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

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.

Chemobrain as a Product of Growing Success in Chemotherapy - Focus On Glia As Both A Victim And A Cure

“…A combination of oxygen radical production and cytokine dysregulation are the main suspects for chemobrain induction [27–29]. It has been shown that aggressive, three- drug chemotherapy consisting of a combination of docetaxel, adriamycin, and cyclophosphamide led to a cytokine dysregulation and disruptions in neuroplasticity [30]. The mice subjected to chemotherapy in this study have spent less time in the target quadrant of the water maze in comparison to control mice.…”

Pathogenesis, Assessments, and Management of Chemotherapy-Related Cognitive Impairment (CRCI): An Updated Literature Review

“…The study found that the volume of hippocampus in the breast cancer group receiving chemotherapy was relatively low and was associated with higher TNF- α levels and lower IL-6 levels, providing a basis for inflammatory cytokine-mediated CRCI [ 25 ]. In addition to hippocampal dysfunction, increased cytokines caused by chemotherapy appear to be associated with disruption of neuroplasticity [ 26 ]. Cheung et al conducted a multicenter, prospective cohort study to verify the relationship between inflammatory cytokine levels and CRCI in breast cancer patients.…”

Cellular mechanisms and treatments for chemobrain: insight from aging and neurodegenerative diseases

“…Few studies using animal models have examined the direct release of cytokines by activated microglia and astrocytes in the CNS. 5‐Fluorouracil and a combination of docetaxel, doxorubicin, and cyclophosphamide upregulated cytokines in the hippocampus (Groves et al , ; Shi et al , ). Methotrexate activated microglia, but no changes in CNS cytokine levels were observed (Seigers et al , ).…”