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Elimination of senescent cells by treatment with Navitoclax/ABT263 reverses whole brain irradiation-induced blood-brain barrier disruption in the mouse brain

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Abstract

Whole brain irradiation (WBI), a commonly employed therapy for multiple brain metastases and as a prophylactic measure after cerebral metastasis resection, is associated with a progressive decline in neurocognitive function, significantly impacting the quality of life for approximately half of the surviving patients. Recent preclinical investigations have shed light on the multifaceted cerebrovascular injury mechanisms underlying this side effect of WBI. In this study, we aimed to test the hypothesis that WBI induces endothelial senescence, contributing to chronic disruption of the blood-brain barrier (BBB) and microvascular rarefaction. To accomplish this, we utilized transgenic p16-3MR mice, which enable the identification and selective elimination of senescent cells. These mice were subjected to a clinically relevant fractionated WBI protocol (5 Gy twice weekly for 4 weeks), and cranial windows were applied to both WBI-treated and control mice. Quantitative assessment of BBB permeability and capillary density was performed using two-photon microscopy at the 6-month post-irradiation time point. The presence of senescent microvascular endothelial cells was assessed by imaging flow cytometry, immunolabeling, and single-cell RNA-sequencing (scRNA-seq). WBI induced endothelial senescence, which associated with chronic BBB disruption and a trend for decreased microvascular density in the mouse cortex. In order to investigate the cause-and-effect relationship between WBI-induced senescence and microvascular injury, senescent cells were selectively removed from animals subjected to WBI treatment using Navitoclax/ABT263, a well-known senolytic drug. This intervention was carried out at the 3-month post-WBI time point. In WBI-treated mice, Navitoclax/ABT263 effectively eliminated senescent endothelial cells, which was associated with decreased BBB permeability and a trend for increased cortical capillarization. Our findings provide additional preclinical evidence that senolytic treatment approaches may be developed for prevention of the side effects of WBI.

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Acknowledgements

This work was supported by grants from the American Heart Association (ANT: AHA834339) and (ST: AHA CDA941290), the Oklahoma Center for the Advancement of Science and Technology, the National Institute on Aging (RF1AG072295, R01AG055395, R01AG068295; R01AG070915, K01AG073614, K01AG073613, R03AG070479), the National Institute of Neurological Disorders and Stroke (R01NS100782), the National Cancer Institute (R01CA255840), the Oklahoma Shared Clinical and Translational Resources (U54GM104938) with an Institutional Development Award (IDeA) from NIGMS, the Presbyterian Health Foundation, the Reynolds Foundation, the Oklahoma Nathan Shock Center (P30AG050911), and the Cellular and Molecular GeroScience CoBRE (P20GM125528), the NCI Cancer Center Support Grant (P30 CA225520), and the Oklahoma Tobacco Settlement Endowment Trust. Analysis help was provided by the Oklahoma Medical Research Foundation Quantitative Analysis Core supported by COBRE grant 1 P30 GM110766-01 and the Oklahoma Shared Clinical and Translational Resources (U54GM104938) with an Institutional Development Award (IDeA) from NIGMS. PP was supported by the Intramural Program of NIAAA/NIH. TK was supported by Project no. TKP2021-NKTA-47, implemented with the support provided by the Ministry of Innovation and Technology of Hungary from the National Research, Development and Innovation Fund, financed under the TKP2021-NKTA funding scheme; by funding through the National Cardiovascular Laboratory Program (RRF-2.3.1-21-2022-00003) provided by the Ministry of Innovation and Technology of Hungary from the National Research, Development and Innovation Fund; Project no. 135784 implemented with the support provided from the National Research, Development and Innovation Fund of Hungary, financed under the K_20 funding scheme and the European University for Well-Being (EUniWell) program (grant agreement number: 101004093/ EUniWell/EAC-A02-2019/EAC-A02-2019-1). The authors express their gratitude for Unity Biotechnology, Inc. for providing the p16-3MR mouse model. The funding sources had no role in the study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the article for publication. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health, the American Heart Association, or the Presbyterian Health Foundation.

