Adenosine A 2A receptor blockade prevents cisplatin-induced impairments in neurogenesis and cognitive function.
Alfredo OliverosKi Hyun YooMohammad Abdur RashidAna Corujo-RamirezBenjamin HurJaeyun SungYuanhang LiuJohn R HawseDoo-Sup ChoiDetlev BoisonMi-Hyeon JangPublished in: Proceedings of the National Academy of Sciences of the United States of America (2022)
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.
Keyphrases
- drug administration
- chemotherapy induced
- cognitive impairment
- cerebral ischemia
- protein kinase
- binding protein
- healthcare
- signaling pathway
- white matter
- spinal cord
- cancer therapy
- single cell
- squamous cell carcinoma
- resting state
- gestational age
- dna methylation
- gene expression
- blood brain barrier
- human health
- risk assessment
- young adults
- preterm birth