8-(3-chlorostyryl)caffeine may attenuate MPTP neurotoxicity through dual actions of monoamine oxidase inhibition and A2A receptor antagonism

被引:82
作者
Chen, JF
Steyn, S
Staal, R
Petzer, JP
Xu, K
Van der Schyf, CJ
Castagnoli, K
Sonsalla, PK
Castagnoli, N
Schwarzschild, MA
机构
[1] Massachusetts Gen Hosp, Mol Neurobiol Lab, Dept Neurol, Boston, MA 02129 USA
[2] Harvard Univ, Sch Med, Boston, MA 02129 USA
[3] Virginia Tech, Dept Chem, Harvey W Peters Ctr, Blacksburg, VA 24061 USA
[4] Univ Med & Dent New Jersey, Dept Neurol, Piscataway, NJ 08854 USA
关键词
D O I
10.1074/jbc.M206830200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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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页码:36040 / 36044
页数:5
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