Cisplatin and methotrexate induce brain microvascular endothelial and microglial senescence in mouse models of chemotherapy-associated cognitive impairment

Abstract

The increasing number of cancer survivors has brought heightened attention to the side effects of cancer therapies, including chemotherapy-related cognitive impairment (CRCI, commonly referred to as “chemobrain”). Cisplatin and methotrexate, commonly used first-line chemotherapeutics in gynecologic oncology for cancers such as breast, ovarian, and bladder cancer, are clinically associated with long-term cognitive deficits. Building on our previous preclinical studies demonstrating that paclitaxel chemotherapy induces cerebrovascular endothelial and microglial senescence—leading to blood–brain barrier (BBB) disruption, neuroinflammation, and cognitive impairments—we hypothesized that cisplatin and methotrexate might similarly promote senescence in these cells. Senescent endothelial cells and microglia are known to contribute to neuroinflammation, cerebral blood flow dysregulation, and white matter damage, exacerbating cognitive decline. Using the p16-3MR mouse model, which expresses red fluorescent protein (RFP) in p16 + senescent cells, we evaluated the impact of these drugs on brain endothelial and microglial senescence through flow cytometry. Our results show a significant increase in senescent endothelial and microglial cells two months post-treatment with cisplatin or methotrexate compared to controls. These findings offer new insights into the shared mechanisms underlying CRCI associated with cisplatin or methotrexate treatment, extending our understanding of chemotherapy-induced vascular cognitive impairments.