Editorial [Hot Topic: Regulation of Brain Functions by Adenosine A2A Receptors:Implication for Therapeutics (Executive Editor: Patrizia Popoli) ]

Adenosine is an endogenous modulator which regulates many Central Nervous System (CNS) functions and which activities are mediated by the binding to four distinct G-protein-coupled receptors: the A1, A2A, A2B, and A3 adenosine receptor subtypes. In the last few years adenosine A2A receptors have been shown to play a significant role in different physiological and pathological processes in the brain. The aim of this issue is to review and critically discuss the evidence supporting adenosine A2A receptors as possible therapeutic targets for CNS disorders. It is my genuine belief that this topic, albeit controversial, is actually worth exploring and debating, and thus I'm particularly grateful to Prof. Banks for inviting me to edit this issue. I'm also very grateful to all the contributors (most of whom have actually pioneered the field), who accepted to share their thoughts and experience in this fascinating topic. On their whole, the articles of this issue very nicely and comprehensively summarize the state of the art and outline the many aspects which still need to be clarified. From these articles it becomes clear that, despite the many controversial evidence and the current “druggability” problems, adenosine A2A receptors continue to represent promising drug targets for CNS diseases. I wish that this issue of Current Pharmaceutical Design will further stimulate the research in this field. In neurons, the highest expression of the adenosine A2A receptors is found in the basal ganglia, in particular in the corpus striatum, which is involved in the control and learning of complex motor activities. The discovery of the colocalization of dopamine D2 and adenosine A2A receptors in a subset of striatal neurons has provided an anatomical basis to the functional antagonism between adenosine and dopamine in the basal ganglia. In their review, Ferre et al. [1] show that the A2A-D2 receptor interactions provide an example of the capabilities of information processing by just two different G protein-coupled receptors. They report the evidence for the coexistence of two reciprocal antagonistic interactions between A2A and D2 receptors in the same neurons (the GABAergic enkephalinergic neurons) but, at the same time, they show that under particular conditions (such as chronic treatment with addictive drugs), a synergistic A2A-D2 receptor interaction can also be demonstrated. The analysis of A2-D2 receptor interactions can thus have important implications for the pathophysiology and treatment of basal ganglia disorders and drug addiction. Adenosine A2A receptor antagonists currently constitute an attractive non-dopaminergic option for the treatment of Parkinson's disease (PD). The highly enriched distribution 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 behaviour, 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. The state of the art and the future directions in the field of A2A receptor antagonists as antiparkinsonian drugs is comprehensively covered by the review of Simola et al. [2] in this issue. Their article examines preclinical studies 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. Recently, the A2A receptor has emerged as an attractive therapeutic target for modulating brain ischaemia. The evidence we have to date indicates that both adenosine and A2A antagonists are neuroprotective in ischaemic brain injury. In their review, Chen and Pedata [3] propose that, from drug development perspective, administering A2A antagonists in association with inhibitors of adenosine kinase may represent a novel strategy for treating stroke. Their article also summarizes the experimental evidence for A2AR modulation of glial function as possible contribution to the modulation of brain injury and points out the fact that, in contrast to the generally held view that the A2AR exerts predominantly anti-inflammatory effects (based upon studies in peripheral organs), the A2AR modulation of neuroinflammation may differentially affect the outcome of brain injury, depending on the nature of brain insults.