Evaluating the NLRP3 inflammasome in chemotherapy-induced cognitive impairment: A multi-timepoint study of methotrexate and 5-fluorouracil in female rats.

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Chemotherapy-induced cognitive impairment (CICI) affects many cancer survivors, who often report cognitive difficulties during and/or after treatment that reduce quality of life. While the exact mechanisms that underlie CICI are unclear, neuroinflammation is widely proposed to contribute. One candidate mediator is the nucleotide-binding domain leucine-rich repeat and pyrin domain containing receptor protein 3 (NLRP3) inflammasome, which drives microglial inflammation and is implicated in Parkinson's and Alzheimer's disease. This study therefore investigated whether NLRP3 inflammasome components are altered in a rat model of CICI. Female Sprague Dawley rats were randomly allocated to receive methotrexate (MTX), 5-fluorouracil (5-FU) or saline (n = 18/treatment) and were euthanised at 96-hours, 31-days or 93-days post-treatment (n = 6/treatment/timepoint). This cohort was previously shown to develop cognitive deficits. In the prefrontal cortex and hippocampus, NLRP3 and pro-caspase-1 were measured by western blot, and interleukin-1β (IL-1β) by ELISA. Microglial number and activation were assessed by ionized calcium-binding adaptor molecule 1 (IBA1) immunohistochemistry (n = 4/treatment/timepoint). Compared with saline controls, neither chemotherapy altered NLRP3 or pro-caspase-1 in either brain region at any timepoint, and treatment effect sizes were small (ηp² ≤ 0.06). IL-1β, detectable only at 96-hours, was also unchanged. Similarly, there were no differences in either total microglial number or the percentage of activated microglia. These findings provide no evidence that NLRP3 inflammasome components are altered in this female rat model of CICI at the timepoints examined. However, as inflammasome assembly and activation were not directly assessed, future work should measure ASC speck formation, cleaved caspase-1 and mature IL-1β, and include earlier timepoints, particularly within the first two weeks after chemotherapy.

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