Adenosine A2A receptor blockade prevents cisplatin-induced impairments in neurogenesis and cognitive function

Proc Natl Acad Sci U S A. 2022 Jul 12;119(28):e2206415119. doi: 10.1073/pnas.2206415119. Epub 2022 Jul 7.


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 A2A receptor (A2AR) and its downstream effectors, cAMP and CREB, by cisplatin in the adult mouse hippocampus, a critical brain structure for learning and memory. Notably, A2AR inhibition by the Food and Drug Administration-approved A2AR 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 A2AR signaling as a key pathway that can be therapeutically targeted to prevent cisplatin-induced cognitive impairments.

Keywords: KW-6002; adenosine A2A receptor; adult neurogenesis; chemobrain; chemotherapy-induced cognitive impairment.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine A2 Receptor Antagonists* / therapeutic use
  • Animals
  • Antineoplastic Agents* / administration & dosage
  • Antineoplastic Agents* / adverse effects
  • Chemotherapy-Related Cognitive Impairment* / prevention & control
  • Cisplatin* / adverse effects
  • Cognition / drug effects
  • Hippocampus / drug effects
  • Hippocampus / physiopathology
  • Mice
  • Mice, Inbred C57BL
  • Neural Stem Cells / drug effects
  • Neural Stem Cells / physiology
  • Neurogenesis* / drug effects
  • Purines* / administration & dosage
  • Purines* / therapeutic use
  • Receptor, Adenosine A2A* / metabolism


  • Adenosine A2 Receptor Antagonists
  • Antineoplastic Agents
  • Purines
  • Receptor, Adenosine A2A
  • istradefylline
  • Cisplatin