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The Journal of Neuroscience, 2001, 21:RC143:1-6
RAPID COMMUNICATION
Neuroprotection by Caffeine and A2A Adenosine
Receptor Inactivation in a Model of Parkinson's Disease
Jiang-Fan
Chen1,
Kui
Xu1,
Jacobus P.
Petzer2,
Roland
Staal3,
Yue-Hang
Xu1,
Mark
Beilstein1,
Patricia K.
Sonsalla3,
Kay
Castagnoli2,
Neal
Castagnoli Jr2, and
Michael A.
Schwarzschild1
1 Molecular Neurobiology Laboratory, Department of
Neurology, Massachusetts General Hospital, Charlestown,
Massachusetts 02129, 2 Harvey W. Peters Center, Department
of Chemistry, Virginia Tech, Blacksburg, Virginia 24061-0212, and
3 Department of Neurology, University of Medicine and
Dentistry of New Jersey, Piscataway, New Jersey 08854-5635
Recent epidemiological studies have established an association
between the common consumption of coffee or other caffeinated beverages
and a reduced risk of developing Parkinson's disease (PD). To explore
the possibility that caffeine helps prevent the dopaminergic deficits
characteristic of PD, we investigated the effects of caffeine and the
adenosine receptor subtypes through which it may act in the
1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) neurotoxin model of
PD. Caffeine, at doses comparable to those of typical human exposure,
attenuated MPTP-induced loss of striatal dopamine and
dopamine transporter binding sites. The effects of caffeine were
mimicked by several A2A antagonists
(7-(2-phenylethyl)-5-amino-2-(2-furyl)-pyrazolo-[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine (SCH 58261), 3,7-dimethyl-1-propargylxanthine, and (E)-1,3-diethyl-8 (KW-6002)-(3,4-dimethoxystyryl)-7-methyl-3,7-dihydro-1H-purine-2,6-dione) (KW-6002) and by genetic inactivation of the A2A receptor,
but not by A1 receptor blockade with
8-cyclopentyl-1,3-dipropylxanthine, suggesting that caffeine attenuates
MPTP toxicity by A2A receptor blockade. These data
establish a potential neural basis for the inverse association of
caffeine with the development of PD, and they enhance the potential of
A2A antagonists as a novel treatment for this
neurodegenerative disease.
Key words:
adenosine receptor; methylxanthine; neurotoxin; 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; dopamine transporter; Parkinson's disease; knock-out; mice
Copyright © Society for Neuroscience 0270-6474//$05.00/0
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