Changes in cognition and astrocytic reactivity in a female rodent model of chemotherapy-induced cognitive impairment are variable both acutely and chronically.

Abstract

Chemotherapy-induced cognitive impairment (CICI) affects female cancer survivors, with impairment recognised in populations such as breast cancer survivors, where 1 in 3 are affected. Impairments include issues with memory, learning, concentration, and processing speed, negatively impacting quality of life. Several mechanisms are proposed to drive these, with evidence implicating neuroinflammation as a key contributor. However, the time course over which impairments occur is less well-established, with fewer longer-term time-points investigated. This study aimed to understand the evolution of cognitive changes following methotrexate (MTX) or 5- fluorouracil (5-FU) chemotherapy, 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 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 and prefrontal cortex tissue was examined for GFAP expression. Both MTX and 5-FU exposure were associated with spatial memory, task acquisition, and processing speed impairments at 31-days, with impairment ameliorated by 93-days. While both MTX and 5-FU induced changes in GFAP expression across various time-points and regions, with most notable changes at 96-hours, 5-FU exhibited expression changes in the hippocampus consistently across all time-points. These results provide valuable insight into the complexity of a mediator of neuroinflammation in CICI. While neuroinflammation may be a promising therapeutic target, further markers should be assessed to elucidate the full neuroimmune response, and thus which aspects to target and when, to ensure optimal outcomes for cancer patients treated with chemotherapy.