Impaired Cognitive Function and Hippocampal Neurogenesis Following Cancer Chemotherapy
Clin Cancer Res. 2012 Feb 14;
Christie LA, Acharya MM, Parihar VK, Nguyen A, Martirosian V, Limoli CL
PURPOSE: A substantial proportion of breast cancer survivors report significant, long-lasting impairments in cognitive function, often referred to as "chemobrain." Advances in detection and treatment mean that many more patients are surviving long-term following diagnosis of invasive breast cancer. Thus, it is important to define the types, extent and persistence of cognitive impairments following treatment with cytotoxic cancer drugs. EXPERIMENTAL DESIGN: We examined the effects of chronic treatment with two agents commonly used in breast cancer patients, cyclophosphamide and doxorubicin (Adriamycin). Athymic nude rats were given 50mg/kg cyclophosphamide, 2mg/kg doxorubicin or saline injections once per week for 4 weeks. A novel place recognition task and contextual and cued fear conditioning were employed to characterize learning and memory ability. Immunofluorescence staining for immature and mature neurons and activated microglia was used to assess changes in neurogenesis and neuroinflammation.RESULTS: Cyclophosphamide- and doxorubicin-treated rats showed significantly impaired performance on the novel place recognition task and the contextual fear conditioning task compared to untreated controls, suggesting disrupted hippocampal-based memory function. Chemotherapy-treated animals showed a significant decline in neurogenesis (80 to 90% drop in BrdU labeled cells expressing NeuN). Activated microglia (ED1 positive) were found after cyclophosphamide, but not doxorubicin treatment.CONCLUSIONS: Our results demonstrate that chronic treatment with either of two commonly-used chemotherapeutic agents impairs cognitive ability, and suggest that strategies to prevent or repair disrupted hippocampal neurogenesis may be effective in ameliorating this serious side effect in cancer survivors.
PMID: 22338017 [PubMed - as supplied by publisher]