8-(3-Chlorostyryl)caffeine May Attenuate MPTP Neurotoxicity through Dual Actions of Monoamine Oxidase Inhibition and A2A Receptor Antagonism*

Caffeine and more specific antagonists of the adenosine A2A receptor 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 A2A antagonist 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 A2A receptors on monoamine oxidase (MAO) activity, we found that CSC potently and specifically inhibited mouse brain mitochondrial MAO-B activity in vitro with aK i value of 100 nm, whereas caffeine and another relatively specific A2A antagonist produced little or no inhibition. The A2A receptor independence of MAO-B inhibition by CSC was further supported by the similarity of brain MAO activities derived from A2A receptor knockout and wild-type mice and was confirmed by demonstrating potent inhibition of A2A receptor knockout-derived MAO-B by CSC. Together, these data indicate that CSC possesses dual actions of MAO-B inhibition and A2A receptor antagonism, a unique combination suggesting a new class of compounds with the potential for enhanced neuroprotective properties.

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