Novel neuroprotection by caffeine and adenosine A2A receptor antagonists in animal models of Parkinson's disease

The adenosine A2A receptor has recently emerged as a leading non-dopaminergic therapeutic target for Parkinson's disease, largely due to the restricted distribution of the receptor in the striatum and the profound interaction between adenosine and dopamine receptors in brain. Two lines of research in particular have demonstrated the promise of the A2A receptor antagonists as novel anti-parkinsonian drugs. First, building on extensive preclinical animal studies, the A2A receptor antagonist KW6002 has demonstrated its potential to increase motor activity in PD patients of the advanced stage in a recent clinical phase IIB trial. Second, recently two prospective epidemiological studies of large cohorts have firmly established the inverse relationship between the consumption of caffeine (a non-specific adenosine antagonist) and the risk of developing PD. The potential neuroprotective effect of caffeine and A2A receptor antagonists in PD is further substantiated by the demonstration that pharmacological blockade (by caffeine or specific A2A antagonists) or genetic depletion of the A2A receptor attenuated dopaminergic neurotoxicity and neurodegeneration in animal models of PD. Moreover, A2A receptor antagonism-mediated neuroprotection goes beyond PD models and can be extended to a variety of other brain injuries induced by stroke, excitotoxicity and mitochondrial toxins. Intensive investigations are under way to dissect out common cellular mechanisms (such as A2A receptor modulation of neuroinflammation) which may underlie the broad spectrum of neuroprotection by A2A receptor inactivation in brain.