Low Sucrose, Omega-3 Enriched Diet Has Region-Specific Effects on Neuroinflammation and Synaptic Function Markers in a Mouse Model of Doxorubicin-Based Chemotherapy.

Tonya S Orchard,Martha A Belury,Panchita Phuwamongkolwiwat-Chu,A Courtney Devries,Rebecca Andridge,Maryam B Lustberg,Monica M Gaudier-Diaz,Joshua Bomser,Rachel M Cole

doi:10.3390/nu10122004

Tonya S Orchard, Martha A Belury + Show 7 more

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https://doi.org/10.3390/nu10122004

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Abstract

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.

Highlights

Chemotherapy treatment for breast cancer has contributed to improved survival rates for millions of women [1]
In study 1, there was a significant effect of diet on cumulative food intake (p < 0.001) such that mice in the No eicosapentaenoic acid (EPA) + docosahexaenoic acid (DHA) groups averaged 6% greater food intake than mice in the 2% EPA + DHA/chemotherapy group at end of the study (Table S4)
There was a significant injection by day effect on body weight (p < 0.0001); mice in the chemotherapy groups lost a mean of 0.72 ± 1.03 g of body weight from first injection to second injection, while mice in vehicle groups gained a mean of 0.30 ± 1.57 g. (Table S4)

Summary

Introduction

Chemotherapy treatment for breast cancer has contributed to improved survival rates for millions of women [1]. Studies report cognitive side effects in up to 75% of individuals treated with chemotherapy for cancer [1]; cognitive deficits negatively impact quality of life in nearly 30% of breast cancer survivors [3,4] by interfering with activities of daily living such as reading, working, and driving [5]. These cognitive deficits may persist for up to 15 years post-treatment [6], affecting verbal fluency, working memory and processing speed [7]. The mechanisms underlying chemotherapy-induced behavioral toxicities have not been conclusively established, research suggests that neuroinflammation, oxidative stress and their effects on neuronal structure and function may play a key role [8,9,11,12,13,14]

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