Toxicological evaluation of convulsant and anticonvulsant drugs in human induced pluripotent stem cell-derived cortical neuronal networks using an MEA system.
Toxicological evaluation of convulsant and anticonvulsant drugs in human induced pluripotent stem cell-derived cortical neuronal networks using an MEA system.
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DOI：
10.1038/s41598-018-28835-7
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发表时间：
2018-07-10
影响因子：
4.6
通讯作者：
Suzuki I
中科院分区：
文献类型：
--
作者：
Odawara A;Matsuda N;Ishibashi Y;Yokoi R;Suzuki I
利用人诱导多能干细胞（hiPSC）来源的神经元进行功能评价试验，可以预测新药的惊厥毒性和抗癫痫药物的神经学作用。然而，反应性的差异取决于惊厥类型和抗癫痫药物，以及能够比较体外反应和体内反应的评价指标尚不清楚。采用多电极阵列（MEAs）观察了不同作用机制的戊四唑（PTZ）和4-氨基吡啶（4-AP）诱导的癫痫样活动同步爆发模式的差异；我们还观察到100µM的抗癫痫药物苯妥英抑制了PTZ诱导的癫痫样活性，但增加了4-AP诱导的癫痫样活性。为了比较体外结果和体内惊厥反应，进行了低于250 Hz的频率分析，不包括尖峰成分。在体外星形胶质细胞共培养hipsc来源的神经元中，观察到高γ波和β波成分在体内的惊厥放电增强。对星形胶质细胞共培养的hipsc来源神经元的MEA测量和我们的分析方法，包括频率分析，似乎可以有效预测惊厥的毒性、副作用及其作用机制，以及体内引起的惊厥的比较。
Functional evaluation assays using human induced pluripotent stem cell (hiPSC)-derived neurons can predict the convulsion toxicity of new drugs and the neurological effects of antiepileptic drugs. However, differences in responsiveness depending on convulsant type and antiepileptic drugs, and an evaluation index capable of comparing in vitro responses with in vivo responses are not well known. We observed the difference in synchronized burst patterns in the epileptiform activities induced by pentylentetrazole (PTZ) and 4-aminopryridine (4-AP) with different action mechanisms using multi-electrode arrays (MEAs); we also observed that 100 µM of the antiepileptic drug phenytoin suppressed epileptiform activities induced by PTZ, but increased those induced by 4-AP. To compare in vitro results with in vivo convulsive responses, frequency analysis of below 250 Hz, excluding the spike component, was performed. The in vivo convulsive firing enhancement of the high γ wave and β wave component were observed remarkably in in vitro hiPSC-derived neurons with astrocytes in co-culture. MEA measurement of hiPSC-derived neurons in co-culture with astrocytes and our analysis methods, including frequency analysis, appear effective for predicting convulsion toxicity, side effects, and their mechanism of action as well as the comparison of convulsions induced in vivo.
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DOI：
10.4103/0976-0105.168054
发表时间：
2015-09
期刊：
Journal of basic and clinical pharmacy
影响因子：
--
作者：
Indu TH;Basutkar RS
通讯作者：
Basutkar RS
影响因子：
120.1
作者：
Cook, David;Brown, Dearg;Pangalos, Menelas N.
通讯作者：
Pangalos, Menelas N.
影响因子：
3.7
作者：
Iimura Y;Sugano H;Nakajima M;Higo T;Suzuki H;Nakanishi H;Arai H
通讯作者：
Arai H
影响因子：
4.5
作者：
Arechiga-Figueroa, Ivan A.;Rodriguez-Martinez, Martin;Sanchez-Chapula, Jose A.
通讯作者：
Sanchez-Chapula, Jose A.
影响因子：
4.4
作者：
Galván, E;Sitges, M
通讯作者：
Sitges, M