Antiparkinsonian effect of a new selective adenosine A2A receptor antagonist in MPTP-treated monkeys.
BACKGROUND
Chronic treatment with L-3,4-dihydroxyphenylalanine (L-dopa) is often associated with motor side effects in PD patients. The search for new therapeutic approaches has led to study the role of other neuromodulators including adenosine. Among the four adenosine receptors characterized so far, the A2A subtype is distinctively present on striatopallidal output neurons containing enkephalin and mainly bearing dopamine (DA) D2 receptors (indirect pathway). Studies in DA-denervated rats suggest that blockade of adenosine A2A receptors might be used in PD.


OBJECTIVE
To evaluate the antiparkinsonian effect of a new selective adenosine A2A receptor antagonist, KW-6002, in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkeys.


METHODS
In the present study, we used six MPTP-exposed cynomolgus monkeys already primed and exhibiting L-dopa-induced dyskinesias to evaluate both the antiparkinsonian and dyskinetic effect upon challenge with two oral doses (60 and 90 mg/kg) of KW-6002 administered alone or in combination with L-dopa/benserazide (50/12.5 mg).


RESULTS
KW-6002 administered alone produced a dose-dependent antiparkinsonian response that reached the level of efficacy of L-dopa/benserazide but was less likely to reproduce dyskinesias in these animals. When co-administered, KW-6002 potentiated the effects of L-dopa/benserazide on motor activity (up to 30%) without affecting the dyskinetic response.


CONCLUSIONS
Adenosine A2A receptor antagonists have antiparkinsonian effects of their own with a reduced propensity to elicit dyskinesias. They might therefore be useful agents in the treatment of PD.
Grondin
R
R
Neuroscience Research Unit, Laval University Research Center, Quebec, Canada.
Bédard
P J
PJ
Hadj Tahar
A
A
Grégoire
L
L
Mori
A
A
Kase
H
H
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000009:adverse effects*; D000818:Animals; D001921:Brain / Q000187:drug effects; D005260:Female; D007980:Levodopa / Q000494:pharmacology* / Q000627:therapeutic use; D008124:Locomotion / Q000187:drug effects; D008252:Macaca fascicularis; D010302:Parkinson Disease, Secondary / Q000139:chemically induced* / Q000188:drug therapy; D058915:Purinergic P1 Receptor Antagonists; D011687:Purines / Q000494:pharmacology* / Q000627:therapeutic use; D043705:Receptor, Adenosine A2A
D058915:Purinergic P1 Receptor Antagonists; D011687:Purines; D043705:Receptor, Adenosine A2A; C111599:istradefylline; D007980:Levodopa; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine