Targeting the adenosine A2A receptor for neuroprotection and cognitive improvement in traumatic brain injury and Parkinson's disease

Abstract

Adenosine exerts its dual functions of homeostasis and neuromodulation in the brain by acting at mainly 2 G-protein coupled receptors, called A₁ and A_2A receptors. The adenosine A_2A receptor (A_2AR) antagonists have been clinically pursued for the last 2 decades, leading to final approval of the istradefylline, an A_2AR antagonist, for the treatment of OFF-Parkinson's disease (PD) patients. The approval paves the way to develop novel therapeutic methods for A_2AR antagonists to address 2 major unmet medical needs in PD and traumatic brain injury (TBI), namely neuroprotection or improving cognition. In this review, we first consider the evidence for aberrantly increased adenosine signaling in PD and TBI and the sufficiency of the increased A_2AR signaling to trigger neurotoxicity and cognitive impairment. We further discuss the increasing preclinical data on the reversal of cognitive deficits in PD and TBI by A_2AR antagonists through control of degenerative proteins and synaptotoxicity, and on protection against TBI and PD pathologies by A_2AR antagonists through control of neuroinflammation. Moreover, we provide the supporting evidence from multiple human prospective epidemiological studies which revealed an inverse relation between the consumption of caffeine and the risk of developing PD and cognitive decline in aging population and Alzheimer's disease patients. Collectively, the convergence of clinical, epidemiological and experimental evidence supports the validity of A_2AR as a new therapeutic target and facilitates the design of A_2AR antagonists in clinical trials for disease-modifying and cognitive benefit in PD and TBI patients.