Accelerated cerebromicrovascular senescence contributes to cognitive decline in a mouse model of paclitaxel (Taxol)-induced chemobrain.

Mice Animals Chemotherapy-Related Cognitive Impairment Endothelial Cells Paclitaxel / adverse effects Senotherapeutics Cognitive Dysfunction Disease Models, Animal
aging chemotherapy chemotherapy-induced cognitive impairment dementia functional hyperemia senescence vascular cognitive impairment

Journal

Aging cell
ISSN: 1474-9726
Titre abrégé: Aging Cell
Pays: England
ID NLM: 101130839

Informations de publication

Date de publication:
07 2023
Historique:
revised: 20 03 2023
received: 29 01 2023
accepted: 21 03 2023
medline: 19 7 2023
pubmed: 27 5 2023
entrez: 27 5 2023
Statut: ppublish

Résumé

Chemotherapy-induced cognitive impairment ("chemobrain") is a frequent side-effect in cancer survivors treated with paclitaxel (PTX). The mechanisms responsible for PTX-induced cognitive impairment remain obscure, and there are no effective treatments or prevention strategies. Here, we test the hypothesis that PTX induces endothelial senescence, which impairs microvascular function and contributes to the genesis of cognitive decline. We treated transgenic p16-3MR mice, which allows the detection and selective elimination of senescent cells, with PTX (5 mg/kg/day, 2 cycles; 5 days/cycle). PTX-treated and control mice were tested for spatial memory performance, neurovascular coupling (NVC) responses (whisker-stimulation-induced increases in cerebral blood flow), microvascular density, blood-brain barrier (BBB) permeability and the presence of senescent endothelial cells (by flow cytometry and single-cell transcriptomics) at 6 months post-treatment. PTX induced senescence in endothelial cells, which associated with microvascular rarefaction, NVC dysfunction, BBB disruption, neuroinflammation, and impaired performance on cognitive tasks. To establish a causal relationship between PTX-induced senescence and impaired microvascular functions, senescent cells were depleted from PTX-treated animals (at 3 months post-treatment) by genetic (ganciclovir) or pharmacological (treatment with the senolytic drug ABT263/Navitoclax) means. In PTX treated mice, both treatments effectively eliminated senescent endothelial cells, rescued endothelium-mediated NVC responses and BBB integrity, increased capillarization and improved cognitive performance. Our findings suggest that senolytic treatments can be a promising strategy for preventing chemotherapy-induced cognitive impairment.

Identifiants

DOI: 10.1111/acel.13832 PMID: 37243381 PMC: PMC10352561
pubmed: 37243381
doi: 10.1111/acel.13832
pmc: PMC10352561
doi:

Substances chimiques

Paclitaxel P88XT4IS4D
Senotherapeutics 0

Types de publication

Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

e13832

Subventions

Organisme : NIA NIH HHS
ID : R03 AG070479
Pays : United States
Organisme : NIA NIH HHS
ID : K01 AG073613
Pays : United States
Organisme : NIA NIH HHS
ID : R01 AG068295
Pays : United States
Organisme : NIA NIH HHS
ID : R01 AG055395
Pays : United States
Organisme : NIA NIH HHS
ID : K01 AG073614
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS056218
Pays : United States
Organisme : NIA NIH HHS
ID : RF1 AG072295
Pays : United States
Organisme : NIGMS NIH HHS
ID : U54 GM104938
Pays : United States
Organisme : NIGMS NIH HHS
ID : P30 GM110766
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA225520
Pays : United States
Organisme : NIA NIH HHS
ID : P30 AG050911
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA255840
Pays : United States
Organisme : NIGMS NIH HHS
ID : P20 GM125528
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS100782
Pays : United States
Organisme : NIA NIH HHS
ID : R01 AG070915
Pays : United States

Informations de copyright

© 2023 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

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Auteurs

Chetan Ahire (C)

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

Adam Nyul-Toth (A)

Vascular Cognitive Impairment, Neurodegeneration and Healthy Brain Aging Program, Department of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
Oklahoma Center for Geroscience and Healthy Brain Aging, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
International Training Program in Geroscience, Doctoral School of Basic and Translational Medicine/Departments of Public Health and Translational Medicine, Semmelweis University, Budapest, Hungary.
International Training Program in Geroscience, Institute of Biophysics, Biological Research Centre, ELKH, Szeged, Hungary.

Jordan DelFavero (J)

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

Rafal Gulej (R)

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

Janet A Faakye (JA)

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

Stefano Tarantini (S)

Vascular Cognitive Impairment, Neurodegeneration and Healthy Brain Aging Program, Department of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
Oklahoma Center for Geroscience and Healthy Brain Aging, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
International Training Program in Geroscience, Doctoral School of Basic and Translational Medicine/Departments of Public Health and Translational Medicine, Semmelweis University, Budapest, Hungary.
Department of Health Promotion Sciences, College of Public Health, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
The Peggy and Charles Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.

