A2A antagonist prevents dopamine agonist-induced motor complications in animal models of Parkinson's disease.
Adenosine A(2A) receptors, abundantly expressed on striatal medium spiny neurons, appear to activate signaling cascades implicated in the regulation of coexpressed ionotropic glutamatergic receptors. To evaluate the contribution of adenosinergic mechanisms to the pathogenesis of the response alterations induced by dopaminergic treatment, we studied the ability of the selective adenosine A(2A) receptor antagonist KW-6002 to prevent as well as palliate these syndromes in rodent and primate models of Parkinson's disease. In rats, KW-6002 reversed the shortened motor response produced by chronic levodopa treatment while reducing levodopa-induced hyperphosphorylation at S845 residues on AMPA receptor GluR1 subunits. In primates, KW-6002 evidenced modest antiparkinsonian activity when given alone. Once-daily coadministration of KW-6002 with apomorphine prevented the development of dyskinesias, which appeared in control animals 7-10 days after initiating apomorphine treatment. Animals initially given apomorphine plus KW-6002 for 3 weeks did not begin to manifest apomorphine-induced dyskinesias until 10-12 days after discontinuing the A(2A) antagonist. These results suggest that KW-6002 can attenuate the induction as well as the expression of motor response alterations to chronic dopaminergic stimulation in parkinsonian animals, possibly by blocking A(2A) receptor-stimulated signaling pathways. Our findings strengthen the rationale for developing A(2A) antagonists as an early treatment strategy for Parkinson's disease.
Bibbiani
F
F
ETB, NINDS, National Institutes of Health, Bethesda, MD 20892, USA.
Oh
J D
JD
Petzer
J P
JP
Castagnoli
N
N
Chen
J-F
JF
Schwarzschild
M A
MA
Chase
T N
TN
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000037:antagonists & inhibitors; D058917:Adenosine A2 Receptor Antagonists; D000818:Animals; D000978:Antiparkinson Agents / Q000627:therapeutic use; D001058:Apomorphine / Q000633:toxicity; D003714:Denervation; D018491:Dopamine Agonists / Q000633:toxicity*; D004409:Dyskinesia, Drug-Induced / Q000473:pathology / Q000517:prevention & control; D007980:Levodopa / Q000627:therapeutic use; D008252:Macaca fascicularis; D008297:Male; D009474:Neurons / Q000473:pathology; D016627:Oxidopamine / Q000037:antagonists & inhibitors / Q000633:toxicity; D010302:Parkinson Disease, Secondary / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology*; D010766:Phosphorylation; D011687:Purines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000378:metabolism; D017447:Receptors, Dopamine D1 / Q000819:agonists; D017448:Receptors, Dopamine D2 / Q000819:agonists; D013565:Sympatholytics / Q000037:antagonists & inhibitors / Q000633:toxicity
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D058917:Adenosine A2 Receptor Antagonists; D000978:Antiparkinson Agents; D001058:Apomorphine; D018491:Dopamine Agonists; D007980:Levodopa; D016627:Oxidopamine; D011687:Purines; D018091:Receptors, AMPA; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D013565:Sympatholytics; C111599:istradefylline