PhD Scientific Days 2025

Poster Session II. - J: Theoretical and Translational Medicine

Chemo- and Radiotherapy Promote Cerebrovascular Senescence, Blood–Brain Barrier Dysfunction and Microhemorrhages in a Preclinical Model of Pediatric Medulloblastoma

Name of the presenter

Nagy Dorina

Institute/workplace of the presenter

Vascular Cognitive Impairment, Neurodegeneration and Healthy Brain Aging Program, Department of Neurosurgery, OUHSC, OKC, OK, USA

Authors

Dorina Nagy^1,2, Boglarka Csik^2,3, Kiana Vali Kordestan^2,3, Roland Patai^2,3, Adam Nyul-Toth^2,3, Siva Sai Chandragiri^2,3, Rafal Gulej^2,3, Raghavendra Y. Nagaraja^2,3, Santny Shanmugarama^2,3, Shoba Ekambaram^2,3, Mark Nagykaldi^2,3, Zoltan Benyo¹, Zoltan Ungvari^2,3, Anna Csiszar^2,3

1: Institute of Translational Medicine, Budapest, Semmelweis University
2: Oklahoma Center for Geroscience and Healthy Brain Aging, OUHSC, OKC, OK, USA
3: Vascular Cognitive Impairment, Neurodegeneration and Healthy Brain Aging Program, Department of Neurosurgery, OUHSC, OKC, OK, USA

Text of the abstract

Introduction: Chemotherapy-induced cognitive impairment is a long-term consequence in survivors of pediatric medulloblastoma, particularly prevalent among those treated with combination chemotherapy (CCT) and cranial radiotherapy (CRT). These survivors face late-onset cerebrovascular complications, such as cerebral small vessel disease, microhemorrhages, and stroke, suggesting a possible vascular contribution to cognitive decline. However, the link between therapy-induced vascular injury and neurocognitive dysfunction is not fully understood. Growing evidence suggests that the accumulation of senescent cells in the cerebral microvasculature impairs blood-brain barrier (BBB) integrity and promotes neurovascular injury.
Aims: To determine whether CCT+CRT accelerates cerebrovascular aging by promoting endothelial and microglial senescence, thereby leading to BBB disruption, cerebral microhemorrhage (CMH) formation, and ultimately, neurovascular dysfunction.
Methods: Transgenic p16-3MR mice, which express red fluorescent protein enabling the identification of senescent cells, received clinically relevant fractionated CRT (5 Gy, twice weekly for 2.5 weeks) and CCT (cisplatin, vincristine, cyclophosphamide) treatment. Senescence in brain endothelial cells and microglia was quantified by flow cytometry. BBB permeability was assessed via intravital two-photon imaging using 40kDa, 3kDa, and 0.3kDa fluorescent dextrans. Since mice do not spontaneously develop CMHs, we used a fluctuating high blood pressure model (angiotensin-II and L-NAME) as a vascular stressor to promote CMH formation. Then, the number, volume, and regional distribution of CMHs were quantified.
Results: Preliminary results of flow cytometry confirmed that CCT+CRT significantly increased endothelial senescence. BBB assessment revealed that CCT+CRT causes severe leakage and structural degradation. CCT+CRT significantly accelerated the onset of neurological signs associated with CMHs, and the number and volume of CMHs were markedly higher in the treated group compared to controls.
Conclusion: CCT+CRT-induced cellular senescence compromises cerebrovascular integrity, leading to BBB breakdown and CMH formation. These therapy-induced changes recapitulate an accelerated aging phenotype that may underlie progressive cognitive impairment in childhood brain tumor survivors.
Funds: NCIR01CA255840