicity: targeting glial responses and glia-derived cytokines. Current Neuropharmacology, 2011, 9(2): 388-398.
25.	Terrone G, Salamone A, Vezzani A. Inflammation and epilepsy: Preclinical findings and potential clinical translation. Current Pharmaceutical Design, 2017, 23(37): 5569-5576.
26.	Tylek K, Trojan E, Leśkiewicz M, et al. Time-dependent protective and pro-resolving effects of fpr2 agonists on lipopolysaccharide-exposed microglia cells involve inhibition of nf-κb and mapks pathways. Cells, 2021, 10(9): 2373.
27.	Liu Q, Zhang Y, Liu S, et al. Cathepsin c promotes microglia m1 polarization and aggravates neuroinflammation via activation of ca(2+)-dependent pkc/p38mapk/nf-κb pathway. Journal of Neuroinflammation, 2019, 16(1): 10.
28.	Ryu KY, Lee HJ, Woo H, et al. Dasatinib regulates lps-induced microglial and astrocytic neuroinflammatory responses by inhibiting akt/stat3 signaling. Journal of Neuroinflammation, 2019, 16(1): 190.
29.	Shen K, Mao Q, Yin X, et al. Nlrp3 inflammasome activation leads to epileptic neuronal apoptosis. Current Neurovascular Research, 2018, 15(4): 276-281.
30.	独盟盟, 袁治轩, 李佳佳, 等. 星形胶质细胞膜电位门控钙离子通道调控神经元癫痫放电. 动力学与控制学报, 2020, 18(1): 49-55.
31.	Baruah J, Vasudevan A, Köhling R. Vascular integrity and signaling determining brain development, network excitability, and epileptogenesis. Frontiers in Physiology, 2019, 10: 1583.
32.	张海妮, 张瑞丽, 王千秋. 体外血脑屏障模型的研究及其应用. 国际神经病学神经外科学杂志, 2021, 48(3): 303-306.
33.	扶宇, 李经纶, 王本瀚, 等. 癫痫生物标志物的研究进展. 中国临床神经外科杂志, 2018, 23(05): 376-378.
34.	Pitkänen A, Ekolle Ndode-Ekane X, Lapinlampi N, et al. Epilepsy biomarkers - toward etiology and pathology specificity. Neurobiology of Disease, 2019, 123: 42-58.
35.	Iyer A, Zurolo E, Prabowo A, et al. Microrna-146a: a key regulator of astrocyte-mediated inflammatory response. PloS One, 2012, 7(9): e44789.
36.	Van Scheppingen J, Mills JD, Zimmer TS, et al. Mir147b: a novel key regulator of interleukin 1 beta-mediated inflammation in human astrocytes. Glia, 2018, 66(5): 1082-1097.
37.	Korotkov A, Broekaart DWM, Banchaewa L, et al. Microrna-132 is overexpressed in glia in temporal lobe epilepsy and reduces the expression of pro-epileptogenic factors in human cultured astrocytes. Glia, 2020, 68(1): 60-75.
38.	Wan Y, Yang ZQ. Lncrna neat1 affects inflammatory response by targeting mir-129-5p and regulating notch signaling pathway in epilepsy. Cell Cycle (Georgetown, Tex), 2020, 19(4): 419-431.
39.	Zaben M, Haan N, Sharouf F, et al. Il-1β and hmgb1 are anti-neurogenic to endogenous neural stem cells in the sclerotic epileptic human hippocampus. Journal of Neuroinflammation, 2021, 18(1): 218.
40.	Walker LE, Sills GJ, Jorgensen A, et al. High-mobility group box 1 as a predictive biomarker for drug-resistant epilepsy: a proof-of-concept study. Epilepsia, 2022, 63(1): e1-e6.

1. Stern JM, Sankar R, Sperling M. Medication-resistant epilepsy: diagnosis and treatment. Cambridge University Press, 2020.
2. 顾友余, 陈文杰, 秦炯. 癫痫研究中常用的体外模型及啮齿类动物模型. 生理科学进展, 2019, 50(5): 375-380.
