title: Impaired cognitive function and hippocampal neurogenesis following cancer chemotherapy.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  We examined the effects of chronic treatment with two agents commonly used in patients with breast cancer, cyclophosphamide and doxorubicin (Adriamycin). Athymic nude rats were given 50 mg/kg cyclophosphamide, 2 mg/kg doxorubicin, or saline injections once per week for 4 weeks. A novel place recognition task and contextual and cued fear conditioning were used 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 with untreated controls, suggesting disrupted hippocampal-based memory function. Chemotherapy-treated animals showed a significant decline in neurogenesis [80%-90% drop in bromodeoxyuridine (BrdUrd)-labeled cells expressing NeuN]. Activated microglia (ED1-positive) were found after cyclophosphamide but not doxorubicin treatment.
  
  
  CONCLUSIONS
  Our results show 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.
authors.affiliation: Department of Radiation Oncology, University of California, Irvine, CA 92697, USA. climoli@uci.edu
authors.forename: Lori-Ann
authors.initials: LA
authors.lastname: Christie
authors.forename: Munjal M
authors.initials: MM
authors.lastname: Acharya
authors.forename: Vipan K
authors.initials: VK
authors.lastname: Parihar
authors.forename: Anna
authors.initials: A
authors.lastname: Nguyen
authors.forename: Vahan
authors.initials: V
authors.lastname: Martirosian
authors.forename: Charles L
authors.initials: CL
authors.lastname: Limoli
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use / Q000633:toxicity*; D001835:Body Weight / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy; D001973:Bromodeoxyuridine / Q000378:metabolism; D003072:Cognition Disorders / Q000139:chemically induced / Q000503:physiopathology*; D003213:Conditioning, Psychological / Q000187:drug effects; D003520:Cyclophosphamide / Q000627:therapeutic use / Q000633:toxicity; D004317:Doxorubicin / Q000627:therapeutic use / Q000633:toxicity; D005239:Fear / Q000187:drug effects / Q000523:psychology; D005260:Female; D005455:Fluorescent Antibody Technique; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D006801:Humans; D007858:Learning / Q000187:drug effects; D008297:Male; D008568:Memory / Q000187:drug effects; D009043:Motor Activity / Q000187:drug effects; D055495:Neurogenesis / Q000187:drug effects*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D011923:Rats, Nude
chemical_list: D000970:Antineoplastic Agents; D004317:Doxorubicin; D003520:Cyclophosphamide; D001973:Bromodeoxyuridine