Abstract
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.
Highlights
The neurodegeneration of Parkinson’s disease (PD)1 targets dopaminergic neurons that project to the striatum [1]
Because the neurotoxicity of MPTP requires its oxidation to the active toxin, the 1-methyl-4-phenylpyridinium (MPPϩ) 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 Effect of CSC on MPTP Neurotoxicity—The loss of striatal dopamine induced by MPTP in C57Bl/6 mice was significantly attenuated by CSC (5 mg/kg intraperitoneal 10 min prior to each MPTP dose; Fig. 1A, left panel)
Summary
The neurodegeneration of Parkinson’s disease (PD)1 targets dopaminergic neurons that project to the striatum [1]. In assessing the direct effects of CSC and A2A receptors on monoamine oxidase (MAO) activity, we found that CSC potently and inhibited mouse brain mitochondrial MAO-B activity in vitro with a Ki value of 100 nM, whereas caffeine and another relatively specific A2A antagonist produced little or no inhibition.
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