TY - JOUR
T1 - Doxorubicin and cyclophosphamide treatment produces anxiety-like behavior and spatial cognition impairment in rats
T2 - Possible involvement of hippocampal neurogenesis via brain-derived neurotrophic factor and cyclin D1 regulation
AU - Kitamura, Yoshihisa
AU - Hattori, Sayo
AU - Yoneda, Saori
AU - Watanabe, Saori
AU - Kanemoto, Erika
AU - Sugimoto, Misaki
AU - Kawai, Toshiki
AU - Machida, Ayumi
AU - Kanzaki, Hirotaka
AU - Miyazaki, Ikuko
AU - Asanuma, Masato
AU - Sendo, Toshiaki
N1 - Funding Information:
This work was supported by a grant from the Smoking Research Foundation in Japan (YK). The funders had no role in study design, data collection, analysis, or the decision to prepare or submit the manuscript.
Publisher Copyright:
© 2015 Elsevier B.V.
PY - 2015/10/1
Y1 - 2015/10/1
N2 - 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.
AB - 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.
KW - Anhedonia
KW - Anxiety
KW - Brain-derived neurotrophic factor
KW - Cognitive impairment
KW - Cyclin D1
KW - Cyclophosphamide
KW - Doxorubicin
KW - Neurogenesis
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U2 - 10.1016/j.bbr.2015.06.007
DO - 10.1016/j.bbr.2015.06.007
M3 - Article
C2 - 26057360
AN - SCOPUS:84932629917
SN - 0166-4328
VL - 292
SP - 184
EP - 193
JO - Behavioural Brain Research
JF - Behavioural Brain Research
ER -
