Doxorubicin and cyclophosphamide treatment produces anxiety-like behavior and spatial cognition impairment in rats: Possible involvement of hippocampal neurogenesis via brain-derived neurotrophic factor and cyclin D1 regulation

Yoshihisa Kitamura, Sayo Hattori, Saori Yoneda, Saori Watanabe, Erika Kanemoto, Misaki Sugimoto, Toshiki Kawai, Ayumi Machida, Hirotaka Kanzaki, Ikuko Miyazaki, Masato Asanuma, Toshiaki Sendo

Research output: Contribution to journalArticle

27 Citations (Scopus)


Many patients who have received chemotherapy to treat cancer experience depressive- and anxiety-like symptoms or cognitive impairment. However, despite the evidence for this, the underlying mechanisms are still not understood. This study investigated behavioral and biochemical changes upon treatment with doxorubicin and cyclophosphamide, focusing on mental and cognitive systems, as well as neurogenesis in male rats. Doxorubicin (2. mg/kg), cyclophosphamide (50. mg/kg), and the combination of doxorubicin and cyclophosphamide were injected intraperitoneally once per week for 4 weeks. In particular, the co-administration of doxorubicin and cyclophosphamide produced anhedonia-like, anxiety-like, and spatial cognitive impairments in rats. It also reduced both the number of proliferating cells in the subgranular zone of the hippocampal dentate gyrus and their survival. Serum brain-derived neurotrophic factor (BDNF) levels were decreased along with chemotherapy-induced decreases in platelet levels. However, hippocampal BDNF levels and Bdnf mRNA levels were not decreased by this treatment. On the other hand, hippocampal cyclin D1 levels were significantly decreased by chemotherapy. These results suggest that the co-administration of doxorubicin and cyclophosphamide induces psychological and cognitive impairment, in addition to negatively affecting hippocampal neurogenesis, which may be related to hippocampal cyclin D1 levels, but not hippocampal BDNF levels.

Original languageEnglish
Pages (from-to)184-193
Number of pages10
JournalBehavioural Brain Research
Publication statusPublished - Oct 1 2015



  • Anhedonia
  • Anxiety
  • Brain-derived neurotrophic factor
  • Cognitive impairment
  • Cyclin D1
  • Cyclophosphamide
  • Doxorubicin
  • Neurogenesis

ASJC Scopus subject areas

  • Behavioral Neuroscience

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