3. Di Nunzio M, Di Sapia R, Sorrentino D, et al. Microglia proliferation plays distinct roles in acquired epilepsy depending on disease stages. Epilepsia, 2021, 62(8): 1931-1945.
4. Aronica E, Bauer S, Bozzi Y, et al. Neuroinflammatory targets and treatments for epilepsy validated in experimental models . Epilepsia, 2017, 58(Suppl 3): 27-38.
5. Robel S, Buckingham SC, Boni JL, et al. Reactive astrogliosis causes the development of spontaneous seizures. The Journal of Neuroscience, 2015, 35(8): 3330-3345.
6. Zheng YF, Zhou X, Chang D, et al. A novel tri-culture model for neuroinflammation. Journal of neurochemistry, 2021, 156(2): 249-261.
7. 杨盛, 何然, 张飞燕, 等. 细胞共培养模型及其在中枢神经系统疾病研究中的应用. 药学学报, 2016, 51(3): 338-346.
8. 郭雅静, 薛国芳. 小胶质细胞和星形胶质细胞及其相互作用对癫痫发生影响的研究进展. 癫痫杂志, 2021, 7(3): 252-256.
9. Faustmann TJ, Corvace F, Faustmann PM, et al. Effects of lamotrigine and topiramate on glial properties in an astrocyte-microglia co-culture model of inflammation. The International Journal of Neuropsychopharmacology, 2022, 25(3): 185-196.
10. Deshpande LS, Delorenzo RJ, Churn SB, et al. Neuronal-specific inhibition of endoplasmic reticulum mg(2+)/ca(2+) atpase ca(2+) uptake in a mixed primary hippocampal culture model of status epilepticus. Brain Sciences, 2020, 10(7): 438.
11. 体外共培养癫痫细胞模型中沉默突触的转化及AMPA受体亚基的变化. 重庆医科大学, 硕士学位论文, 2014: 1-58.
12. Yang MT, Lin YC, Ho WH, et al. Everolimus is better than rapamycin in attenuating neuroinflammation in kainic acid-induced seizures. Journal of Neuroinflammation, 2017, 14(1): 15.
13. 高茉菡. 匹鲁卡品诱导神经细胞铁死亡的发生及其机制研究. 河北师范大学, 硕士学位论文, 2021: 1-69.
14. Delorenzo RJ, Sun DA, Blair RE, et al. An in vitro model of stroke-induced epilepsy: Elucidation of the roles of glutamate and calcium in the induction and maintenance of stroke-induced epileptogenesis. International Review of Neurobiology, 2007, 81: 59-84.
15. Zhu X, Chen Y, Du Y, et al. Astragaloside iv attenuates penicillin-induced epilepsy via inhibiting activation of the mapk signaling pathway. Molecular Medicine Reports, 2018, 17(1): 643-647.
16. Ostendorf AP, Wong M. Mtor inhibition in epilepsy: Rationale and clinical perspectives. CNS Drugs, 2015, 29(2): 91-99.
17. Kaur T, Manchanda S, Saini V, et al. Efficacy of anti-epileptic drugs in the treatment of tumor and its associated epilepsy: An in vitro perspective. Annals of Neurosciences, 2016, 23(1): 33-43.
18. Lyseng-Williamson KA. Levetiracetam: a review of its use in epilepsy. Drugs, 2011, 71(4): 489-514.
19. Haghikia A, Ladage K, Hinkerohe D, et al. Implications of antiinflammatory properties of the anticonvulsant drug levetiracetam in astrocytes. Journal of Neuroscience Research, 2008, 86(8): 1781-1788.
20. Stienen MN, Haghikia A, Dambach H, et al. Anti-inflammatory effects of the anticonvulsant drug levetiracetam on electrophysiological properties of astroglia are mediated via tgfβ1 regulation. British Journal of Pharmacology, 2011, 162(2): 491-507.
21. Itoh K, Ishihara Y, Komori R, et al. Levetiracetam treatment influences blood-brain barrier failure associated with angiogenesis and inflammatory responses in the acute phase of epileptogenesis in post-status epilepticus mice. Brain Research, 2016, 1652: 1-13.
