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Senolytic treatment alleviates doxorubicin-induced chemobrain

ABSTRACT: Doxorubicin (Dox) is a widely used treatment for cancer, which can result in chemotherapy induced cognitive impairments (chemobrain). Chemobrain is associated with inflammation and oxidative stress similar to aging. As such, Dox treatment has also been used as a model of aging. However, it is unclear if Dox induces brain changes similar to that observed during aging, since Dox does not readily enter the brain. Rather, the mechanism for chemobrain likely involves induction of peripheral cellular senescence and the release ofsenescence-associated secretory phenotype (SASP) factors, which enter the brain to disrupt cognition. We examined the effect of Dox on peripheral and brain markers of aging and cognition. In addition, we employed the senolytic, ABT-263, which also has limited access to the brain. While Dox treatment influenced several measures linked to aging, including peripheral inflammation, morphological measure of microglial activation, cognition, and synaptic function,the effects of Dox treatment on brain (i.e. dentate gyrus) gene expression did not approximate aging to the same degree as other measures.Regardless, ABT-263 prevent or limited most of the Dox induced effects, including brain gene expression. The resultsemphasize a link between cognitive decline and the release of SASP factors from peripheral senescent cells and indicate thatdifferences between aging and Dox treatment on brain gene expression are important in considering Dox treatment as a model of aging.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE236404 | GEO | 2024/02/26

REPOSITORIES: GEO

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