癲癇細胞模型的建立及應用_Journal of Epilepsy

Authors：

李碩 ¹ ,  薛國芳 ²

1. ;
2. ;

Corresponding?author：

薛國芳, Email: xueguofangty@163.com

Keywords：

癲癇; 細胞模型; 神經膠質細胞; 神經元

DOI：

10.7507/2096-0247.202204007

Video：

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癲癇是神經系統的第二大疾病，癲癇模型是癲癇相關研究的重要工具，其中細胞模型具有造模簡單、干擾因素少、結果直觀等優點，且從單細胞培養向多細胞共培養發展，以在維持其上述優點的同時更大程度上地還原其在體環境，也滿足了不同的實驗需求。在抗癲癇發作藥物、癲癇病理生理學以及生物標志物等研究中有廣泛的應用。癲癇細胞模型可初步篩選可能抗癲癇發作的藥物，而已被證實的抗癲癇發作藥物也可進一步探索其作用機制。癲癇病理生理學機制復雜，在細胞模型中可針對某種機制進行獨立研究，排除其他因素的干擾。生物標志物對于疾病臨床有極大意義，細胞模型可對癲癇的生物標志物進行初步篩選和驗證。本文概述了常用癲癇細胞模型的細胞系、培養體系、誘導方法及應用，可作為選擇癲癇模型時的參考依據。

Citation： 李碩, 薛國芳. 癲癇細胞模型的建立及應用. 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.	顧友余, 陳文杰, 秦炯. 癲癇研究中常用的體外模型及嚙齒類動物模型. 生理科學進展, 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.	楊盛, 何然, 張飛燕, 等. 細胞共培養模型及其在中樞神經系統疾病研究中的應用. 藥學學報, 2016, 51(3): 338-346.
8.	郭雅靜, 薛國芳. 小膠質細胞和星形膠質細胞及其相互作用對癲癇發生影響的研究進展. 癲癇雜志, 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.	體外共培養癲癇細胞模型中沉默突觸的轉化及AMPA受體亞基的變化. 重慶醫科大學, 碩士學位論文, 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. 匹魯卡品誘導神經細胞鐵死亡的發生及其機制研究. 河北師范大學, 碩士學位論文, 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, Le?kiewicz 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.	獨盟盟, 袁治軒, 李佳佳, 等. 星形膠質細胞膜電位門控鈣離子通道調控神經元癲癇放電. 動力學與控制學報, 2020, 18(1): 49-55.
31.	Baruah J, Vasudevan A, K?hling R. Vascular integrity and signaling determining brain development, network excitability, and epileptogenesis. Frontiers in Physiology, 2019, 10: 1583.
32.	張海妮, 張瑞麗, 王千秋. 體外血腦屏障模型的研究及其應用. 國際神經病學神經外科學雜志, 2021, 48(3): 303-306.
33.	扶宇, 李經綸, 王本瀚, 等. 癲癇生物標志物的研究進展. 中國臨床神經外科雜志, 2018, 23(05): 376-378.
34.	Pitk?nen 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. 顧友余, 陳文杰, 秦炯. 癲癇研究中常用的體外模型及嚙齒類動物模型. 生理科學進展, 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. 楊盛, 何然, 張飛燕, 等. 細胞共培養模型及其在中樞神經系統疾病研究中的應用. 藥學學報, 2016, 51(3): 338-346.
8. 郭雅靜, 薛國芳. 小膠質細胞和星形膠質細胞及其相互作用對癲癇發生影響的研究進展. 癲癇雜志, 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. 體外共培養癲癇細胞模型中沉默突觸的轉化及AMPA受體亞基的變化. 重慶醫科大學, 碩士學位論文, 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. 匹魯卡品誘導神經細胞鐵死亡的發生及其機制研究. 河北師范大學, 碩士學位論文, 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, Le?kiewicz 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. 獨盟盟, 袁治軒, 李佳佳, 等. 星形膠質細胞膜電位門控鈣離子通道調控神經元癲癇放電. 動力學與控制學報, 2020, 18(1): 49-55.
31. Baruah J, Vasudevan A, K?hling R. Vascular integrity and signaling determining brain development, network excitability, and epileptogenesis. Frontiers in Physiology, 2019, 10: 1583.
32. 張海妮, 張瑞麗, 王千秋. 體外血腦屏障模型的研究及其應用. 國際神經病學神經外科學雜志, 2021, 48(3): 303-306.
33. 扶宇, 李經綸, 王本瀚, 等. 癲癇生物標志物的研究進展. 中國臨床神經外科雜志, 2018, 23(05): 376-378.
34. Pitk?nen 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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癲癇細胞模型的建立及應用

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