Chandragiri Siva Sai, Nyul-Toth Adam, Negri Sharon, Patai Roland, Gulej Rafal, Csik Boglarka, Shanmugarama Santny, Vali Kordestan Kiana, Nagykaldi Mark, Mukli Peter, Ungvari Anna, Yabluchanskiy Andriy, Ungvari Zoltan, Tarantini Stefano, 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 Mar 25. doi: 10.1007/s11357-025-01624-7.
Chemotherapy-induced cognitive impairment (CICI), often referred to as "chemobrain," significantly affects the quality of life in cancer survivors. Although traditionally attributed to neuronal toxicity, emerging evidence suggests a key role of cerebrovascular dysfunction in its pathogenesis. We hypothesized that paclitaxel (PTX, Taxol) treatment induces long-term cerebrovascular dysfunction, including microvascular rarefaction, impaired neurovascular coupling (NVC), and altered cerebral blood flow (CBF), which contribute to CICI. Using a clinically relevant PTX treatment regimen in non-tumor-bearing mice, we evaluated the long-term effects of PTX on cerebrovascular health. Ultrasound localization microscopy (ULM) and functional ultrasound imaging (fUS) were employed to assess microvascular density, CBF, and NVC. PTX treatment resulted in a significant reduction in microvascular density in the cerebral cortex and hippocampus, key regions involved in cognitive function. PTX significantly reduced blood velocity in the middle cerebral artery. Moreover, PTX impaired NVC responses, as evidenced by a diminished CBF increase in response to whisker stimulation, indicative of impaired reactive hyperemia. In conclusion, these findings demonstrate that PTX induces long-lasting cerebrovascular dysfunction, including microvascular rarefaction, impaired NVC, and altered CBF dynamics, which likely contribute to CICI. This study underscores the critical role of cerebrovascular health in cognitive function and highlights the potential of targeting cerebrovascular pathways as a therapeutic approach for mitigating chemotherapy-induced cognitive deficits.
化疗引起的认知障碍（CICI），通常被称为“化疗脑”，严重影响癌症幸存者的生活质量。尽管传统上认为其归因于神经元毒性，但新出现的证据表明脑血管功能障碍在其发病机制中起关键作用。我们假设紫杉醇（PTX，泰素）治疗会导致长期的脑血管功能障碍，包括微血管稀疏、神经血管耦合（NVC）受损和脑血流量（CBF）改变，这些因素导致了CICI。在无肿瘤小鼠中使用临床相关的PTX治疗方案，我们评估了PTX对脑血管健康的长期影响。采用超声定位显微镜（ULM）和功能超声成像（fUS）来评估微血管密度、CBF和NVC。PTX治疗导致大脑皮层和海马体（认知功能的关键区域）的微血管密度显著降低。PTX显著降低了大脑中动脉的血流速度。此外，PTX损害了NVC反应，表现为对触须刺激的反应中CBF增加减弱，这表明反应性充血受损。总之，这些发现表明PTX会导致持久的脑血管功能障碍，包括微血管稀疏、NVC受损和CBF动态改变，这可能导致了CICI。这项研究强调了脑血管健康在认知功能中的关键作用，并突出了靶向脑血管途径作为减轻化疗引起的认知缺陷的治疗方法的潜力。
