Senolytic treatment alleviates doxorubicin-induced chemobrain.

Autor: Budamagunta V; Department of Neuroscience, McKnight Brain Institute, University of Florida, Gainesville, Florida, USA.; Genetics and Genomics Graduate Program, Genetics Institute, University of Florida, Gainesville, Florida, USA.; Department of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, Florida, USA., Kumar A; Department of Neuroscience, McKnight Brain Institute, University of Florida, Gainesville, Florida, USA., Rani A; Department of Neuroscience, McKnight Brain Institute, University of Florida, Gainesville, Florida, USA., Manohar Sindhu S; Genetics and Genomics Graduate Program, Genetics Institute, University of Florida, Gainesville, Florida, USA., Yang Y; Department of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, Florida, USA., Zhou D; Department of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, Florida, USA.; Department of Biochemistry and Structural Biology, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA., Foster TC; Department of Neuroscience, McKnight Brain Institute, University of Florida, Gainesville, Florida, USA.; Genetics and Genomics Graduate Program, Genetics Institute, University of Florida, Gainesville, Florida, USA.
Jazyk: angličtina
Zdroj: Aging cell [Aging Cell] 2024 Feb; Vol. 23 (2), pp. e14037. Date of Electronic Publication: 2024 Jan 15.
DOI: 10.1111/acel.14037
Abstrakt: 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.
(© 2024 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.)
Databáze: MEDLINE
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