Chemotherapeutic agents such as doxorubicin may negatively affect long-term brain functioning in cancer survivors; neuroinflammation may play a causal role. Dietary approaches that reduce inflammation, such as lowering sucrose and increasing eicosapentaenoic acid plus docosahexaenoic acid (EPA + DHA), may attenuate chemotherapy-induced neuroinflammation and synaptic damage, thereby improving quality of life. Ovariectomized, C57BL/6 mice were assigned to a chemotherapy (9 mg/kg doxorubicin + 90 mg/kg cyclophosphamide) or vehicle two-injection regimen, with injections two and four weeks after starting diets. In Study 1, mice received low sucrose diets with EPA + DHA or No EPA + DHA for four to six weeks; tissues were collected four, seven, or 14 days after the second injection. Compared to vehicle, chemotherapy increased pro-inflammatory cytokine IL-1β at day seven in the cortex and hippocampus, and reduced gene expression of synaptic marker Shank 3 at all timepoints in cortex, while EPA + DHA increased expression of Shank 3. In Study 2, high or low sucrose/EPA + DHA or No EPA + DHA diets were fed for five weeks; tissues were collected ten days after the second injection. Among chemotherapy-treated mice, brain DHA was higher with low sucrose feeding. Furthermore, low sucrose increased gene expression of Shank 1, while EPA + DHA increased expression of Shank 3 and reduced protein concentrations of pro-inflammatory markers IL-5, IL-6 and KC/GRO in the cortex, but not the hippocampus. Low sucrose, EPA + DHA diets may attenuate neuroinflammation and synaptic damage induced by doxorubicin-based chemotherapy in specific brain regions.

Objectives Our prior work in ovariectomized mice suggested that dietary eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), as well as low sucrose during chemotherapy, reduced anxiety-like behavior. Our current objective was to examine the effect of diet and chemotherapy on differences in cerebellum fatty acids and associations with glucose metabolism and anxiety-like behavior. Methods Female, ovariectomized C57BL/6 mice (7–8 weeks old; n = 84) were fed one of four diets: 2% kcals EPA + DHA or low omega-3 with low or high sucrose. At weeks 2 and 4, mice received a saline or chemotherapy injection (doxorubicin + cyclophosphamide). Seven days after the second injection, mice completed a marble burying test to assess anxiety-like behavior and were sacrificed 10 days later. Cerebellum fatty acids were measured by gas chromatography. At sacrifice, fasted serum insulin was measured by ELISA, fasted blood glucose was measure by glucometer, and homeostatic model assessment of insulin resistance (HOMA-IR) was assessed. Data were analyzed via 3-way ANOVA, Pearson, and Spearman's Correlation; P < 0.05 was considered significant. Results Mice on the 2% EPA + DHA diets had significantly higher relative amounts of EPA and DHA in the brain than mice on the low sucrose and high sucrose low omega-3 diets (P < 0.0001, P < 0.0001 respectively). Relative amounts of brain AA were not significantly different between the 2% EPA + DHA diets. Mice on the 2% EPA + DHA diets had significantly lower brain AA than both low omega-3 diets (P < 0.001 for all). Low omega-3, low sucrose diet fed mice had significantly lower AA than mice fed the low omega-3, high sucrose diet (P < 0.05). Mice on the 2% EPA + DHA diet had significantly lower HOMA-IR at sacrifice regardless of sucrose and injection type than mice on the low omega-3 diet (P < 0.01). Brain AA was significantly correlated with serum insulin (P < 0.05) and with marbles buried 100%, indicating anxiety-like behavior (P < 0.01). Conclusions Feeding 2% kcals as EPA + DHA increased brain EPA and DHA while decreasing AA in this mouse model. When omega-3 was low in the diet, low dietary sucrose reduced brain AA compared to high sucrose diets. Dietary EPA + DHA decreased insulin resistance regardless of chemotherapy injection or sucrose. Higher brain AA was associated with higher serum insulin and more anxiety-like behavior. Funding Sources NIH #5R01CA18994.