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

Adenosine exerts its dual functions of homeostasis and neuromodulation in the brain by acting at mainly 2 G-protein coupled receptors, called A and A receptors. The adenosine A receptor (AR) antagonists have been clinically pursued for the last 2 decades, leading to final approval of the istradefylline, an AR antagonist, for the treatment of OFF-Parkinson's disease (PD) patients. The approval paves the way to develop novel therapeutic methods for AR 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 AR 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 AR antagonists through control of degenerative proteins and synaptotoxicity, and on protection against TBI and PD pathologies by AR 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 AR as a new therapeutic target and facilitates the design of AR antagonists in clinical trials for disease-modifying and cognitive benefit in PD and TBI patients.