Changes in cognition and neuroinflammation in a rodent model of chemotherapy-induced cognitive impairment are variable both acutely and chronically

Abstract

Chemotherapy-induced cognitive impairment (CICI) affects up to 75% of cancer survivors between 6-months and 20-years post-treatment. Impairments include memory loss, learning difficulties, inability to concentrate and a decrease in processing speed, all of which can negatively impact quality of life. Several mechanisms are proposed to drive these impairments, with evidence implicating neuroinflammation as a key contributor. However, the time course over which impairments occur is less well-established. Several preclinical studies have focused on acute (0-7 days) and sub-acute (8-days to 12-weeks) time-points following chemotherapy, but few have investigated more longer-term time-points. This study therefore aimed to understand the evolution of cognitive changes following methotrexate (MTX) or 5-flurouracil (5-FU) chemotherapy treatment, assessing three time-points: acute (96-hour), sub-acute (31-days) and chronic (93-days). Further, we investigated whether alterations in cognition were associated with concomitant changes in neuroinflammation, assessed via astrocytic reactivity. Female Sprague Dawley rats received two intraperitoneal injections of MTX, 5-FU or saline and were assessed on the novel object recognition, 5-choice serial reaction time task and Barnes maze. Hippocampal (HIPP) and pre-frontal cortex (PFC) tissue was examined for GFAP expression. Results indicate that both MTX and 5-FU exposure were associated with impairments in spatial memory, task acquisition, and processing speed at 31-days, with impairment ameliorated by 93-days post-treatment. While MTX and 5-FU increased GFAP expression across all time-points, with the largest changes at 96-hours and 31-days, drug-specific and region-specific variations were noted. These results provide valuable insight into the complexity of the neuroinflammatory response in CICI. While neuroinflammation may be a promising therapeutic target, further work is required to fully understand this response, including which aspects to target and at what time-points, to ensure optimal outcomes for cancer patients treated with chemotherapy.