| 屈哲,吕建军,张硕,耿兴超,李波,赵德明.SD大鼠神经干细胞评价药物神经毒性模型研究[J].中国药事,2018,32(8):1079-1087 |
| SD大鼠神经干细胞评价药物神经毒性模型研究 |
| On Evaluation of Drug Neurotoxicity by Using SD Rat Neural Stem Cells |
| 投稿时间：2018-05-30 |
| DOI：10.16153/j.1002-7777.2018.08.012 |
| 中文关键词: 神经毒性 神经干细胞 神经球聚集 增殖毒性 体外替代方法 |
| 英文关键词: neurotoxicity neural stem cells neurosphere aggregation proliferation toxicity in vitro alternative method |
| 基金项目:十三五重大新药创制专项课题"创新药物非临床安全性评价研究关键技术"（编号2018ZX09201017） |
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| 中文摘要: |
| 目的：应用SD大鼠神经干细胞评价药物的神经毒性，为新药早期筛选和临床前安全性评价提供体外替代方法。方法：体外培养SD大鼠神经干细胞，传代后得到稳定的第二代神经球。以已知具有神经毒性的长春新碱、顺铂、瑞芬太尼、丙泊酚注射液、丙戊酸钠、苯妥英钠、丙烯酰胺、乙醇、氧化铁纳米粒子作为神经毒性阳性物质，以培养基作为神经毒性空白对照品；以没有神经毒性且具有促进神经细胞生长的神经生长因子作为检测模型的敏感性；以验证SD大鼠神经干细胞模型对神经毒性药物的检出能力。结果：长春新碱、顺铂、丙泊酚注射液、苯妥英钠、丙烯酰胺、氧化铁纳米粒子可引起全部或部分神经球解离破碎，神经干细胞坏死。顺铂、丙戊酸钠和苯妥英钠可见显著性的抑制神经球聚集。长春新碱、顺铂、瑞芬太尼、氧化铁纳米粒子、丙泊酚注射液、丙戊酸钠、苯妥英钠、丙烯酰胺、乙醇均表现剂量相关性的神经干细胞增殖毒性作用。神经生长因子可见促进神经球聚集及神经干细胞增殖。结论：本文以SD大鼠神经干细胞模型，以神经干细胞体外生长发育指标，验证了已知神经毒性抗肿瘤药物、麻醉剂、抗癫痫药物等的神经毒性特征。评价结果与这些药物已知的神经毒性作用特点一致，该评价方法可作为药物神经毒性临床前安全性评价研究的体外替代试验。 |
| 英文摘要: |
| Objective:To evaluate drug neurotoxicity by using SD rat neural stem cell and to provide an in vitro alternative method for the early screening and preclinical safety evaluation of new drugs. Methods:SD rat neural stem cells were cultured in vitro and the stable second generation of neurospheres was obtained by subculture of cells. Vincristine, cisplatin, remifentanil, propofol, sodium valproate, phenytoin, acrylamide, ethanol, and ironoxide nanoparticles with known neurotoxicity were used as positive substances. Cell medium was used as a neurotoxicity negative control. Nerve growth factor (NGF) that is non-neurotoxic but can promote the growth of neural stem cell was used to detect the sensitivity of the model and to verify the capacity of the SD rat neural stem cell model to detect the neurotoxicity in the drug. Results:Vincristine, cisplatin, propofol, phenytoin, acrylamide and iron-oxide nanoparticles could cause disintegration of all or part of neurospheres, indicating necrosis of neural stem cells. Cisplatin, sodium valproate and phenytoin had a significant inhibitory effect on the neurosphere aggregation. Vincristine, cisplatin, remifentanil, iron-oxide nanoparticles, propofol, sodium valproate, phenytoin, acrylamide and ethanol showed dose-related proliferation and cell toxicity effect of neural stem cells. NGF is found to promote neurosphere aggregation and the proliferation of neural stem cells. Conclusion:In this study, the neurotoxicity of several antitumor drugs, anesthetics, and antiepileptic drugs with neurotoxicity was verified with SD rat neural stem cells as model and growth and development of neural stem cells in vitro as indicators. The results were consistent with the neurotoxicity characteristics of these drugs, indicating the method can be used as an alternative method in vitro for preclinical safety evaluation of drug neurotoxicity. |
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