Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 119, Issue 28, Pages -Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2206415119
Keywords
chemotherapy-induced cognitive impairment; chemobrain; adenosine A2A receptor; KW-6002; adult neurogenesis
Categories
Funding
- NIH [R01CA242158, R01AG058560]
- Regenerative Medicine Minnesota [RMM091718DS005]
- Rutgers Cancer Institute of New Jersey (CINJ)
- Rutgers CINJ Pediatric Cancer and Blood Disorders Research Center
- American Association for Cancer Research-Bosarge Family Foundation-Waun Ki Hong Scholar Regenerative Cancer Medicine Award [19-4060-OLIV]
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Chemotherapy-induced cognitive impairment (CICI) can be prevented by blocking the adenosine A(2A) receptor signaling pathway. In this study, the A(2A) receptor antagonist KW-6002 was used to prevent neural damage caused by the chemotherapy drug cisplatin, and improve memory and anxiety-like behavior.
Chemotherapy-induced cognitive impairment (CICI) has emerged as a significant medical problem without therapeutic options. Using the platinum-based chemotherapy cisplatin to model CICI, we revealed robust elevations in the adenosine A(2A) receptor (A(2A)R) and its downstream effectors, cAMP and CREB, by cisplatin in the adult mouse hippocampus, a critical brain structure for learning and memory. Notably, A(2A)R inhibition by the Food and Drug Administration-approved A(2A)R antagonist KW-6002 prevented cisplatin-induced impairments in neural progenitor proliferation and dendrite morphogenesis of adult-born neurons, while improving memory and anxiety-like behavior, without affecting tumor growth or cisplatin's antitumor activity. Collectively, our study identifies A(2A)R signaling as a key pathway that can be therapeutically targeted to prevent cisplatin-induced cognitive impairments.
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