The Effects of 5‐Fluorouracil/Leucovorin Chemotherapy on Cognitive Function in Mice

Abstract

5‐fluorouracil (5‐Fu) and leucovorin (LV) are often given in combination to treat colorectal cancer. 5‐Fu/LV prevents cell proliferation by inhibiting thymidylate synthase (TS), which is an enzyme that catalyzes the conversion of deoxyuridine monophosphate to deoxythymidine monophosphate. While 5‐Fu has been shown to cause cognitive impairments, the synergistic effect of 5‐Fu with LV has not been fully explored. The present investigation was designed to assess how the combination of 5‐Fu and LV affect cognition in a murine model. A total of 30 nine‐month‐old male mice were used in this study; 8 mice received 0.9 % saline injections, 6 mice received LV (90 mg/kg) injections, 8 mice received 5‐Fu (50 mg/kg) injections, and 8 mice received 5‐Fu and LV (50 mg/kg and 90 mg/kg) injections. One‐month post‐treatment, Y‐maze and Morris water maze (MWM) behavioral tasks were performed. Brains were then extracted, cryosectioned, and stained with CD68 and tomato lectin. All animals in the MWM task were able to locate the visible and hidden platform locations in the water maze; however, treatment effects were seen when spatial memory retention was assessed in the probe trials (no platform). A significant impairment in spatial memory retention was observed in the probe trial after the first day of hidden platform training (first probe trial) in animals that received LV, 5‐Fu, and 5‐Fu/LV. However, by day 5, animals that received 5‐Fu only and 5‐Fu/LV showed spatial memory retention in the probe trials, whereas the LV only mice were impaired. We are currently performing microscopy to quantify changes in the activated microglia and brain vasculature. In studies conducted by Mustafa et. al and El Betagy et. al, Lister‐hooded rats were given 5‐Fu and LV and performed the novel location recognition task. For both studies, rats that received 5‐Fu/LV failed to discriminate between the two object locations, suggesting a spatial memory deficit. While these studies are promising, there is still a need to determine how this drug combination affects other aspects of memory and brain function. The present data suggests that LV may exacerbate the cognitive deficits seen with 5‐Fu treatment, as mice that received LV treatment only remained impaired by day 5 of the MWM. Mice that received 5‐Fu and 5‐Fu/LV were also impaired but showed spatial memory retention by day 5.Support or Funding InformationThis work was supported by Pilot Grant under NIH P20 GM109005 (ARA).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.