Chronic Treatment with Combined Chemotherapeutic Agents Affects Hippocampal Micromorphometry and Function in Mice, Independently of Neuroinflammation.
- Author:
Sohi KANG
1
;
Sueun LEE
;
Juhwan KIM
;
Jong Choon KIM
;
Sung Ho KIM
;
Yeonghoon SON
;
Taekyun SHIN
;
BuHyun YOUN
;
Joong Sun KIM
;
Hongbing WANG
;
Miyoung YANG
;
Changjong MOON
Author Information
- Publication Type:Original Article
- Keywords: Chemotherapy; Hippocampus; Neurogenesis; Neuroinflammation; Neuronal architecture; Vasculature
- MeSH: Adult; Animals; Breast Neoplasms; Cognition Disorders; Cyclophosphamide; Cytokines; Doxorubicin; Drug Therapy; Female; Hindlimb Suspension; Hippocampus; Humans; Macrophages; Memory; Mice*; Mood Disorders; Neurogenesis; Neurons; Spine; Survivors
- From:Experimental Neurobiology 2018;27(5):419-436
- CountryRepublic of Korea
- Language:English
- Abstract: Chemotherapeutic agents induce long-term side effects, including cognitive impairment and mood disorders, particularly in breast cancer survivors who have undergone chemotherapy. However, the precise mechanisms underpinning chemotherapy-induced hippocampal dysfunction remain unknown. In this study, we investigated the detrimental effects of chronic treatment with a combination of adriamycin and cyclophosphamide (AC) on the neuronal architecture and functions of the hippocampi of female C57BL/6 mice. After chronic AC administration, mice showed memory impairment (measured using a novel object recognition memory task) and depression-like behavior (measured using the tail suspension test and forced swim test). According to Golgi staining, chronic AC treatment significantly reduced the total dendritic length, ramification, and complexity as well as spine density and maturation in hippocampal neurons in a sub-region-specific manner. Additionally, the AC combination significantly reduced adult neurogenesis, the extent of the vascular network, and the levels of hippocampal angiogenesis-related factors. However, chronic AC treatment did not increase the levels of inflammation-related signals (microglial or astrocytic distribution, or the levels of pro-inflammatory cytokines or M1/M2 macrophage markers). Thus, chronic AC treatment changed the neuronal architecture of the adult hippocampus, possibly by reducing neurogenesis and the extent of the vasculature, independently of neuroinflammation. Such detrimental changes in micromorphometric parameters may explain the hippocampal dysfunction observed after cancer chemotherapy.
