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Caffeine and more specific antagonists of the adenosine A2Areceptor recently have been found to be neuroprotective in the MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) model of Parkinson's disease. Here we show that 8-(3-chlorostyryl)caffeine (CSC), a specific A2Aantagonist closely related to caffeine, also attenuates MPTP-induced neurotoxicity. Because the neurotoxicity of MPTP relies on its oxidative metabolism to the mitochondrial toxin MPP+, we investigated the actions of CSC on striatal MPTP metabolism in vivo. CSC elevated striatal levels of MPTP but lowered levels of the oxidative intermediate MPDP+and of MPP+, suggesting that CSC blocks the conversion of MPTP to MPDP+in vivo. In assessing the direct effects of CSC and A2Areceptors on monoamine oxidase (MAO) activity, we found that CSC potently and specifically inhibited mouse brain mitochondrial MAO-B activity in vitrowith aKivalue of 100 nm, whereas caffeine and another relatively specific A2Aantagonist produced little or no inhibition. The A2Areceptor independence of MAO-B inhibition by CSC was further supported by the similarity of brain MAO activities derived from A2Areceptor knockout and wild-type mice and was confirmed by demonstrating potent inhibition of A2Areceptor knockout-derived MAO-B by CSC. Together, these data indicate that CSC possesses dual actions of MAO-B inhibition and A2Areceptor antagonism, a unique combination suggesting a new class of compounds with the potential for enhanced neuroprotective properties.