Tamas Kiss (T)

Oklahoma Center for Geroscience and Healthy Brain Aging, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
International Training Program in Geroscience, First Department of Pediatrics, Semmelweis University, Budapest, Hungary.

Anna Kuan-Celarier (A)

Oklahoma Center for Geroscience and Healthy Brain Aging, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
The Peggy and Charles Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.

Priya Balasubramanian (P)

Vascular Cognitive Impairment, Neurodegeneration and Healthy Brain Aging Program, Department of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
Oklahoma Center for Geroscience and Healthy Brain Aging, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
The Peggy and Charles Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.

Anna Ungvari (A)

Vascular Cognitive Impairment, Neurodegeneration and Healthy Brain Aging Program, Department of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
Oklahoma Center for Geroscience and Healthy Brain Aging, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
International Training Program in Geroscience, Doctoral School of Basic and Translational Medicine/Departments of Public Health and Translational Medicine, Semmelweis University, Budapest, Hungary.

Amber Tarantini (A)

Vascular Cognitive Impairment, Neurodegeneration and Healthy Brain Aging Program, Department of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
Oklahoma Center for Geroscience and Healthy Brain Aging, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
International Training Program in Geroscience, Doctoral School of Basic and Translational Medicine/Departments of Public Health and Translational Medicine, Semmelweis University, Budapest, Hungary.
The Peggy and Charles Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.

Raghavendra Nagaraja (R)

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

Feng Yan (F)

Stephenson School of Biomedical Engineering, Gallogly College of Engineering, The University of Oklahoma, Norman, Oklahoma, USA.

Qinggong Tang (Q)

Stephenson School of Biomedical Engineering, Gallogly College of Engineering, The University of Oklahoma, Norman, Oklahoma, USA.

Peter Mukli (P)

Vascular Cognitive Impairment, Neurodegeneration and Healthy Brain Aging Program, Department of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
Oklahoma Center for Geroscience and Healthy Brain Aging, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
International Training Program in Geroscience, Doctoral School of Basic and Translational Medicine/Departments of Public Health and Translational Medicine, Semmelweis University, Budapest, Hungary.

Tamas Csipo (T)

Oklahoma Center for Geroscience and Healthy Brain Aging, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
International Training Program in Geroscience, Doctoral School of Basic and Translational Medicine/Departments of Public Health and Translational Medicine, Semmelweis University, Budapest, Hungary.

Andriy Yabluchanskiy (A)

Vascular Cognitive Impairment, Neurodegeneration and Healthy Brain Aging Program, Department of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
Oklahoma Center for Geroscience and Healthy Brain Aging, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
Department of Health Promotion Sciences, College of Public Health, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
The Peggy and Charles Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.

Judith Campisi (J)

Buck Institute for Research on Aging, Novato, California, USA.
ORCID: 0000-0001-6858-9462

Zoltan Ungvari (Z)

Vascular Cognitive Impairment, Neurodegeneration and Healthy Brain Aging Program, Department of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
Oklahoma Center for Geroscience and Healthy Brain Aging, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
International Training Program in Geroscience, Doctoral School of Basic and Translational Medicine/Departments of Public Health and Translational Medicine, Semmelweis University, Budapest, Hungary.
Department of Health Promotion Sciences, College of Public Health, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
The Peggy and Charles Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
ORCID: 0000-0002-6035-6039

Anna Csiszar (A)

Vascular Cognitive Impairment, Neurodegeneration and Healthy Brain Aging Program, Department of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
Oklahoma Center for Geroscience and Healthy Brain Aging, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
International Training Program in Geroscience, Doctoral School of Basic and Translational Medicine/Departments of Public Health and Translational Medicine, Semmelweis University, Budapest, Hungary.
The Peggy and Charles Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.

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Classifications MeSH

questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Accelerated cerebromicrovascular senescence...
questionsmedicales.fr › Eucaryotes › Animaux › Accelerated cerebromicrovascular senescence...
questionsmedicales.fr › Troubles mentaux › Troubles neurocognitifs › Troubles de la cognition › Dysfonctionnement cognitif › Altération cognitive liée à la chimiothérapie › Accelerated cerebromicrovascular senescence...
questionsmedicales.fr › Cellules › Cellules épithéliales › Cellules endothéliales › Accelerated cerebromicrovascular senescence...
questionsmedicales.fr › Composés chimiques organiques › Hydrocarbures › Terpènes › Diterpènes › Taxoïdes › Paclitaxel › Accelerated cerebromicrovascular senescence...
questionsmedicales.fr › Actions chimiques et utilisations › Actions pharmacologiques › Utilisations thérapeutiques › Sénothérapie › Accelerated cerebromicrovascular senescence...
questionsmedicales.fr › Troubles mentaux › Troubles neurocognitifs › Troubles de la cognition › Dysfonctionnement cognitif › Accelerated cerebromicrovascular senescence...
questionsmedicales.fr › Techniques d'investigation › Modèles théoriques › Modèles biologiques › Modèles animaux de maladie humaine › Accelerated cerebromicrovascular senescence...