Accelerated cerebromicrovascular senescence contributes to cognitive decline in a mouse model of paclitaxel (Taxol)-induced chemobrain.
Chetan AhireAdam Nyul-TothJordan DelFaveroRafal GulejJanet A FaakyeStefano TarantiniTamas KissAnna Kuan-CelarierPriya BalasubramanianAnna UngvariAmber TarantiniRaghavendra NagarajaFeng YanQinggong TangPeter MukliTamas CsipoAndriy YabluchanskiyPierre-Yves DesprezZoltan I UngvariAnna CsiszarPublished in: Aging cell (2023)
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.
Keyphrases
- endothelial cells
- high glucose
- cognitive decline
- blood brain barrier
- cognitive impairment
- mild cognitive impairment
- chemotherapy induced
- diabetic rats
- single cell
- dna damage
- mouse model
- drug induced
- flow cytometry
- nitric oxide
- stress induced
- induced apoptosis
- oxidative stress
- magnetic resonance imaging
- vascular endothelial growth factor
- dna methylation
- brain injury
- lipopolysaccharide induced
- cell death
- metabolic syndrome
- adipose tissue
- cerebral ischemia
- young adults
- lps induced
- pi k akt
- ionic liquid
- signaling pathway
- newly diagnosed
- rna seq
- insulin resistance