Breast cancer (BC) is the most common cancer among women. Fortunately, BC survival rates have increased since the implementation of adjuvant chemotherapy leading to a growing population of survivors. However, chemotherapy-induced cognitive impairments (CICIs) affect up to 75% of BC survivors and may be driven by inflammation and oxidative stress. CICIs can persist 20 years and hinder survivors' quality of life (QOL). To establish an animal model demonstrating CICIs, BC chemotherapy (CMF) was administered in female mice to gauge cognitive function at various timepoints post-chemotherapy. We identified impaired hippocampal-dependent long-term memory (LTM) at 2-weeks post-chemotherapy and short-term memory (STM) at 3-months post-chemotherapy. We also aimed to identify early and late effects on peripheral inflammation and hippocampal physiology; however, no changes in peripheral leukocytes or hippocampal synaptic markers were identified at 1-week, 2-weeks, or 3-months post-chemotherapy.

Behavioral testing was then expanded to include neighboring cognitive domains. Ameliorative ability of carnosic acid (CA) and sulforaphane (SFN) to rescue CMF-induced cognitive deficits and subsequent alterations to macrophage polarization and hippocampal physiology was assessed. Both CA and SFN exert antioxidative and anti-inflammatory properties through Nrf2-Keap1 pathway activation. At 4-to-6 weeks post-chemotherapy, we identified impaired LTM, impaired cognitive flexibility, and heightened anxiety; CA did not ameliorate these deficits. CMF decreased neurotoxic M1 macrophages in cultured bone marrow-derived macrophages (BMDMs); CA did not potentiate. However, CMF+CA increased neuroprotective M2 macrophages. Both CMF and CA treatment increased dendritic length within CA1 dendrites. CMF decreased dendritic length in the DG; however, CA rescued this effect. At 2-4 weeks post-chemotherapy, we identified impairments in STM, LTM, and cognitive flexibility. SFN did not rescue STM/LTM but did improve cognitive flexibility. CMF+SFN increased M2 in splenic macrophages; CMF increased in BMDMs. No CMF-induced alterations in neurogenesis were identified. Accordingly, no changes in hippocampal Nrf2-Keap1 pathway-related genes were identified in either CA or SFN cohorts.

Thus, CMF induced cognitive deficits in STM, LTM, cognitive flexibility and anxiety across several post-chemotherapy timepoints. CMF decreased M1 and increased M2; CMF with either CA or SFN increased M2. SFN rescued CMF-induced cognitive flexibility impairment and CA potentiated loss of dendritic length in the DG.