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Chemotherapy‐Induced Vascular Cognitive Impairment: Role of Endothelial Senescence
Author(s) -
Ahire Chetan,
Balasubramanian Priya,
Tarantini Stefano,
Toth Adam Nyul,
Kiss Tamas,
Ungvari Zoltan,
Csiszar Anna
Publication year - 2021
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2021.35.s1.02839
Subject(s) - neuroinflammation , medicine , chemotherapy , blood–brain barrier , senescence , adverse effect , cognitive decline , endothelial dysfunction , cognition , neuroscience , oncology , immunology , psychology , inflammation , dementia , disease , psychiatry , central nervous system
There is overwhelming evidence from studies on long‐term breast cancer survivors that chemotherapy induces progressive, long‐lasting adverse effects on cognitive function in 30 to 50% of patients. Chemotherapy affects multiple cognitive domains, including working memory, visual and verbal function, attention, processing speed, and executive function. Importantly, no strategies exist to prevent/reverse chemotherapy induced cognitive impairment (CICI). Progress in this field is hampered by the lack of adequately controlled clinical studies, making it difficult to draw definitive conclusions regarding CICI mechanisms. We have established an innovative mouse model to address this question, i.e., cancer‐free p16‐3MR mice treated with the chemotherapeutic drug paclitaxel (PTX). Hypothesis Our working hypothesis is that endothelial senescence is a major contributor to neurovascular dysfunction, microvascular rarefaction, dysregulation of cerebral blood flow and blood‐brain barrier (BBB) disruption causing adverse cognitive outcomes after chemotherapy. Result Behavioral assessment with radial arm water maze provided evidence for chronically impaired cognitive function ( n=20, p<0.05). Although chemotherapeutics does not cross the blood‐brain barrier; endothelial cells linings of blood vessels are exposed to the highest concentrations of these drugs, making them uniquely vulnerable to drug‐induced DNA damage. This DNA damage was observed in the cortex of PTX treated mice quantitively. An increase in number and activation of microglia ( p=0.0001) were also observed in response to PTX treatment, highlighting the involvement of DNA damage and neuroinflammation in response to PTX treatment. Flow cytometry‐based analysis of cerebrovascular endothelial cells proved that the number of senescent endothelial cells has increased in the brain following chronic PTX treatment ( p<0.05). Also, endothelial senescence has also been observed to regulate inflammatory cytokine production in the brain. Additionally, in past we showed that endothelial vasodilator dysfunction affects cognitive function; thus, functional hyperemia responses and the blood‐brain barrier (BBB) integrity were assessed in the somatosensory cortex. Comparison of the results from control and PTX‐treated animals showed that endothelial‐dependent cerebral blood flow responses were markedly attenuated ( p=0.07) and BBB integrity (40KDa tracer; p=0.0412 ) is compromised in PTX treated mice. Treatment with PTX has also been observed to cause vascular rarefaction in the somatosensory cortex ( p<0.05) . Conclusion Our findings concur with our hypothesis that PTX treatment induces cellular senescence in cerebromicrovascular endothelial cells as a DNA damage response and contributing to vascular rarefaction, decreased cerebral blood flow and BBB impairment, thus inducing neuroinflammation and cognitive impairment.