Articles Adenosine A 2A receptor antagonist treatment of Parkinson’s disease W. Bara-Jimenez, MD; A. Sherzai, MD; T. Dimitrova, MD; A. Favit, MD; F. Bibbiani, MD; M. Gillespie, NP; M.J. Morris, MRCPsych; M.M. Mouradian, MD; and T.N. Chase, MD Abstract—Background: Observations in animal models suggest that A 2A antagonists confer benefit by modulating dopaminergic effects on the striatal dysfunction associated with motor disability. This double-blind, placebo-controlled, proof-of-principle study evaluated the pathogenic contribution and therapeutic potential of adenosine A 2A receptor– mediated mechanisms in Parkinson disease (PD) and levodopa-induced motor complications. Methods: Fifteen patients with moderate to advanced PD consented to participate. All were randomized to either the selective A 2A antagonist KW-6002 or matching placebo capsules in a 6-week dose-rising design (40 and 80 mg/day). Motor function was rated on the Unified PD Rating Scale. Results: KW-6002 alone or in combination with a steady-state IV infusion of each patient’s optimal levodopa dose had no effect on parkinsonian severity. At a low dose of levodopa, however, KW-6002 (80 mg) potentiated the antiparkinsonian response by 36% (p  0.02), but with 45% less dyskinesia compared with that induced by optimal dose levodopa alone (p  0.05). All cardinal parkinsonian signs improved, especially resting tremor. In addition, KW-6002 prolonged the efficacy half-time of levodopa by an average of 47 minutes (76%; p  0.05). No medically important drug toxicity occurred. Conclusions: The results support the hypothesis that A 2A receptor mechanisms contrib- ute to symptom production in PD and that drugs able to selectively block these receptors may help palliate symptoms in levodopa-treated patients with this disorder. NEUROLOGY 2003;61:293–296 Recent studies suggest that motor dysfunction in Parkinson disease (PD) arises in part due to reactive alterations in striatal medium spiny neurons. Func- tion of these GABAergic efferents changes as dopa- minergic innervation declines and especially when their denervated dopamine (DA) receptors are sub- jected to the intermittent stimulation associated with standard dopaminomimetic therapy. 1,2 In either case, signaling kinases and phosphatases that regu- late the phosphorylation state and thus the synaptic efficacy of coexpressed ionotropic glutamatergic re- ceptors become aberrantly activated. 3,4 Resultant changes in cortical glutamatergic input evidently modify striatal output in ways that compromise mo- tor function. Based on the foregoing considerations, pharmaco- logic agents that inhibit signaling events in spiny neurons produced by the nonphysiologic stimulation of their DA receptors might be expected to alleviate resultant motor dysfunction. Recent observations suggest that drugs interacting with striatal ad- enosinergic receptors could serve in this capacity. The A 2A subtype of adenosine receptor, for example, is abundantly expressed on medium spiny neuron dendrites 5 and appears to signal, in part, through activation of serine/threonine kinases 6,7 known to modulate the phosphorylation state of ionotropic glu- tamate receptors. 8,9 A 2A receptor blockade might thus alleviate motor abnormalities in parkinsonian patients by limiting the hyperphosphorylation of striatal glutamatergic receptor subunits that attends dopaminergic denervation and subsequent intermit- tent stimulation. Recent results from rodent and pri- mate models of PD, 10-15 as well as preliminary clinical observations, 16,17 lend support for this concept. To evaluate this hypothesis, we administered ris- ing doses of the potent and selective A 2A receptor antagonist KW-6002 18 under randomized controlled conditions to patients with moderately advanced PD. Special attention was directed toward the possibility that A 2A receptor blockade will enhance the antipar- kinsonian effect of coadministered dopaminomimet- ics without exacerbating dyskinesias. See also pages 286 and 297 From the Experimental Therapeutics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD. Received October 21, 2002. Accepted in final form March 22, 2003. Address correspondence and reprint requests to Dr. Thomas N. Chase, Building 10, Room 5C103, National Institutes of Health, Bethesda, MD 20892; e-mail: chaset@ninds.nih.gov Copyright © 2003 by AAN Enterprises, Inc. 293