Inhibition of NLRP3 Alleviated Chemotherapy-Induced Cognitive Impairment in Rats

Chemotherapy results in long-term effects on cognitive dysfunction called chemotherapy-induced cognitive impairment (CICI) in cancer survivors. However, little is known about the potential molecular mechanisms of CICI. This study aimed to determine the role and potential underlying mechanisms of the nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome in cognitive impairments induced by chemotherapeutic agents commonly used in breast cancer. The cognitive effects of chemotherapy were investigated in a rat model using the cocktail of doxorubicin and cyclophosphamide. The NLRP3 pathway was found to be differentially expressed after chemotherapy by iTRAQ-based proteomic analysis of normal and chemotherapeutic hippocampi. Treatment with the NLRP3 inhibitor MCC950 following chemotherapy significantly reduced cognitive impairment and decreased the expression of NLRP3, caspase-1 and ASC. Chemotherapy led to increased expression of the glial response markers Iba-1 and GFAP and the axonal injury markers NF-L and NF-M, an elevated number of apoptotic cells and enhanced microstructural damage to axons and mitochondria, while MCC950 treatment alleviated the glial response, cell death and axonal injury. The protective effect of MCC950 was related to the NLRP3 pathway and levels of inflammatory cytokines (TNF-α, IL-1β, IL-18, IL-6, IL-4, and IL-10) and oxidative stress-responsive markers (SOD, MDA, CAT and GSH). The results indicate that CICI is associated with NLRP3 pathway-induced oxidative damage and the inflammatory response and provide a potential therapeutic target to treat cognitive impairment after chemotherapy (doxorubicin and cyclophosphamide).