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Establishing a model for assessing DNA damage in murine brain cells as a molecular marker of chemotherapy-associated cognitive impairment

机译：建立评估小鼠脑细胞DNA损伤的模型作为化学疗法相关认知障碍的分子标记

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Aims Chemotherapy-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 methods Male, 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 findings We 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). Significance Our 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.
机译：目的与化疗相关的认知障碍通常在癌症化疗之后进行。我们探索了用5-氟尿嘧啶（5FU）（一种抗肿瘤药）治疗的小鼠脑细胞中化学诱导的DNA损伤，以将DNA损伤的程度与化学诱导的学习和记忆的自动塑形小鼠模型中的行为功能相关联赤字（Foley et al。，2008）。主要方法在0、12和24小时给雄性Swiss-Webster小鼠注射盐水或75 mg / kg 5FU一次，每24小时称重一次。最后一次注射后二十四小时，对小鼠进行了为期两天的采集测试，并保留了新的强化食物反应任务。通过单细胞凝胶电泳分析（彗星分析）分析鼠脑细胞中单链和双链DNA断裂的存在。关键发现我们在对照组小鼠和5FU治疗组的所有DNA损伤特征（DNA“彗星”尾巴形状，迁移模式，尾巴矩和橄榄矩）上发现了显着差异（p <0.0001）：尾巴长-119 vs. 5FU。 153;尾矩-101对136;橄榄时刻-分别为60对82。我们发现在第1天，应答率增加（r = 0.52，p <0.05）和错误率增加（r = 0.51，p <0.05）与DNA损伤之间呈正相关。对于所有15只小鼠（盐水处理和5FU）治疗小鼠），我们发现DNA损伤与体重之间呈负相关（r =-0.75，p <0.02）。意义我们的结果表明，化学疗法诱发的DNA损伤改变了脑细胞的生理状态，并可能为癌症化学疗法后认知障碍的机制提供见解。

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