Adenosine A(2A) receptor blockade prevents cisplatin-induced impairments in neurogenesis and cognitive function

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.