Acute toxicity screening of novel AChE inhibitors using neuronal networks on microelectrode arrays
Acute toxicity screening of novel AChE inhibitors using neuronal networks on microelectrode arrays
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DOI：
10.1016/s0161-813x(00)00014-0
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发表时间：
2001-02-01
期刊：
影响因子：
3.4
通讯作者：
Gross, GW
中科院分区：
文献类型：
--
作者：
Keefer, EW;Norton, SJ;Gross, GW
在具有64个记录位点的衬底集成电极阵列上，从胚胎小鼠额叶皮层培养出自发活动的神经网络，用于评估一系列具有抗胆碱酯酶活性的七种对称双功能烷基烯连接双硫代碳酸化合物的急性神经生物学和毒性作用。在没有细胞毒性的情况下，急性功能性神经毒性被定义为自发活动的完全崩溃。所有化合物均为AChE的混合抑制剂，其K-i值在10(-7)-10(-6)M范围内。神经网络分析显示，每种化合物的重复性都很高，但令人惊讶的是，这些密切相关的化合物之间的效果却各不相同。7种化合物中的6种在10-350 muM的浓度下产生了网络活性的变化。其中三种化合物是兴奋性的，两种是双相的（兴奋性较低）。两种抑制性化合物产生了不可逆的活性抑制，皮层培养物对eserine的反应与测试化合物产生的效果进行了比较，七种化合物中只有一种与eserine的特征密切匹配。反应模式的匹配允许新药的分类，根据他们的反应相似性表征良好的药物。自发活动的神经网络反映了多种神经递质的相互作用。和受体系统，并且可以揭示由于继发性结合而产生的意想不到的副作用。通过更快速地识别生理组织反应，利用这种网络有望提高研究效率。(C) 2001爱思唯尔科学公司版权所有。
Spontaneously active neuronal networks grown from embryonic murine frontal cortex on substrate integrated electrode arrays with 64 recording sites were used to assess acute neurobiological and toxic effects of a series of seven symmetrical, bifunctional alkylene-linked bis-thiocarbonate compounds designed to possess anticholinesterase activity. Acute functional neurotoxicity in the absence of cytotoxicity was defined as total collapse of spontaneous activity. All of the compounds were characterized as mixed inhibitors of AChE, with K-i's in the 10(-7)-10(-6) M range. The neuronal network assays revealed high repeatability for each compound, but surprisingly diverse effects among these closely related compounds. Six of the seven compounds produced changes in network activity at concentrations of 10-350 muM. Three of the compounds were excitatory, two were biphasic (excitatory at lower. concentrations, inhibitory at higher), ai rd one was solely inhibitory Two Of the inhibitory compounds produced irreversible inhibition of activity Responses of cortical cultures to eserine were compared to the effects produced by the test compounds, with only one of seven providing a close match to the eserine profile. Matching of response patterns allows the classification of new drugs according to their response similarity to well-characterized agents. Spontaneously active neuronal networks reflect the interactions of multiple neurotransmitter. and receptor systems, and can reveal unexpected side effects due to secondary binding. Utilizing such networks holds the promise of greater research efficiency through a more rapid recognition of physiological tissue responses. (C) 2001 Elsevier Science Inc. All rights reserved.