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J. Biol. Chem., Vol. 277, Issue 39, 36040-36044, September 27, 2002

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8-(3-Chlorostyryl)caffeine May Attenuate MPTP Neurotoxicity through Dual Actions of Monoamine Oxidase Inhibition and A_2A Receptor Antagonism^*

Jiang-Fan Chen^§, Salome Steyn^¶, Roland Staal, Jacobus P. Petzer^¶, Kui Xu, Cornelis J. Van der Schyf^¶, Kay Castagnoli^¶, Patricia K. Sonsalla, Neal Castagnoli Jr.^¶, and Michael A. Schwarzschild^**

From the Department of Neurology, Molecular Neurobiology Laboratory, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02129, the ^¶ Harvey W. Peters Center, Department of Chemistry, Virginia Tech, Blacksburg, Virginia 24061, and the  Department of Neurology, University of Medicine and Dentistry of New Jersey, Piscataway, New Jersey 08854

Caffeine and more specific antagonists of the adenosine A_2A 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 A_2A 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 A_2A receptors on monoamine oxidase (MAO) activity, we found that CSC potently and specifically inhibited mouse brain mitochondrial MAO-B activity in vitro with a K_i value of 100 nM, whereas caffeine and another relatively specific A_2A antagonist produced little or no inhibition. The A_2A receptor independence of MAO-B inhibition by CSC was further supported by the similarity of brain MAO activities derived from A_2A receptor knockout and wild-type mice and was confirmed by demonstrating potent inhibition of A_2A receptor knockout-derived MAO-B by CSC. Together, these data indicate that CSC possesses dual actions of MAO-B inhibition and A_2A receptor antagonism, a unique combination suggesting a new class of compounds with the potential for enhanced neuroprotective properties.

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