Trends in Neurosciences
ReviewTargeting adenosine A2A receptors in Parkinson's disease
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.
References (75)
- et al.
Dopamine denervation leads to an increase in the intramembrane interaction between adenosine A2 and dopamine D2 receptors in the neostriatum
Brain Res.
(1992) - et al.
Synergistic interaction between an adenosine antagonist and a D1 dopamine agonist on rotational behavior and striatal c-Fos induction in 6-hydroxydopamine-lesioned rats
Brain Res.
(1996) Adenosine A2A receptor antagonism potentiates l-dopa-induced turning behaviour and c-fos expression in 6-hydroxydopamine-lesioned rats
Eur. J. Pharmacol.
(1997)Therapeutic potential of adenosine A2A receptor antagonists in Parkinson's disease
Pharmacol. Ther.
(2005)The adenosine A2A antagonist KF17837 reverses the locomotor suppression and tremulous jaw movements induced by haloperidol in rats: possible relevance to parkinsonism
Behav. Brain Res.
(2004)Blockade of adenosine A2A receptors antagonizes parkinsonian tremor in the rat tacrine model by an action on specific striatal regions
Exp. Neurol.
(2004)Molecular cloning of the rat A2 adenosine receptor: selective co-expression with D2 dopamine receptors in rat striatum
Mol. Brain Res.
(1992)- et al.
Adenosine antagonists potentiate D2 dopamine-dependent activation of Fos in the striatopallidal pathway
Neuroscience
(1995) Systemic administration of adenosine A2A receptor antagonist reverses increased GABA release in the globus pallidus of unilateral 6-hydroxydopamine-lesioned rats: a microdialysis study
Neuroscience
(2000)Caffeine's neuroprotection against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine toxicity shows no tolerance to chronic caffeine administration in mice
Neurosci. Lett.
(2002)
The effects of selective A1 and A2a adenosine receptor antagonists on cerebral ischemic injury in the gerbil
Brain Res.
Protection against hippocampal kainate excitotoxicity by intracerebral administration of an adenosine A2A receptor antagonist
Brain Res.
Adenosine enhances glial glutamate efflux via A2A adenosine receptors
Life Sci.
KW-6002 protects from MPTP induced dopaminergic toxicity in the mouse
Neuropharmacology
A2A antagonist prevents dopamine agonist-induced motor complications in animal models of Parkinson's disease
Exp. Neurol.
Expression of dyskinetic movements and turning behaviour in subchronic l-DOPA 6-hydroxydopamine-treated rats is influenced by the testing environment
Behav. Brain Res.
Blockade of A2A receptors plus l-DOPA after nigrostriatal lesion results in GAD67 mRNA changes different from l-DOPA alone in the rat globus pallidus and substantia nigra reticulata
Exp. Neurol.
Coaggregation, cointernalization, and codesensitization of adenosine A2A receptors and dopamine D2 receptors
J. Biol. Chem.
Adenosine A2A–dopamine D2 receptor–receptor heteromerization: qualitative and quantitative assessment by fluorescence and bioluminescence energy transfer
J. Biol. Chem.
Oligomerization of adenosine A2A and dopamine D2 receptors in living cells
Biochem. Biophys. Res. Commun.
Expression of dopamine D3 receptor dimers and tetramers in brain and in transfected cells
J. Biol. Chem.
Adenosine A2A and group I metabotropic glutamate receptors synergistically modulate the binding characteristics of dopamine D2 receptors in the rat striatum
Neuropharmacology
The selective mGlu5 receptor agonist CHPG inhibits quinpirole-induced turning in 6-hydroxydopamine-lesioned rats and modulates the binding characteristics of dopamine D2 receptors in the rat striatum: interactions with adenosine A2a receptors
Neuropsychopharmacology
Metabotropic glutamate mGlu5 receptor-mediated modulation of the ventral striopallidal GABA pathway in rats. Interactions with adenosine A2A and dopamine D2 receptors
Neurosci. Lett.
Pathophysiology of the basal ganglia in Parkinson's disease
Trends Neurosci.
The striopallidal neuron: a main locus for adenosine–dopamine interactions in the brain
J. Neurosci.
Antagonistic A2A/D2 receptor interactions in the striatum as a basis for adenosine/dopamine interactions in the central nervous system
Drug Dev. Res.
Blockade of A2A adenosine receptors positively modulates turning behaviour and c-Fos expression induced by D1 agonists in dopamine-denervated rats
Eur. J. Neurosci.
Dopamine-adenosine interactions in the striatum and the globus pallidus: inhibition of striatopallidal neurons through either D2 or A2A receptors enhances D1 receptor-mediated effects on c-fos expression
J. Neurosci.
Adenosine A2A antagonist: a novel antiparkinsonian agent that does not provoke dyskinesia in parkinsonian monkeys
Ann. Neurol.
Motor stimulant effects of the adenosine A2A receptor antagonist SCH 58261 do not develop tolerance after repeated treatment in 6-hydroxydopamine-lesioned rats
Synapse
Antiparkinsonian effect of a new selective adenosine A2A receptor antagonist in MPTP-treated monkeys
Neurology
Adenosine A2A receptor antagonist treatment of Parkinson's disease
Neurology
Randomized trial of the adenosine A2A receptor antagonist istradefylline in advanced PD
Neurology
SCH 58261, an A2A adenosine receptor antagonist, counteracts parkinsonian-like muscle rigidity in rats
Synapse
The striatal restricted adenosine A2 receptor (RDC8) is expressed by enkephalin but not by substance P neurons. An in situ hybridization histochemistry study
J. Neurochem.
Actions of adenosine at its receptors in the CNS: insights from knockouts and drugs
Annu. Rev. Pharmacol. Toxicol.
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