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A2A antagonists as novel non-dopaminergic therapy for motor dysfunction in PD.

Authors
  • Jenner, Peter
Type
Published Article
Journal
Neurology
Publisher
Ovid Technologies (Wolters Kluwer) - American Academy of Neurology
Publication Date
Dec 09, 2003
Volume
61
Issue
11 Suppl 6
Identifiers
PMID: 14663007
Source
Medline
License
Unknown

Abstract

The future management of Parkinson's disease (PD) requires pharmacologic agents that do not lose efficacy with disease progression or induce dyskinesia and that are free of other dopaminergic side effects. A2A receptor antagonists may provide an opportunity to introduce nondopaminergic management of PD. A2A receptors are selectively localized in basal ganglia and to the indirect output pathway where they control GABA and acetylcholine release. The A2A antagonists are effective in rodent models of PD, reversing motor deficits in haloperidol-treated, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated, or reserpinized mice, and potentiating L-dopa-induced rotation in 6-hydroxydopamine-lesioned rats without inducing dyskinesia. Importantly, the selective A2A antagonist KW6002 reverses motor disability and increases locomotor activity in MPTP-treated primates without provoking dyskinesia established by previous exposure to L-dopa. In addition, KW6002 shows additive antiparkinsonian activity with L-dopa and the D2 agonist quinpirole in MPTP-treated primates without enhancing the intensity of dyskinesia. The data available suggest that A2A antagonists, such as KW6002, may be effective as monotherapy for the management of PD and that they will also produce additional benefit when administered in combination with L-dopa or dopamine agonist therapy.

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