The Effects of 5-Fluorouracil/Leucovorin Chemotherapy on Cognitive Function in Male Mice.
The Effects of 5-Fluorouracil/Leucovorin Chemotherapy on Cognitive Function in Male Mice.
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DOI：
10.3389/fmolb.2021.762116
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发表时间：
2021
影响因子：
5
通讯作者：
Allen AR
中科院分区：
文献类型：
--
作者：
Groves T;Corley C;Byrum SD;Allen AR
5-氟尿嘧啶(5-FU)和亚叶酸钙(LV)常用于结直肠癌的联合治疗。5-FU/LV通过抑制胸苷合成酶来抑制细胞增殖，胸苷合成酶催化脱氧尿苷单磷酸转化为脱氧胸苷单磷酸。虽然5-FU已被证明会导致认知功能障碍，但5-FU与LV的协同作用尚未被充分研究。本研究旨在评估5-FU和LV联合用药对小鼠认知功能的影响。这项研究使用的是6个月大的雄性小鼠；15只小鼠接受生理盐水注射，15只小鼠接受5-FU/LV注射。治疗1个月后进行高架+迷宫、Y迷宫和Morris水迷宫行为测试。然后提取大脑，冷冻切片，用CD68染色来检测小胶质细胞的激活，用番茄凝集素来检测血管系统。所有动物都能在水迷宫中找到可见和隐藏的平台位置。然而，在接受5-FU/LV的动物中，在隐藏平台训练的第一天(第一次探查试验)，在探查试验中观察到显著的空间记忆保持能力受损，但这些动物在第5天表现出空间记忆保持。CD68检测没有显著增加炎症反应，但5-FU/LV治疗确实调节了血管的形态。串联质量标签蛋白质组学分析鉴定了6,049个蛋白质，其中7个差异表达的p值为<；0.05，倍数变化为>；1.5。目前的数据表明，5-FU/LV增加了焦虑，并显著损害了空间记忆保持。
5-Fluorouracil (5-Fu) and leucovorin (LV) are often given in combination to treat colorectal cancer. 5-Fu/LV prevents cell proliferation by inhibiting thymidylate synthase, which catalyzes the conversion of deoxyuridine monophosphate to deoxythymidine monophosphate. While 5-Fu has been shown to cause cognitive impairment, the synergistic effect of 5-Fu with LV has not been fully explored. The present investigation was designed to assess how the combination of 5-Fu and LV affect cognition in a murine model. Six-month-old male mice were used in this study; 15 mice received saline injections and 15 mice received 5-Fu/LV injections. One month after treatment, the elevated plus maze, Y-maze, and Morris water maze behavioral tasks were performed. Brains were then extracted, cryosectioned, and stained for CD68 to assay microglial activation and with tomato lectin to assay the vasculature. All animals were able to locate the visible and hidden platform locations in the water maze. However, a significant impairment in spatial memory retention was observed in the probe trial after the first day of hidden-platform training (first probe trial) in animals that received 5-Fu/LV, but these animals showed spatial memory retention by day 5. There were no significant increases in inflammation as measured by CD68, but 5-Fu/LV treatment did modulate blood vessel morphology. Tandem mass tag proteomics analysis identified 6,049 proteins, 7 of which were differentially expressed with a p-value of <0.05 and a fold change of >1.5. The present data demonstrate that 5-Fu/LV increases anxiety and significantly impairs spatial memory retention.