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首页> 外文期刊>The European Journal of Neuroscience >5-Fluorouracil chemotherapy affects spatial working memory and newborn neurons in the adult rat hippocampus.
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5-Fluorouracil chemotherapy affects spatial working memory and newborn neurons in the adult rat hippocampus.

机译：5-氟尿嘧啶化疗会影响成年大鼠海马中的空间工作记忆和新生神经元。

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Chemotherapy-associated memory deficits in adults are prevalent with systemic treatment utilizing 5-fluorouracil (5-Fu). 5-Fu disrupts cell proliferation and readily crosses the blood-brain barrier. Proliferating cells within the adult dentate gyrus of the hippocampus give rise to new neurons involved in memory and learning and require neurotrophic factors such as brain-derived neurotrophic factor (BDNF) to nurture this process of adult neurogenesis. Some of these proliferating cells are anatomically and functionally supported by vascular endothelial cells. We propose that systemically administered 5-Fu chemotherapy will cause deficits in hippocampal memory that are associated with altered BDNF levels and proliferating cells (particularly vascular-associated cells) in the dentate gyrus. This was tested by determining the effect of 5-Fu on spatial working memory as modelled by the object location recognition test. Numbers of vascular-associated (VA) and non-vascular-associated (NVA) proliferating cells in the dentate gyrus were measured using double-labelling immunohistochemistry with markers of proliferation (Ki67) and endothelial cells (RECA-1). 5-Fu-induced changes in hippocampal BDNF and doublecortin (DCX) protein levels were quantified using Western immunoblotting. 5-Fu chemotherapy caused a marginal disruption in spatial working memory and did not alter the total proliferating cell counts or the percentage of VA and NVA proliferating cells in the dentate gyrus. In contrast, 5-Fu significantly reduced BDNF and DCX levels in the hippocampus, indicating alterations in neurotrophin levels and neurogenesis. These findings highlight the usefulness of animal models of 'chemobrain' for understanding the mechanisms that underlie chemotherapy-associated declines in cognitive performance and memory.
机译：在成年人中，与化学疗法有关的记忆缺陷普遍存在于使用5-氟尿嘧啶（5-Fu）的全身治疗中。 5-Fu破坏细胞增殖并容易越过血脑屏障。海马的成年齿状回中的增殖细胞产生涉及记忆和学习的新神经元，并且需要神经营养因子，例如脑源性神经营养因子（BDNF）来培养成年神经发生的这一过程。这些增殖细胞中的一些在解剖学上和功能上受到血管内皮细胞的支持。我们建议全身给药的5-Fu化疗将导致海马记忆缺陷，这与改变的BDNF水平和齿状回中的增殖细胞（特别是血管相关细胞）有关。通过确定5-Fu对空间工作记忆的影响进行了测试，这是通过对象位置识别测试建模的。使用具有增殖标志物（Ki67）和内皮细胞（RECA-1）的双标记免疫组织化学方法测量齿状回中血管相关（VA）和非血管相关（NVA）增殖细胞的数量。使用Western免疫印迹法对5-Fu诱导的海马BDNF和双皮质素（DCX）蛋白水平的变化进行了定量。 5-Fu化疗引起空间工作记忆的边缘破坏，并且没有改变齿状回中总增殖细胞数或VA和NVA增殖细胞的百分比。相反，5-Fu明显降低海马中的BDNF和DCX水平，表明神经营养蛋白水平和神经发生改变。这些发现强调了“化学障碍”动物模型对于理解与化学疗法相关的认知能力和记忆力下降基础的机制的有用性。

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