5-Fluorouracil chemotherapy upregulates cytokines and alters hippocampal dendritic complexity in aged mice

Abstract

5-fluorouracil (5-Fu) is commonly used chemotherapy drug, but it can lead to the impairment of cognitive function. The pathogenesis of this injury is unknown but may involve modifications to dendritic structure and/or alterations in dendritic spine density and morphology. Dendritic spines are sites of excitatory synaptic transmission and changes in spine structure and dendrite morphology are thought to represent a morphological correlate of altered brain functions associated with hippocampal dependent learning and memory. A total of 28 one-year-old C57BL6/J male mice were used in this study; 14 mice received 5-Fu treatment and 14 were given saline injections. One month post treatment, 14 cytokines were measured at the same time Golgi samples were taken. 8 analytes were significantly elevated in mice treated with 5-Fu. 5-Fu significantly compromised the dendritic architecture and reduced spine density throughout the hippocampal tri-synaptic network. The present data provide the evidence that 5-Fu has deleterious effects on mature neurons associated with hippocampal learning and memory.

Effects of thioTEPA chemotherapy on cognition and motor coordination

“…In this study, mice were administered intraperitoneal injections of 5‐Fu, brains were collected, and Golgi staining was performed. Analogous to our results with thioTEPA, 5‐Fu significantly decreased dendritic branching and complexity (Groves et al, ). Cisplatin, another chemotherapy drug, also contributes to cognitive decline.…”

“…We found significantly lower levels of IL‐2, IL‐3, IL‐5, and GM‐CSF in thioTEPA‐treated animals compared to controls. However, previous studies generally observed an increase in cytokines during cognitive decline (Cheung et al, ; Groves et al, ; Lyons et al, ; Wilson, Finch, & Cohen, ). Because our data indicate a decrease in proinflammatory cytokines in thioTEPA‐treated mice, cognition should have been spared.…”

“…Many different chemotherapy drugs are associated with cognitive decline (Moore, 2014)-doxorubicin, cyclophosphamide, cisplatin, and 5-fluorouracil (5-Fu) are all associated with cognitive dysfunction (Kitamura et al, 2015;Lomeli, Di, Czerniawski, Guzowski, & Bota, 2017;Lyons, ElBeltagy, Bennett, & Wigmore, 2012). Previously, we showed that 5-Fu decreases dendritic arborization in the mouse hippocampus (Groves et al, 2017). Dendritic complexity can be indicative of cognitive function-decreased complexity is associated with cognitive decline and increased complexity is associated with increased function (Dang et al, 2014;Dickstein, Brautigam, Stockton, Schmeidler, & Hof, 2010).…”

Assessing the Effects of Redox Modifier MnTnBuOE-2-PyP 5+ on Cognition and Hippocampal Physiology Following Doxorubicin, Cyclophosphamide, and Paclitaxel Treatment

“…Specifically, Thiotepa administration in adult male mice caused deficits in short-term memory and in spatial memory retention [22]. 5-FU administrations compromised the structure of neurons in the hippocampus as seen by decreased dendritic length, complexity, and spine density [23]. Seigers et al showed that administration of cyclophosphamide or doxorubicin in adult male mice resulted in deficits in novel location recognition, a hippocampal dependent memory task.…”

Chronic Treatment with Combined Chemotherapeutic Agents Affects Hippocampal Micromorphometry and Function in Mice, Independently of Neuroinflammation

“…In addition, several animal studies have revealed an important role for neuroinflammation in terms of dendritic spine structure. Increased cytokine levels inhibited the maintenance of dendritic spines either directly or indirectly, impairing hippocampus-dependent behaviors [ 22 23 ]. However, other studies suggested that hippocampal dysfunction and neuroinflammation were not linked.…”