Ormiston Kate, Melink Zihan, Andridge Rebecca, Lustberg Maryam, Courtney DeVries A, Murphy Kelly, Emmers Katie, Ziouzenkova Ouliana, Belury Martha A, Orchard Tonya S
Human Nutrition Program, Department of Human Sciences, The Ohio State University, United States.
Division of Biostatistics, College of Public Health, The Ohio State University, United States.
Brain Behav Immun. 2025 Jan;123:370-382. doi: 10.1016/j.bbi.2024.09.021. Epub 2024 Sep 21.
Chemotherapy agents in breast cancer are associated with chemotherapy-related cognitive impairments (CRCI). Mechanisms are not fully clear, but alterations of glucose and lipid metabolism, neuroinflammation and neurodegeneration may contribute to CRCI. The aim of this study was to investigate the combined effects of a high fat (HF) diet combined with doxorubicin-based chemotherapy on glucose and lipid metabolism, neuroinflammation, and neurodegeneration in mice. Additionally, we examined the therapeutic potential of dietary eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) to attenuate these effects. Female C57Bl/6 mice (n = 42) were fed HF, HFn-3 (2 % kcals as EPA + DHA) or Low Fat (LF) diets for seven weeks, with and without chemotherapy. In this study, two chemotherapy injections led to weight and body fat loss associated with a decrease in insulin resistance measured by HOMA-IR. HOMA-IR was significantly greater in HF versus LF groups; but HOMA-IR in HFn-3 group did not significantly differ from either HF or LF groups. Chemotherapy resulted in higher brain concentrations of the inflammatory chemokine KC/GRO. Compared to LF diet plus chemotherapy, HF diet plus chemotherapy upregulated multiple genes involved in neuroinflammation and neurodegeneration pathways. HFn-3 diet plus chemotherapy attenuated gene expression by downregulating multiple genes involved in neuroinflammation and blood brain barrier regulation, including Mapkapk2, Aqp4, and s100b, and upregulating Kcnb1 and Atxn3, genes involved in reduction of oxidative stress and anxiety, respectively. Overall, a HF diet combined with chemotherapy is associated with neuroinflammatory and neurodegenerative gene expression changes in this mouse model; dietary enrichment of EPA and DHA attenuated these effects. Further studies are needed to understand how diet impacts behavioral outcomes of CRCI.
乳腺癌化疗药物与化疗相关认知障碍（CRCI）有关。其机制尚不完全清楚，但葡萄糖和脂质代谢的改变、神经炎症和神经退行性变可能导致CRCI。本研究的目的是探讨高脂肪（HF）饮食联合基于阿霉素的化疗对小鼠葡萄糖和脂质代谢、神经炎症和神经退行性变的综合影响。此外，我们研究了膳食二十碳五烯酸（EPA）和二十二碳六烯酸（DHA）减轻这些影响的治疗潜力。将雌性C57Bl/6小鼠（n = 42）分为三组，分别给予HF、HFn-3（2%千卡为EPA + DHA）或低脂（LF）饮食7周，部分小鼠接受化疗。在本研究中，两次化疗注射导致体重和体脂减少，同时通过HOMA-IR测量的胰岛素抵抗降低。HF组的HOMA-IR显著高于LF组；但HFn-3组的HOMA-IR与HF组或LF组均无显著差异。化疗导致大脑中炎症趋化因子KC/GRO浓度升高。与LF饮食加化疗相比，HF饮食加化疗上调了多个参与神经炎症和神经退行性变途径的基因。HFn-3饮食加化疗通过下调多个参与神经炎症和血脑屏障调节的基因（包括Mapkapk2、Aqp4和s100b）以及上调Kcnb1和Atxn3基因（分别参与氧化应激减轻和焦虑调节）来减弱基因表达。总体而言，在该小鼠模型中，HF饮食联合化疗与神经炎症和神经退行性变基因表达变化有关；膳食中添加EPA和DHA可减轻这些影响。需要进一步研究以了解饮食如何影响CRCI的行为结果。
