Neuroprotection by caffeine and A(2A) adenosine receptor inactivation in a model of Parkinson's disease.
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 A(2A) 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 A(2A) receptor, but not by A(1) receptor blockade with 8-cyclopentyl-1,3-dipropylxanthine, suggesting that caffeine attenuates MPTP toxicity by A(2A) 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 A(2A) antagonists as a novel treatment for this neurodegenerative disease.
Chen
J F
JF
Molecular Neurobiology Laboratory, Department of Neurology, Massachusetts General Hospital, Charlestown, Massachusetts 02129, USA. chenjf@helix.mgh.harvard.edu
Xu
K
K
Petzer
J P
JP
Staal
R
R
Xu
Y H
YH
Beilstein
M
M
Sonsalla
P K
PK
Castagnoli
K
K
Castagnoli
N
N
Schwarzschild
M A
MA
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000037:antagonists & inhibitors; D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000818:Animals; D002110:Caffeine / Q000008:administration & dosage*; D002396:Catechols / Q000378:metabolism; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D007113:Immunity, Innate / Q000235:genetics; D007274:Injections, Intraperitoneal; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018696:Neuroprotective Agents / Q000008:administration & dosage*; D020734:Parkinsonian Disorders / Q000139:chemically induced / Q000188:drug therapy* / Q000235:genetics; D058915:Purinergic P1 Receptor Antagonists; D011687:Purines / Q000008:administration & dosage; D011743:Pyrimidines / Q000008:administration & dosage; D043705:Receptor, Adenosine A2A; D018047:Receptors, Purinergic P1 / Q000172:deficiency / Q000235:genetics; D013805:Theobromine / Q000008:administration & dosage / Q000031:analogs & derivatives; D014230:Triazoles / Q000008:administration & dosage; D014970:Xanthines / Q000008:administration & dosage
C098657:5-amino-7-(2-phenylethyl)-2-(2-furyl)pyrazolo(4,3-e)-1,2,4-triazolo(1,5-c)pyrimidine; D002396:Catechols; D018696:Neuroprotective Agents; D058915:Purinergic P1 Receptor Antagonists; D011687:Purines; D011743:Pyrimidines; D043705:Receptor, Adenosine A2A; D018047:Receptors, Purinergic P1; D014230:Triazoles; D014970:Xanthines; D015102:3,4-Dihydroxyphenylacetic Acid; C111599:istradefylline; D002110:Caffeine; C057837:3,7-dimethyl-1-propargylxanthine; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; C051360:1,3-dipropyl-8-cyclopentylxanthine; D013805:Theobromine; D004298:Dopamine