·论著·乳腺癌化疗药物紫杉醇、表柔比星、环磷酰胺对小鼠认知功能的影响姚婉茹1*任健1*何嘉琦2孙海晨1刘爽1赵越1罗斌1，3【摘要】目的探究乳腺癌化疗常用药物紫杉醇、表柔比星、环磷酰胺对小鼠认知功能的影响。

方法本研究运用随机数字表法将Balb/c小鼠分为4组，每组20只，实验组小鼠分别腹腔注射紫杉醇（30mg/kg）、表柔比星（10mg/kg）、环磷酰胺（200mg/kg），对照组小鼠给予注射等体积的0.9%NaCl溶液。

给药4周后进行Morris水迷宫定位航行实验和空间探索实验，分别记录小鼠找到水下平台的时间（即逃避潜伏期），在目标象限时间占总时间的比率及穿越目标象限的次数。

逃避潜伏期比较采用重复测量的方差分析，目标象限时间占总时间的比率比较采用单因素方差分析，穿越平台次数比较用Kruskal-Wallis秩和检验。

结果在定位航行实验中，实验组和对照组小鼠在5个时间点（给药后第1、2、3、4、5天）的逃避潜伏期均随训练天数增加而逐渐缩短，呈下降趋势（F=11.25，P=0.001）。

紫杉醇组、表柔比星组、环磷酰胺组与对照组小鼠逃避潜伏期差异无统计学意义，不同时间点差异有统计学意义（组间比较：F=1.23，P=0.251；时间点比较：F=5.94，P＜0.001；组别与时间点的交互作用：F=0.77，P=0.676）。

空间探索实验中，小鼠在目标象限的时间所占总时间的比率组间差异有统计学意义（F=3.26，P=0.027）；与对照组相比，环磷酰胺组在目标象限的时间占总时间的比率降低（13.6%ʃ8.9%比23.9%ʃ13.9%，t=－3.05，P=0.009）。

各组小鼠穿越平台次数差异无统计学意义（χ2=1.86，P=0.602）。

结论环磷酰胺可降低小鼠的空间记忆能力，部分化疗药有可能改变小鼠的空间学习记忆能力。

【关键词】乳腺肿瘤；药物疗法；迷宫学习；认知障碍【中图法分类号】Ｒ737.9【文献标志码】AEffect of paclitaxel，epirubicin and cyclophosphamide used for breast cancer chemotherapy oncognition function of mice Yao Wanru1*，Ｒen Jian1*，He Jiaqi2，Sun Haichen1，Liu Shuang1，Zhao Yue1，Luo Bin1，3．Department of General Surgery，Xuanwu Hospital，Capital Medical University，Beijing100053，China1；Beijing101Middle School，Beijing100091，China2；Department of General Surgery，Beijing TsinghuaChanggung Hospital，Beijing102218，China3*Yao Wanru andＲen Jian are the first authors who have contributed equally to the articleCorresponding author：Luo Bin，Email：lba01097@btch．edu．cn【Abstract】Objective To explore the effects of paclitaxel，epirubicin and cyclophosphamide，whichare widely used in breast cancer chemotherapy，on the cognition function of mice．Methods Totally80Balb/cmice were randomized into four groups，20mice in each group．The mice in3experimental groups wereintraperitoneally injected with paclitaxel（30mg/kg），epirubicin（10mg/kg），or cyclophosphamide alone（200mg/kg）respectively．The mice in control group were injected with isovolumic saline．At4weeks afterinjection，all groups were given Morris water maze test，including place navigation and spatial probe test，torecord the time the mice spent on underwater platform（escape latency），the ratio of time in every quadrant tototal swimming time and the times of crossing the platforma．The escape latencies of mice were compared amongDOI：10.3877/cma.j.issn.1674－0807.2016.01.005基金项目：北京市医院管理局215高层次卫生技术人才学科带头人项目（2013-2-032）作者单位：100053北京，首都医科大学宣武医院普通外科1；100091北京101中学2；102218北京清华长庚医院普通外科3*为本文共同第一作者通信作者：罗斌，Email：lba01097@btch．edu．cngroups using repeated measurement analysis of variance，the ratio of time in every quadrant to total swimming time was compared using univariate analysis of variance and the times of crossing the platform among groups were compared using Kruskal-Wallis rank sum test．Ｒesults In place navigation test，the escape latencies at 5time points（on days1，2，3，4，5after injection）in four groups were decreased with training time，which showed a trend of decline（F=11.25，P=0.001）．There was no statistically significant difference in escape latency between paclitaxel/epirubicin/cyclophosphamide-treated group and control group，while escape latencies were significantly different at5time points（comparison between groups：F=1.23，P=0.251；comparison at different time points：F=5.94，P＜0.001；interaction between grouping and different time points：F=0.77，P=0.676）．In spatial probe test，the ratio of time spent in every quadrant to the total swimming time in4groups presented a significant difference（F=3.26，P=0.027）；it was significantly lower in cyclophosphamide-treated group than that in control group（13.6%ʃ8.9%vs23.9%ʃ13.9%；t=－3.05，P=0.009）．The difference was not statistically significant between experimental groups and control group in the times of crossing the platform on the sixth day after injection（χ2=1.86，P=0.602）．Conclusions Cyclophosphamide can affect the memory maintenance of mice．There is a possibility that chemotherapy medication can affect the ability of spatial cognition and learning in mice．【Key words】Breast neoplasms；Drug therapy；Maze learning；Cognitive disorders近30多年来，乳腺癌的治疗效果持续改善，取得了长足的进步，化疗在其中的贡献非常重要。

但从上世纪80年代起便有文献报道称化疗可引起患者认知功能受损［1］。

在接受化疗的乳腺癌患者中，16% 75%会在治疗过程中出现轻到中度的认知损伤，其中35%的患者在治疗结束数月到数年的时间内症状持续存在［2］。

越来越多的临床研究证实化疗药物会对患者的记忆力、执行力和注意力产生影响［3-6］。

本研究通过动物实验，采用Morris水迷宫———目前公认较为客观的学习记忆功能评价方法，观察单一乳腺癌化疗药物对小鼠认知功能的影响。

资料与方法一、实验动物和药物80只Balb/c小鼠，雄性，体重25g，购自北京华阜康生物科技股份有限公司。

所有小鼠的饲育条件为屏障环境，室内温度（23ʃ1）ħ，相对湿度（50ʃ10）%，光照明暗交替12h/12h，可自由饮水和进食，饲料经60Co射线辐照法灭菌。

实验小鼠毛发有光泽，无脱落。

本实验已获得北京宣武医院伦理委员会批准。

紫杉醇注射液购自济宁辰欣药业股份有限公司。