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A remarkable convergence of epidemiologic and laboratory data has raised the possibility that caffeine reduces the risk of developing Parkinson's disease (PD) by preventing the degeneration of nigrostriatal dopaminergic neurons. The authors review the evidence that caffeine and more specific antagonists of the adenosine A2A receptor protect dopaminergic neurons in several toxin models of PD. Other studies demonstrating protection by A2A receptor inactivation in animal models of stroke, Huntington's disease, and Alzheimer's disease suggest a more global role of A2A receptors in neuronal injury and degeneration. Although the cellular and molecular mechanisms by which A2A receptors contribute to neuronal death are not yet established, several intriguing possibilities have emerged. Now with preliminary clinical data substantiating the antiparkinsonian symptomatic benefit of A2A receptor blockade, the prospects for a complementary neuroprotective benefit have enhanced the therapeutic potential of A2A antagonists in PD.

The neurodegeneration of Parkinson's disease (PD) 1 targets dopaminergic neurons that project to the striatum (1). In PD the progressive loss of striatal dopamine leads to a progressive deterioration in motor function. Despite the availability of dopamine-replacement strategies that generally offer considerable symptomatic relief early in the disease, as yet no therapy has been shown to slow the underlying neurodegenerative process.Adenosine A 2A receptor antagonists recently have attracted attention as potential neuroprotective agents because of a remarkable convergence of epidemiological and laboratory data that link the A 2A receptor to the development of PD (2). Prospective studies of several large populations have shown that caffeine consumption is associated with a reduced risk of developing PD (3,4). The risk of PD decreased with increasing prior intake of coffee or of caffeine from other sources and was independent of smoking status or other potential confounding factors. Notably, consumption of decaffeinated coffee was not related to PD risk (4).The possibility that the reduced risk of PD among caffeine consumers is due to a neuroprotective effect of caffeine has been supported by our finding that caffeine can reduce dopaminergic neuron toxicity in a mouse model of PD (5). Low doses of caffeine can attenuate the loss of striatal dopamine and of dopamine transporter (DAT) binding sites induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). The neuroprotection by caffeine, a nonspecific adenosine receptor antagonist (6), could be mimicked by relatively specific adenosine A 2A receptor antagonists but not an A 1 antagonist (5, 7). A 2A receptor knockout mice also were resistant to MPTP-induced depletion of striatal dopamine. Together these laboratory data have suggested a potential neurobiological basis for the inverse association between caffeine use and PD.Here we examine the neuroprotective properties of 8-(3-chlorostyryl)caffeine (CSC), a selective and potent A 2A antagonist closely related to caffeine (8) in the MPTP model of PD (9). Because the neurotoxicity of MPTP requires its oxidation to the active toxin, the 1-methyl-4-phenylpyridinium (MPP ϩ ) species, by monoamine oxidase B (MAO-B), we investigated the effects of CSC on MPTP metabolism in vivo and on MAO activity in vitro. The results of these studies offer new insight into structure-activity relationships for MAO-B inhibitors and suggest a