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Publications

Journal Article Ppublish 1 citation

PubMed: 39976845 DOI: 10.1007/s11357-025-01560-6

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

Geroscience 47(3):3447-3459

Authors: Boglarka Csik, Kiana Vali Kordestan, Rafal Gulej, Roland Patai, Adam Nyul-Toth, Santny Shanmugarama, Peter Mukli, Anna Ungvari, Karl E Balsara, Rene Y McNall, Talayeh Razzaghi, Stefano Tarantini, Andriy Yabluchanskiy, Zoltan Ungvari, Anna Csiszar

Affiliations

  • 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.
  • International Training Program in Geroscience, Doctoral College/Institute of Preventive Medicine and Public Health, Semmelweis University, Budapest, Hungary.
  • Institute of Preventive Medicine and Public Health, Semmelweis University, Budapest, Hungary.
  • 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.
  • Institute of Preventive Medicine and Public Health, Semmelweis University, Budapest, Hungary.
  • Department of Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
  • School of Industrial and Systems Engineering, The University of Oklahoma, Norman, OK, USA.
  • 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. International Training Program in Geroscience, Doctoral College/Institute of Preventive Medicine and Public Health, Semmelweis University, Budapest, Hungary. Department of Health Promotion Sciences, College of Public Health, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA. The Peggy and Charles Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
  • Department of Health Promotion Sciences, College of Public Health, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
  • The Peggy and Charles Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
  • International Training Program in Geroscience, Doctoral College/Institute of Translational Medicine, Semmelweis University, Budapest, Hungary.

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.

MeSH

Microglia, Cells, Blood, Aging, Brain, Neoplasms, Cognitive Dysfunction, Drug Therapy, Aged, Cognition Disorders, Therapeutics, Chemotherapy-Related Cognitive Impairment, Genes, P16, Methotrexate, Chemotherapy

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