Abstract
Objectives
Incidence of anxiety is nearly three times higher in breast cancer patients compared to healthy women, and chemotherapy may increase risk. Chemotherapy-induced neuroinflammation may contribute to anxiety. Omega-3 fatty acids (n-3 FAs), specifically eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), improve symptoms of anxiety in some studies. However, the effects of n-3 FAs on anxiety during chemotherapy have not been examined. We hypothesized that a diet enriched with n-3 FAs and low in sucrose would significantly improve anxiety-like behavior in chemotherapy treated mice.
Methods
Female, ovariectomized C57BL/6 mice (7–8 weeks old) were randomly assigned to one of four diets: 2% kcal EPA + DHA or no EPA + DHA with low sucrose or high sucrose. After two and four weeks of diets, mice received a saline or chemotherapy injection (9 mg/kg doxorubicin + 90 mg/kg cyclophosphamide), then continued on diets. Seven days after the second injection, mice completed a marble burying test to assess anxiety-like behavior and were sacrificed 10 days later. Significant differences (P < 0.05) were determined using negative binomial regression models. Gene expression of inflammatory cytokines in the hippocampus and cortex was measured using PCR. Spearman correlations assessed associations of cytokines with anxiety.
Results
Twenty-one % of mice completely buried (i.e., 100% buried) at least one marble; 85% of mice partially buried (>50% but <100% buried) at least one marble. There was a significant n-3 FA effect on number of marbles 100% buried (P = 0.01); fewer marbles were buried by the 2% EPA + DHA group, indicative of less anxiety-like behavior in these mice. There was a significant interaction effect of injection and sucrose on number of marbles 100% buried (P = 0.03); in the chemotherapy group, mice fed low sucrose completely buried fewer marbles than mice fed high sucrose (P < 0.001), but in the saline group, there was no significant difference. There was a significant negative correlation (r = −0.24, P = 0.04) between interleukin-6 in the cortex and number of marbles partially buried.
Conclusions
Our findings suggest that dietary EPA + DHA reduces, while sucrose and chemotherapy increase, anxiety-like behavior in our mouse model. Future studies should investigate underlying mechanisms.
Funding Sources
National Cancer Institute.