The Influence of Omega-3 Fatty Acid Supplementation on the Brain Lipidome After Chemotherapy (P15-024-19)

Abstract

ObjectivesSolid tumor chemotherapy produces long-term cognitive side effects well beyond treatment, but the structural changes on brain chemistry are unknown. A diet supplemented with omega-3 fatty acids (EPA + DHA) before and during chemotherapy partially protects the cerebral tissue against some of the chemo-induced modifications. We hypothesize that EPA + DHA supplementation results in a greater neuroinflammation-resolving response mediated by specialized pro-resolving mediators (SPMs i.e., omega-3 derived metabolites which attenuate inflammation), and reduces oxidation of structural brain lipids. MethodsFor four weeks, ovariectomized mice were fed a 2% kcal EPA + DHA supplemented (n = 60) or control diet (n = 60), followed by two treatments with vehicle (n = 30 per dietary group) or doxorubicin (n = 30 per dietary group). Animals were sacrificed at 4, 7, and 14 days post-treatment, and samples extracted and purified with SPE. Targeted analyses (LC-MS/MS) were performed on extracts, using stable isotope internal standards for SPM quantitation (i.e., resolvin E1, D1, D2, D3, D5, maresin 1, protectin D1). Untargeted LC-HRMS metabolomics analyses were performed on the hippocampal extracts of follow-up set of animals, to determine changes in the brain lipidome. ResultsResolvin D1 was quantifiable in all samples regardless of dietary or treatment group, and correlations were observed with orthogonal measures of inflammation in chemo-treated animals. Resolvin D3, maresin 1, and protectin D1 were detected in a subset of animals. A cluster of lipid-based metabolites differentiated animals receiving chemotherapy with omega-3 fatty acid supplementation from those not receiving the supplementation. ConclusionsThe protective effects of EPA + DHA supplementation on chemo-induced cerebral damage appear to be only partially correlated with SPM synthesis over the time course observed. Funding SourcesThis research was supported by an OSU Foods for Health Discovery Themes Initiative SEEDS grant. The mouse samples were collected under NIH R01CA189947. The sample analyses were partially supported by NIH Award Number Grant P30 CA016058, OSU, and OSUCCC.