22. Itoh K, Taniguchi R, Matsuo T, et al. Suppressive effects of levetiracetam on neuroinflammation and phagocytic microglia: a comparative study of levetiracetam, valproate and carbamazepine. Neuroscience Letters, 2019, 708: 134363.
23. Niidome K, Taniguchi R, Yamazaki T, et al. Fosl1 is a novel target of levetiracetam for suppressing the microglial inflammatory reaction . Int J Mol Sci, 2021, 22(20):.
24. Zhang XM, Zhu J. Kainic acid-induced neurotoxicity: targeting glial responses and glia-derived cytokines. Current Neuropharmacology, 2011, 9(2): 388-398.
25. Terrone G, Salamone A, Vezzani A. Inflammation and epilepsy: Preclinical findings and potential clinical translation. Current Pharmaceutical Design, 2017, 23(37): 5569-5576.
26. Tylek K, Trojan E, Leśkiewicz M, et al. Time-dependent protective and pro-resolving effects of fpr2 agonists on lipopolysaccharide-exposed microglia cells involve inhibition of nf-κb and mapks pathways. Cells, 2021, 10(9): 2373.
27. Liu Q, Zhang Y, Liu S, et al. Cathepsin c promotes microglia m1 polarization and aggravates neuroinflammation via activation of ca(2+)-dependent pkc/p38mapk/nf-κb pathway. Journal of Neuroinflammation, 2019, 16(1): 10.
28. Ryu KY, Lee HJ, Woo H, et al. Dasatinib regulates lps-induced microglial and astrocytic neuroinflammatory responses by inhibiting akt/stat3 signaling. Journal of Neuroinflammation, 2019, 16(1): 190.
29. Shen K, Mao Q, Yin X, et al. Nlrp3 inflammasome activation leads to epileptic neuronal apoptosis. Current Neurovascular Research, 2018, 15(4): 276-281.
30. 独盟盟, 袁治轩, 李佳佳, 等. 星形胶质细胞膜电位门控钙离子通道调控神经元癫痫放电. 动力学与控制学报, 2020, 18(1): 49-55.
31. Baruah J, Vasudevan A, Köhling R. Vascular integrity and signaling determining brain development, network excitability, and epileptogenesis. Frontiers in Physiology, 2019, 10: 1583.
32. 张海妮, 张瑞丽, 王千秋. 体外血脑屏障模型的研究及其应用. 国际神经病学神经外科学杂志, 2021, 48(3): 303-306.
33. 扶宇, 李经纶, 王本瀚, 等. 癫痫生物标志物的研究进展. 中国临床神经外科杂志, 2018, 23(05): 376-378.
34. Pitkänen A, Ekolle Ndode-Ekane X, Lapinlampi N, et al. Epilepsy biomarkers - toward etiology and pathology specificity. Neurobiology of Disease, 2019, 123: 42-58.
35. Iyer A, Zurolo E, Prabowo A, et al. Microrna-146a: a key regulator of astrocyte-mediated inflammatory response. PloS One, 2012, 7(9): e44789.
36. Van Scheppingen J, Mills JD, Zimmer TS, et al. Mir147b: a novel key regulator of interleukin 1 beta-mediated inflammation in human astrocytes. Glia, 2018, 66(5): 1082-1097.
37. Korotkov A, Broekaart DWM, Banchaewa L, et al. Microrna-132 is overexpressed in glia in temporal lobe epilepsy and reduces the expression of pro-epileptogenic factors in human cultured astrocytes. Glia, 2020, 68(1): 60-75.
38. Wan Y, Yang ZQ. Lncrna neat1 affects inflammatory response by targeting mir-129-5p and regulating notch signaling pathway in epilepsy. Cell Cycle (Georgetown, Tex), 2020, 19(4): 419-431.
39. Zaben M, Haan N, Sharouf F, et al. Il-1β and hmgb1 are anti-neurogenic to endogenous neural stem cells in the sclerotic epileptic human hippocampus. Journal of Neuroinflammation, 2021, 18(1): 218.
40. Walker LE, Sills GJ, Jorgensen A, et al. High-mobility group box 1 as a predictive biomarker for drug-resistant epilepsy: a proof-of-concept study. Epilepsia, 2022, 63(1): e1-e6.

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