Abstract P2-11-04: Chemotherapy Induces Neuroinflammation and Cognitive Deficits in Female Mice

Introduction: Advances in cancer detection and treatment have substantially increased the survival rate for breast cancer patients. Chemotherapeutic drugs, particularly anthracyclines, have potentially toxic side effects in the brain- impacting memory, processing time and verbal fluency. More than 30% of patients undergoing chemotherapy for breast cancer report cognitive deficits during and after treatment. Despite the high incidence and significant impact on quality of life, little is known about the cause of the cognitive deficits and no effective treatment currently exists. Our hypothesis is that chemotherapy-induced neuroinflammation impairs cognition. Methods: Adult female BALB/C mice were ovariectomized and then two weeks later injected intravenous (IV) with a single dose of chemotherapy (45 mg/m2 doxorubicin + 450 mg/m2 cyclophosphamide) or vehicle (n = 10–12/group). The mice were trained for three trials per day across six days in the Barnes Maze, a well-characterized spatial memory task. Results: Both the chemotherapy-treated and vehicle-treated mice were able to acquire the task by the final day of training. However, the vehicle-treated mice reached asymptotic performance after fewer training sessions than the chemotherapy-treated mice. Furthermore, the chemotherapy-treated mice took significantly longer to find the escape box than the vehicle-treated mice on training days 2–5 (p < 0.05). In contrast, there were no group differences in overall locomotor activity level, suggesting that the observed difference in maze performance was not due to a fatigue. (p > 0.05) In addition, chemotherapy increased proinflammatory cytokine expression (TNF-α, IL-1β, and IL-6) in the hippocampus (p < 0.05), a region of the brain that is critical for spatial learning and memory. Likewise, microglia from chemotherapy-treated mice exhibited increased expression of MHCII and CD80 relative to vehicle-treated mice (p < 0.05), thereby suggesting a proinflammatory phenotype. Conclusions: Together, these data suggest that the administration of doxorubicin and cyclophosphamide in doses that are approximately 25% lower than the typical dose for women treated for breast cancer, produce neuroinflammation, including microglia activation, increased proinflammatory cytokine expression and concomitant cognitive deficits in female mice. Additional studies will establish whether a causal relationship exists between chemotherapy-induced neuroinflammation and cognitive deficits. Identifying the mechanism through which chemotherapy induces cognitive deficits is the first step toward designing therapeutic interventions. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P2-11-04.