Senolytic treatment alleviates doxorubicin‐induced chemobrain

Abstract

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.

Failure of senolytic treatment to prevent cognitive decline in a female rodent model of aging

“…Impaired memory in males and females is linked to N-methyl-D-aspartate (NMDA) receptor hypofunction and alterations in synaptic plasticity processes that mediate episodic memory ( Kumar and Foster, 2013 ; Kumar et al, 2018 ; Barter et al, 2020 ; Budamagunta et al, 2023 ). In males, senolytic treatment increases hippocampal synaptic transmission, increasing NMDA receptor function and episodic memory ( Budamagunta et al, 2023 , 2024 ). Similarly, activation of membrane estrogen receptors in females increases NMDA receptor function and episodic memory ( Foster, 2005 ; Bean et al, 2015 ).…”

“…The two treatments act on different mechanisms to promote apoptosis of senescent cells ( Chan et al, 2012 ; Zhu et al, 2016 ) and quercetin is an antioxidant ( Ishisaka et al, 2014 ). Importantly, dasatinib and quercetin, but not ABT-263, cross the blood brain barrier ( Porkka et al, 2008 ; Yamaguchi and Perkins, 2012 ; Ishisaka et al, 2014 ; Mehdipour et al, 2021 ; Budamagunta et al, 2023 , 2024 ). Both treatments improve cognition in males, emphasizing a link between cognitive decline and senescent cells in the periphery ( Budamagunta et al, 2023 , 2024 ).…”

“…Importantly, dasatinib and quercetin, but not ABT-263, cross the blood brain barrier ( Porkka et al, 2008 ; Yamaguchi and Perkins, 2012 ; Ishisaka et al, 2014 ; Mehdipour et al, 2021 ; Budamagunta et al, 2023 , 2024 ). Both treatments improve cognition in males, emphasizing a link between cognitive decline and senescent cells in the periphery ( Budamagunta et al, 2023 , 2024 ). However, there are several mechanisms involved in aging and sex differences, particularly hormonal differences, contribute to age-related cognitive decline ( Foster, 2005 ; Bean et al, 2014 ).…”

Ohwia caudata aqueous extract attenuates senescence in aging adipose-derived mesenchymal stem cells

“…In in vitro studies, low concentrations of doxorubicin have been found to induce aging in various cell types, including cardiomyocytes [ 25 ], human cardiac progenitor cells [ 26 ], vascular smooth muscle cells, human chondrocytes [ 27 ], fibroblasts [ 28 ], and several different types of human stem cells [ 29 , 30 ]. Similarly, in in vivo studies, doxorubicin has been validated to elevate senescence in C57BL/6 mice, result in brain aging in Fischer 344 rats and induce cellular senescence in murine ovaries [ 24 , 31 , 32 ]. Therefore, in the present study, doxorubicin was used as an aging inducer to induce stem cell senescence.…”