Establishing a model for assessing DNA damage in murine brain cells as a molecular marker of chemotherapy-associated cognitive impairment.
Establishing a model for assessing DNA damage in murine brain cells as a molecular marker of chemotherapy-associated cognitive impairment.
复制标题
建立评估小鼠脑细胞 DNA 损伤的模型，作为化疗相关认知障碍的分子标记。
DOI：
10.1016/j.lfs.2013.03.013
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发表时间：
2013
期刊：
影响因子：
6.1
通讯作者：
Walker,Ellen
中科院分区：
文献类型：
--
作者：
Krynetskiy,Evgeny;Krynetskaia,Natalia;Rihawi,Diana;Wieczerzak,Katarzyna;Ciummo,Victoria;Walker,Ellen
化疗相关的认知障碍通常伴随着癌症化疗。我们探索了用5-氟尿嘧啶（5 FU）（一种抗肿瘤剂）处理的小鼠的脑细胞中化疗诱导的DNA损伤，以将DNA损伤的程度与化疗诱导的学习和记忆缺陷的自动成形操作小鼠模型中的行为功能相关联（Foley等人，2008).主要方法雄性Swiss-Webster小鼠在0、12和24 h注射生理盐水或75 mg/kg 5 FU一次，每24 h称重一次。在最后一次注射后24小时，在为期两天的获取和保持食物强化的新反应任务中测试小鼠。通过单细胞凝胶电泳分析小鼠脑细胞中是否存在单链和双链DNA断裂（彗星试验）。关键发现我们检测到显著差异（p< 0.0001）对于所有DNA损伤特征（DNA“彗星”尾形状、迁移模式、尾矩和橄榄矩）：尾长：119对153;尾部力矩- 101 vs. 136;橄榄力矩- 60 vs. 82。我们发现反应率的增加（r= 0.52，p < 0.05）和错误率的增加（r= 0.51，p < 0.05）与第1天的DNA损伤呈正相关。对于所有15只小鼠（生理盐水处理和5 FU处理小鼠），我们发现DNA损伤与体重呈负相关（r=-0.75，p < 0.02）。显著性我们的结果表明，化疗诱导的DNA损伤改变了脑细胞的生理状态，并可能为癌症化疗后认知障碍的机制提供见解。
AimsChemotherapy-associated cognitive impairment often follows cancer chemotherapy. We explored chemotherapy-induced DNA damage in the brain cells of mice treated with 5-fluorouracil (5FU), an antineoplastic agent, to correlate the extent of DNA damage to behavioral functioning in an autoshaping-operant mouse model of chemotherapy-induced learning and memory deficits (Foley et al., 2008).Main methodsMale, Swiss-Webster mice were injected once with saline or 75 mg/kg 5FU at 0, 12, and 24 h and weighed every 24 h. Twenty-four h after the last injection, the mice were tested in a two-day acquisition and the retention of a novel response task for food reinforcement. Murine brain cells were analyzed for the presence of single- and double-strand DNA breaks by the single cell gel electrophoresis assay (the Comet assay).Key findingsWe detected significant differences (p< 0.0001) for all DNA damage characteristics (DNA “comet” tail shape, migration pattern, tail moment and olive moments) between control mice cohort and 5FU-treated mice cohort: tail length – 119 vs. 153; tail moment – 101 vs. 136; olive moment – 60 vs. 82, correspondingly. We found a positive correlation between increased response rates (r= 0.52,p< 0.05) and increased rate of errors (r= 0.51,p< 0.05), and DNA damage on day 1. For all 15 mice (saline-treated and 5FU-treated mice), we found negative correlations between DNA damage and weight (r= − 0.75,p< 0.02).SignificanceOur results indicate that chemotherapy-induced DNA damage changes the physiological status of the brain cells and may provide insights to the mechanisms for cognitive impairment after cancer chemotherapy.