5-Fluorouracil induces an acute reduction in neurogenesis and persistent neuroinflammation in a mouse model of the neuropsychological complications of chemotherapy [post]

Courtney Brooke Subramaniam, Hannah R. Wardill, Maya R. Davies, Vivien Heng, Marc A. Gladman, Joanne M. Bowen
2022 unpublished
The neuropsychological symptoms of chemotherapy treatment remain a major challenge with their prevention hampered by insufficient understanding of pathophysiology. While long term neuroimmune changes have been identified as a hallmark feature shared by neurological symptoms, the exact timeline of mechanistic events preceding and driving neuroinflammation remain unclear. We therefore aimed to longitudinally characterise the neuroimmunological changes following systemic 5-fluorouracil (5-FU) to
more » ... in insight into the timeline of events preceding the well-documented chronic neuroinflammation seen following chemotherapy. Eighteen female C57Bl/6 mice received a single intraperitoneal dose of 5-FU and groups were killed at days 1 and 2 (acute timepoint), days 4 and 8 (subacute timepoint) as well as days 16 and 32 (chronic timepoint). A further six mice were used to control for the effect of ageing and stress, with tissues collected on day 1 and day 32. Levels of neurogenesis were determined through immunofluorescent staining of doublecortin (DCX). The activation of microglia and astrocytes were assessed using immunofluorescence staining of ionised calcium binding adaptor molecular-1 (Iba1) and glial fibrillary acidic protein (GFAP) respectively. 5-FU treatment caused significant decreases to DCX staining (p=0.0030) as well as increases in microglial activation in the prefrontal cortex (p=0.0256), CA3 region (p=0.0283) and dentate gyrus (p=0.0052) of the hippocampus at acute timepoints. Whereas astrocytic reactivity was observed across multiple brain regions at subacute and chronic timepoints. This study has identified acute objective neuroinflammatory changes suggesting that the role of early intervention should be explored to prevent the development of neuropsychological deficits following chemotherapy.
doi:10.21203/rs.3.rs-1337266/v1 fatcat:dtyecmk4h5cvjcfhfcelfugmfa