Csik Boglarka, Vali Kordestan Kiana, Gulej Rafal, Patai Roland, Nyul-Toth Adam, Shanmugarama Santny, Mukli Peter, Ungvari Anna, Balsara Karl E, McNall Rene Y, Razzaghi Talayeh, Tarantini Stefano, Yabluchanskiy Andriy, Ungvari Zoltan, Csiszar Anna
Vascular Cognitive Impairment, Neurodegeneration and Healthy Brain Aging Program, Department of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
Oklahoma Center for Geroscience and Healthy Brain Aging, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
Geroscience. 2025 Feb 20. doi: 10.1007/s11357-025-01560-6.
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.
癌症幸存者数量的增加使得人们更加关注癌症治疗的副作用，包括化疗相关的认知障碍（CRCI，通常称为“化疗脑”）。顺铂和甲氨蝶呤是妇科肿瘤学中用于治疗乳腺癌、卵巢癌和膀胱癌等癌症的常用一线化疗药物，在临床上与长期认知缺陷有关。基于我们之前的临床前研究表明紫杉醇化疗会诱导脑血管内皮细胞和小胶质细胞衰老，导致血脑屏障（BBB）破坏、神经炎症和认知障碍，我们假设顺铂和甲氨蝶呤可能同样会促进这些细胞的衰老。已知衰老的内皮细胞和小胶质细胞会导致神经炎症、脑血流调节异常和白质损伤，加剧认知衰退。使用p16-3MR小鼠模型，该模型在p16 +衰老细胞中表达红色荧光蛋白（RFP），我们通过流式细胞术评估了这些药物对脑内皮细胞和小胶质细胞衰老的影响。我们的结果显示，与对照组相比，顺铂或甲氨蝶呤治疗两个月后，衰老的内皮细胞和小胶质细胞显著增加。这些发现为与顺铂或甲氨蝶呤治疗相关的CRCI的共同机制提供了新的见解，扩展了我们对化疗诱导的血管性认知障碍的理解。
