Senolytic treatment alleviates doxorubicin-induced chemobrain

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.多柔比星（Doxorubicin, Dox）是临床广泛应用的抗肿瘤化疗药物，但其可引发化疗诱导的认知障碍（化疗脑，chemobrain）。化疗脑的病理特征与衰老相似，均伴随炎症反应与氧化应激的发生，因此多柔比星常被用作衰老研究模型。然而，由于多柔比星难以有效透过血脑屏障，目前尚不明确其是否会诱导出与自然衰老一致的脑部改变。现有研究推测，化疗脑的潜在机制并非药物直接作用于脑组织，而是通过诱导外周细胞衰老并释放衰老相关分泌表型（SASP）因子，后者经血液循环进入脑部并破坏认知功能。 本研究评估了多柔比星对外周组织与脑部衰老及认知相关标志物的影响。此外，我们选用了同样难以透过血脑屏障的衰老清除剂（senolytic）ABT-263开展干预实验。结果显示，尽管多柔比星可对多项衰老相关指标产生影响，包括外周炎症水平、小胶质细胞激活的形态学特征、认知功能与突触功能，但该药物对脑部（即齿状回，dentate gyrus）基因表达的影响，并未像其他检测指标那样达到与衰老相似的程度。 尽管如此，ABT-263可有效阻断或缓解绝大多数多柔比星诱导的生物学效应，包括脑部基因表达的异常改变。本研究结果明确了外周衰老细胞释放的SASP因子与认知衰退之间的关联，同时提示，在将多柔比星作为衰老研究模型时，自然衰老与多柔比星处理在脑部基因表达层面的差异，是该模型应用中需重点关注的关键因素。