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

Abstract

The neurodegeneration of Parkinson's disease (PD) 1 targets dopaminergic neurons that project to the striatum (1). In PD the progressive loss of striatal dopamine leads to a progressive deterioration in motor function. Despite the availability of dopamine-replacement strategies that generally offer considerable symptomatic relief early in the disease, as yet no therapy has been shown to slow the underlying neurodegenerative process.Adenosine A 2A receptor antagonists recently have attracted attention as potential neuroprotective agents because of a remarkable convergence of epidemiological and laboratory data that link the A 2A receptor to the development of PD (2). Prospective studies of several large populations have shown that caffeine consumption is associated with a reduced risk of developing PD (3,4). The risk of PD decreased with increasing prior intake of coffee or of caffeine from other sources and was independent of smoking status or other potential confounding factors. Notably, consumption of decaffeinated coffee was not related to PD risk (4).The possibility that the reduced risk of PD among caffeine consumers is due to a neuroprotective effect of caffeine has been supported by our finding that caffeine can reduce dopaminergic neuron toxicity in a mouse model of PD (5). Low doses of caffeine can attenuate the loss of striatal dopamine and of dopamine transporter (DAT) binding sites induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). The neuroprotection by caffeine, a nonspecific adenosine receptor antagonist (6), could be mimicked by relatively specific adenosine A 2A receptor antagonists but not an A 1 antagonist (5, 7). A 2A receptor knockout mice also were resistant to MPTP-induced depletion of striatal dopamine. Together these laboratory data have suggested a potential neurobiological basis for the inverse association between caffeine use and PD.Here we examine the neuroprotective properties of 8-(3-chlorostyryl)caffeine (CSC), a selective and potent A 2A antagonist closely related to caffeine (8) in the MPTP model of PD (9). Because the neurotoxicity of MPTP requires its oxidation to the active toxin, the 1-methyl-4-phenylpyridinium (MPP ϩ ) 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 results of these studies offer new insight into structure-activity relationships for MAO-B inhibitors and suggest a

Effect of Adenosine A2A Receptor Antagonists on l-DOPA-Induced Hydroxyl Radical Formation in Rat Striatum

“…In that experiment, a low single dose of CSC and ZM 241385 either inhibited or did not alter, respectively, generation of hydroxyl radical by L-DOPA; on the other hand, in high dose they were equipotent toward the elevation of hydroxyl radical levels produced by L-DOPA. The suppressing effect of low single dose CSC on hydroxyl radical formation appears to be related to an inhibition of DA metabolism, as CSC has been shown to be a potent competitive monoamine oxidase-B (MAO-B) inhibitor, its K i being 100 nM (Chen et al 2002). Conversely, ZM 241385, which is devoid of MAO-B inhibitory properties, was ineffective in influencing either the L-DOPA-induced DA release or hydroxyl radical production when it was administered acutely in low dose.…”

Interactions between Metabotropic Glutamate 5 and Adenosine A2AReceptors in Normal and Parkinsonian Mice

“…They found that repeated and "chronic" coadministration of (E)-8-(3-chlorostyryl) caffeine, which is a potent monoamine oxidase B inhibitor as well as A 2A antagonist (Chen et al, 2002), and MPEP synergistically alleviated motor deficits in the 6-OHDA-lesioned rat model of PD. In the present study, a similar synergy was demonstrated after "acute" coadministration of A 2A and mGlu5 antagonists, the specificities of which for their receptors were definitively demonstrated using respective KO mice (Fig.…”

Dual-Target–Directed Drugs that Block Monoamine Oxidase B and Adenosine A Receptors for Parkinson's Disease

“…As part of an investigation to determine the mechanism by which CSC protects mice against the neurotoxic effects of MPTP, it was discovered that, in addition to being a potent and selective A 2A antagonist, CSC also acted as a highly potent, competitive, and reversible inhibitor of MAO-B. 26 This finding has raised the possibility of designing dual-target-directed drugs that block at both A 2A receptors and at MAO-B. To determine the structural requirements necessary for methylxanthines to act as MAO-B inhibitors, various substituted methylxanthines were evaluated as MAO-B inhibitors.…”