Adenosine A2A Receptor Antagonists and Parkinson's Disease: State of the Art and Future Directions

Adenosine A2A receptors present in the central nervous system have been implicated in the modulation of motor functions. Accordingly, adenosine A2A receptor antagonists currently constitute an attractive non-dopaminergic option for use in the treatment of Parkinson's disease (PD). The highly enriched distributions of adenosine A2A receptors in striatopallidal neurons, and their ability to form functional heteromeric complexes with dopamine D2 and metabotropic glutamate mGlu5 receptors, render A2A receptor antagonists of particular interest in the modulation of motor behavior, whilst at the same time displaying a low predisposition to inducing non-motor side effects. Furthermore, adenosine A2A receptor antagonists appear to exert a marked efficacy on PD tremor and in reducing the progress of underlying neurodegeneration and maladaptive neuroplasticity that complicates standard dopamine replacement treatments in PD. Finally, recent evidence has illustrated an improvement of cognitive function as well as enhancement of attention in rodents following administration of A2A receptor antagonists. This article is aimed at examining preclinical studies describing these findings as well as reports from clinical trials, in order to provide a comprehensive review of the evidence suggesting that this class of drugs may represent an advance in the treatment of PD.