Persisting Blood-Brain Barrier Disruption Following Cisplatin Treatment in a Mouse Model of Chemotherapy-Associated Cognitive Impairment

Chemotherapy-related cognitive impairment, commonly referred to as "chemobrain," significantly affects cancer survivors' quality of life, yet its underlying mechanisms remain unclear. Most chemotherapeutic agents cannot cross the blood-brain barrier (BBB), yet they cause central nervous system side effects, suggesting alternative pathways of toxicity. Given that these drugs interact with the cerebrovascular endothelium at their highest concentrations, it is logical to hypothesize that endothelial damage contributes to these effects. Our recent studies demonstrated that paclitaxel-induced cognitive impairment in a mouse model results, at least in part, from persistent BBB disruption and subsequent neuroinflammation, mediated by chemotherapy-induced endothelial senescence. In this pilot study, we used two-photon microscopy to assess BBB permeability in mice receiving a clinically relevant cisplatin regimen, evaluating the leakage of fluorescent dextran tracers of varying molecular weights. Two months post-treatment, cisplatin-treated mice exhibited significantly increased BBB permeability to smaller molecular tracers (40, kDa, 3 kDa and 0.3 kDa) compared to controls, indicating sustained BBB disruption. These results align with our findings for paclitaxel and suggest that chemotherapy-induced endothelial damage and senescence play a central role in cognitive impairments. Interventions targeting endothelial health could mitigate these long-term effects, improving cognitive outcomes for cancer survivors. NIA R01AG072295, R01AG055395, R01AG068295, R01AG070915; NINDS R01NS100782; NCI R01CA255840; AHA916225, AHA.24CDA1276505.pc.gr.193648, AHA CDA941290. This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.