Adenosine A <sub>2A</sub> receptor blockade prevents cisplatin-induced impairments in neurogenesis and cognitive function
Alfredo Oliveros, Ki Hyun Yoo, Mohammad Abdur Rashid, Ana Corujo-Ramirez, Benjamin Hur, Jaeyun Sung, Yuanhang Liu, John R. Hawse, Doo‐Sup Choi, Detlev Boison, Mi‐Hyeon Jang
Abstract
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.