Trends in Neurosciences
Volume 29, Issue 11, November 2006, Pages 647-654
Journal home page for Trends in Neurosciences

Review
Targeting adenosine A2A receptors in Parkinson's disease

https://doi.org/10.1016/j.tins.2006.09.004Get rights and content

The adenosine A2A receptor has emerged as an attractive non-dopaminergic target in the pursuit of improved therapy for Parkinson's disease (PD), based in part on its unique CNS distribution. It is highly enriched in striatopallidal neurons and can form functional heteromeric complexes with other G-protein-coupled receptors, including dopamine D2, metabotropic glutamate mGlu5 and adenosine A1 receptors. Blockade of the adenosine A2A receptor in striatopallidal neurons reduces postsynaptic effects of dopamine depletion, and in turn lessens the motor deficits of PD. A2A antagonists might partially improve not only the symptoms of PD but also its course, by slowing the underlying neurodegeneration and reducing the maladaptive neuroplasticity that complicates standard ‘dopamine replacement’ treatments. Thus, we review here a prime example of translational neuroscience, through which antagonism of A2A receptors has now entered the arena of clinical trials with realistic prospects for advancing PD therapeutics.

Introduction

Current pharmacotherapy for Parkinson's disease (PD) can be accurately described as both highly effective and largely inadequate. On the one hand, the dramatic efficacy of standard anti-parkinsonian drugs can be the stuff of Hollywood movies, as when the body of an immobilized patient played by Robert De Niro is ‘awakened’ by l-dopa in the 1990 film Awakenings. The characteristic bradykinesia (slowness), rigidity and tremor of PD are primarily due to an underlying degeneration of dopaminergic nigrostriatal neurons and the resultant depletion of striatal dopamine. Repleting endogenous dopamine using its precursor l-dopa and mimicking it using dopamine agonists constitute ‘dopamine replacement’ strategies – the mainstay of current treatment. By boosting dopamine-mediated transmission, these strategies can dramatically (albeit partially) alleviate the motor deficits in PD.

On the other hand, none of the currently approved anti-parkinsonian agents has been found to alter the underlying degeneration of dopaminergic neurons. Thus, after several years of gratifying improvement using dopamine-replacement therapy, PD patients typically experience great frustration as neuronal loss and symptoms inexorably progress. As the disease advances, disability is often compounded further by the development of l-dopa-triggered involuntary jerking and writhing movements known as dyskinesias. Eventually, most will also suffer from non-motor complications of both the dopaminergic treatments and the disease itself; such complications include sleep disturbance, depression, dementia and psychosis.

The inadequacies and adverse effects of drugs that target the dopaminergic system have prompted a search for alternative or adjunctive approaches that can modulate basal ganglia motor circuitry with a reduced risk of side effects. Antagonists of adenosine A2A receptors have recently emerged as a leading candidate class of non-dopaminergic anti-parkinsonian agents, based in part on the unique CNS distribution of the A2A receptor (Figure 1a). As we review here, promising preclinical features have not only led to clinical trials of A2A receptor antagonists as a novel symptomatic therapy for PD, but also raised the possibility of neuroprotective and anti-dyskinetic benefits.

Section snippets

A2A antagonists as symptomatic anti-parkinsonian therapy

Neurochemical evidence that A2A receptors functionally oppose the actions of dopamine D2 receptors on GABAergic striatopallidal neurons 1, 2, 3 (Figure 1b,c; Box 1) raised the possibility that A2A antagonists might boost the anti-parkinsonian action of dopamine-replacement strategies. Indeed, behavioral studies of hemi-parkinsonian rats, in which the dopaminergic nigrostriatal pathway had been lesioned on one side by 6-hydroxydopamine (6-OHDA), revealed that blockade of A2A receptors markedly

A2A antagonists as potential neuroprotectants in PD

Over past six years, converging epidemiological and experimental evidence has raised the exciting possibility that A2A receptor antagonism might protect dopaminergic neurons from degeneration in PD 13, 21. In 2000, Ross and colleagues reported an inverse relationship between the consumption of caffeine (1,3,7-trimethylxanthine), a non-specific adenosine receptor antagonist, and the risk of developing PD in 8004 Japanese–American men followed for 30 years as part of a prospective study [22]. The

A2A receptors in dyskinesias and non-motor targets

With the progressive loss of dopaminergic neurons in PD come other disabling motor and behavioral problems. Chronic intermittent therapy using l-dopa (or a dopamine agonist) can conspire with the hypodopaminergic state of PD to produce progressively briefer motor benefits and progressively more disruptive involuntary movements (dyskinesias) in response to each dose. The prevention and suppression of l-dopa-induced dyskinesias (LID) have become major targets of new non-dopamine approaches.

A2A antagonists for PD: lackluster or blockbuster?

This question may seem overly theatrical, with ‘lackluster’ too pessimistic given the positive results of initial clinical trials using A2A antagonists for PD, and ‘blockbuster’ too optimistic given that this label is conventionally reserved for conditions even more prevalent than PD. Nevertheless, the possibilities for A2A antagonism in PD are currently wide open. On the one hand, more than the initially demonstrated mild symptomatic benefit of adjunctive A2A antagonists will probably be

Acknowledgements

Our work is supported by USAMRAA W81XWH-04–1-0881 and NIH ES10804 and NS54978.
Disclosure statement

Michael Schwarzschild and Jiang-Fan Chen have received royalty payments from Massachusetts General Hospital (M.S. and J-F.C.) and Boston University School of Medicine (J-F.C.) as part of institutional licensing agreements for the use of an adenosine receptor knockout mouse line.

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