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Authors and Affiliations

  1. Vascular Cognitive Impairment, Neurodegeneration and Healthy Brain Aging Program, Department of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA

    Rafal Gulej, Ádám Nyúl-Tóth, Chetan Ahire, Jordan DelFavero, Priya Balasubramanian, Tamas Kiss, Stefano Tarantini, Boglarka Csik, Andriy Yabluchanskiy, Peter Mukli, Anna Kuan-Celarier, Anna Csiszar & Zoltan Ungvari

  2. Oklahoma Center for Geroscience and Healthy Brain Aging, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA

    Rafal Gulej, Ádám Nyúl-Tóth, Chetan Ahire, Jordan DelFavero, Priya Balasubramanian, Tamas Kiss, Stefano Tarantini, Boglarka Csik, Andriy Yabluchanskiy, Peter Mukli, William E. Sonntag, Anna Csiszar & Zoltan Ungvari

  3. International Training Program in Geroscience, Doctoral School of Basic and Translational Medicine/Department of Public Health, Semmelweis University, Budapest, Hungary

    Rafal Gulej, Ádám Nyúl-Tóth, Stefano Tarantini, Boglarka Csik, Andriy Yabluchanskiy, Peter Mukli & Zoltan Ungvari

  4. International Training Program in Geroscience, Institute of Biophysics, Biological Research Centre, Eötvös Loránd Research Network, Szeged, Hungary

    Ádám Nyúl-Tóth & István A Krizbai

  5. Stephenson Cancer Center, University of Oklahoma, Oklahoma City, OK, USA

    Priya Balasubramanian, Stefano Tarantini, Anna Csiszar & Zoltan Ungvari

  6. International Training Program in Geroscience, First Department of Pediatrics, Semmelweis University, Budapest, Hungary

    Tamas Kiss

  7. Eötvös Loránd Research Network and Semmelweis University (ELKH-SE) Cerebrovascular and Neurocognitive Disorders Research Group, Budapest, Hungary

    Tamas Kiss & Zoltan Benyo

  8. International Training Program in Geroscience, Doctoral School of Basic and Translational Medicine/Department of Translational Medicine, Semmelweis University, Budapest, Hungary

    Tamas Kiss, Zoltan Benyo & Anna Csiszar

  9. Graduate School, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA

    Tamas Kiss & Zoltan Benyo

  10. Laboratory of Cardiovascular Physiology and Tissue Injury, National Institute On Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA

    Pal Pacher

  11. Institute of Life Sciences, Vasile Goldiş Western University of Arad, Arad, Romania

    István A Krizbai

  12. Buck Institute for Research on Aging, Novato, CA, USA

    Judith Campisi

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  1. Rafal Gulej
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  2. Ádám Nyúl-Tóth
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Correspondence to Zoltan Ungvari.

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Competing interests

Dr. Anna Csiszar and Dr. Pal Pacher serve as Associate Editor for The Journal of Gerontology, Series A: Biological Sciences and Medical Sciences and GeroScience. Dr. Zoltan Ungvari serves as Editor-in-Chief for GeroScience and as Consulting Editor for The American Journal of Physiology-Heart and Circulatory Physiology. Dr. Pal Pacher, Dr. Stefano Tarantini, and Dr. Andriy Yabluchanskiy serve as Associate Editors for GeroScience. The authors declare no competing financial interests.

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Rafal Gulej, Ádám Nyúl-Tóth, Chetan Ahire, and Jordan DelFaveroe have qual contributions.

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Gulej, R., Nyúl-Tóth, Á., Ahire, C. et al. Elimination of senescent cells by treatment with Navitoclax/ABT263 reverses whole brain irradiation-induced blood-brain barrier disruption in the mouse brain. GeroScience 45, 2983–3002 (2023). https://doi.org/10.1007/s11357-023-00870-x

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