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Chemotherapy-Induced Cognitive Impairment Is Associated with Cytokine Dysregulation and Disruptions in Neuroplasticity

  • Dong-Dong Shi
  • Yu-Hua Huang
  • Cora Sau Wan Lai
  • Celia M. Dong
  • Leon C. Ho
  • Ed X. Wu
  • Qi Li
  • Xiao-Min Wang
  • Sookja Kim Chung
  • Pak Chung Sham
  • Zhang-Jin Zhang
Article
  • 126 Downloads

Abstract

Chemotherapy-induced cognitive impairment, often referred to as “chemobrain,” is a common side effect. In this study, mice received three intraperitoneal injections of a combination of docetaxel, adriamycin, and cyclophosphamide (DAC) at 2-day intervals. A water maze test was used to examine cognitive performance, and manganese-enhanced magnetic resonance imaging (MEMRI) was used to examine hippocampal neuronal activity. The whole brain, prefrontal cortex, hippocampus, and blood samples were then collected for cytokine measurement. The DAC-treated mice displayed a significantly shorter duration spent in and fewer entries into the target quadrant of the water maze than the control mice and a pronounced decrease in MEMRI signal intensity in the hippocampal subregions. In a separate experiment using in vivo transcranial two-photon imaging, DAC markedly eliminated dendritic spines without changing the rate of spine formation, leading to a striking loss of spines in the medial prefrontal cortex. DAC treatment resulted in significant elevations in the levels of the proinflammatory cytokines interleukin 6 (IL-6) and tumor necrosis factor-α (TNF-α) and in significant decreases in the levels of the anti-inflammatory cytokines IL-4 and IL-10 in most of the sera and brain tissues examined. The IL-6 and TNF-α levels of several sera and brain tissues showed strong inverse correlations with the duration and number of entries in the target quadrant of the water maze and with the hippocampal MEMRI signal intensity, but also showed striking positive correlations with spine elimination and loss. These results indicate that chemobrain is associated with cytokine dysregulation and disrupted neuroplasticity of the brain.

Keywords

Chemotherapy Cognitive impairment Cytokines Neuroplasticity Manganese-enhanced magnetic resonance imaging (MEMRI) In vivo transcranial two-photon imaging 

Notes

Funding

This study was supported by General Research Fund (GRF) of Research Grant Council of HKSAR (17115017 for Z.J.Z.).

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.

Supplementary material

12035_2018_1224_MOESM1_ESM.pptx (409 kb)
Fig. 1S Experimental procedure. Due to high mortality rate of Thy1-YFP transgenic mice during behavioral test, the animals did not undergo OFT and WMT. DAC, Docetaxel + Adriamycin + Cyclophosphamide; OFT, open field test; WMT, water maze test; MEMRI, manganese-enhanced magnetic resonance imaging. (PPTX 409 kb)
12035_2018_1224_MOESM2_ESM.pptx (171 kb)
Fig. 2S Net changes in body weight during habituation, treatment and recovery. Data are expressed as mean ± SEM and analyzed using two-way analysis of variance (ANOVA), followed by pairwise comparisons. Significant body weight loss was observed in mice treated with 10/10/40 mg/kg and 15/15/60 mg/kg DAC in multiple treatment and recovery days compared to controls: *P < 0.05; **P < 0.01 vs. controls. (PPTX 170 kb)
12035_2018_1224_MOESM3_ESM.pptx (60 kb)
Fig. 3S The effects of DAC treatment in open field test. Time spent in central zone (A), number of entry into central zone (B), total distance traveled (C), and movement velocity (D) were obtained. Data are expressed as mean ± SEM (n = 10 each group) and analyzed using one-way ANOVA. No significant differences were observed. (PPTX 60 kb)

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Dong-Dong Shi
    • 1
  • Yu-Hua Huang
    • 2
  • Cora Sau Wan Lai
    • 2
  • Celia M. Dong
    • 3
  • Leon C. Ho
    • 3
  • Ed X. Wu
    • 3
  • Qi Li
    • 4
  • Xiao-Min Wang
    • 5
  • Sookja Kim Chung
    • 2
  • Pak Chung Sham
    • 6
  • Zhang-Jin Zhang
    • 1
  1. 1.School of Chinese Medicine, LKS Faculty of MedicineThe University of Hong KongPokfulamChina
  2. 2.School of Biomedical Sciences, State Key Laboratory of Pharmaceutical Biotechnology, LKS Faculty of MedicineThe University of Hong KongHong KongChina
  3. 3.Laboratory of Biomedical Imaging and Signal Processing, Department of Electrical and Electronic EngineeringThe University of Hong KongHong KongChina
  4. 4.Department of Psychiatry, State Key Laboratory of Cognitive and Brain Sciences, HKU-SIRIThe University of Hong KongHong KongChina
  5. 5.Department of Anesthesiology, LKS Faculty of MedicineThe University of Hong KongHong KongChina
  6. 6.Department of Psychiatry, State Key Laboratory of Cognitive and Brain Sciences, Genome Research CentreThe University of Hong KongHong KongChina

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