Senolytic treatment alleviates doxorubicin-induced chemobrain

Doxorubicin (Dox), a widely used treatment for cancer, 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 the induction of peripheral cellular senescence and the release of senescence-associated secretory phenotype (SASP) factors and these SASP factors can 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. The results indicate that plasma SASP factors enter the brain, activating microglia, increasing oxidative stress, and altering gene transcription. In turn, the synaptic function required for memory was reduced in response to altered redox signaling. ABT-263 prevented or limited most of the Dox-induced effects. The results emphasize a link between cognitive decline and the release of SASP factors from peripheral senescent cells and indicate some differences as well as similarities between advanced age and Dox treatment. Doxorubicin (Dox) has limited brain access, and Dox treatments have nominal effects on brain genes that change with age. Nevertheless, Dox treatments mirrored other markers of aging; promoting peripheral cell senescence, pro-inflammatory cytokines, microglial activation, a redox-sensitive decrease in synaptic function, and impaired memory. The senolytic, ABT-263, also has limited brain access. ABT-263 treatments counteracted Dox effects to maintain memory function. The results highlight a link between peripheral cell senescence and the age-related impairment of synaptic function required for memory.image