ReviewAdenosine, adenosine A2A antagonists, and Parkinson's disease
Introduction
The number of individuals afflicted by Parkinson's disease (PD) is expected to double by 2030 in line with the aging population and increase in life expectancy [1]. Therefore, if quality of life is to be maintained and the socio-economic burden is to be reduced, more effective antiparkinsonian therapies need to be developed for use over a longer portion of the illness. This requires new pharmacologic approaches to PD management. Current therapy is as dependent on dopamine replacement strategies as it was 40 years ago, with levodopa and dopamine agonists forming the primary means of controlling motor symptoms and no truly novel drug class has been introduced into therapy for decades.
As a consequence, the problems associated with the treatment of PD remain largely unchanged. For example, the onset of motor complications (wearing-off, ON–OFF, dyskinesia) is almost inevitable [2], although the incidence of severe dyskinesia has been reduced by early use of dopamine agonists, more judicious use of levodopa [3], and the introduction of surgical approaches such as deep brain stimulation [4]. Dopaminergic side effects, including psychosis and dopamine dysregulation syndromes (e.g., compulsive gambling, hypersexuality), can become treatment limiting, and all of these phenomena are difficult to manage with currently available therapies [5]. The recognition of non-motor symptoms of PD (e.g., cognitive dysfunction, fatigue, sleep disturbance, autonomic dysfunction) as a key component of the illness has brought another area of unmet therapeutic need to the fore [6]. Non-motor features of PD invariably do not respond to dopaminergic medication and probably form the major challenge faced in the clinical management of PD [6]. Disease progression also remains untreated, with no drugs currently approved for use as neuroprotective agents or for disease modification.
Dopamine replacement therapy has provided the backbone of treatment and is based on the importance of nigral dopaminergic cell loss, the ensuing striatal dopamine depletion, and onset of motor symptoms [7]. However, the role of other neurotransmitters and neuromodulators is increasingly recognized in the appearance of motor and non-motor symptoms both as a result of pathology in a range of brainstem and forebrain regions and as adaptive changes to the alterations in basal ganglia function that occur following striatal dopamine depletion [8]. This resurgence of interest had led to extensive investigation of non-dopaminergic drugs as potential symptomatic treatments for PD. Such strategies offer the opportunity to treat PD without the involvement of the side effects common to dopaminergic therapy and to treat the non-motor symptoms of the illness. Despite some impressive effects in preclinical models of PD, to date, none has been introduced into general clinical practice, and some have failed during clinical evaluation [9].
A logical approach to a non-dopaminergic therapy for PD is to reverse the disruption to basal ganglia function by moving beyond the damaged dopaminergic input to striatum and focusing on the activity of striatal output pathways, which is known to be important in the expression of motor symptoms and the onset and/or expression of dyskinesia [8]. There are varying views on whether changes in the direct D1-mediated GABAergic output to the internal segment of the globus pallidus (GPi) or in the indirect D2-mediated GABAergic pathway to the external globus pallidus (GPe) are responsible for the development of dyskinesia. The indirect output pathway forms an important target not only because of alterations in its activity in PD but also because of the selective loss of spines on the medium spiny neurons comprising its cell bodies that does not occur in the direct output pathway, leading to a loss of cortical command through the glutamatergic corticostriatal pathway [10].
For these reasons, the selective localization of adenosine A2A receptors to the cell bodies and terminals of the GABAergic neurons of the indirect pathway [11], [12] has attracted attention to the use of adenosine antagonists for controlling the motor symptoms of PD. How adenosine acts to modulate basal ganglia function is a new concept to this area, and it is necessary to understand the function of adenosine and the receptor subtypes with which it interacts under normal physiological conditions and in the abnormal basal ganglia in PD. This, and the potential of adenosine A2A antagonists to affect striatal output and to form a novel target for the treatment of PD, is the basis of this review. The preclinical and clinical evidence for efficacy in PD are presented, and the potential for A2A antagonists to exert neuroprotective activity in PD is considered.
Section snippets
The adenosine system
Adenosine is a nucleoside composed of the purine base adenine and ribose. It is not a transmitter substance, but rather a normal metabolite that also serves as a signalling function. As such, adenosine can be said to stand at a crossroads between several metabolic pathways [13]. All cells have intracellular adenosine in all circumstances, and equilibriative transporters ensure that extra- and intracellular adenosine concentrations are equivalent. Because there is always adenosine
Adenosine and adenosine A2A receptors in the basal ganglia
Adenosine A2A receptor localization in basal ganglia is restricted to GABAergic neurons of the indirect pathway, projecting from the caudate putamen (CPu) to the GPe, which also selectively expresses the D2 dopamine receptor and the peptide enkephalin [34]. Conversely, neurons of the direct pathway projecting to the substantia nigra pars reticulata (SNr) or the GPi, which selectively express the D1 dopamine receptor and the peptide dynorphin, do not contain appreciable levels of A2A receptors
Rodent studies
Adenosine A2A receptor antagonists produce an antiparkinsonian effect in rodent models of PD. They increase locomotor activity in MPTP-treated or reserpinized mice and reverse haloperidol-induced catalepsy [42], [43]. In addition, the A2A receptor antagonists istradefylline and SCH 58261 potentiate rotational behavior produced by levodopa or dopamine agonists in 6-OHDA-lesioned rats [44], [45], [46]. In 6-OHDA-lesioned rats rendered dyskinetic by prior treatment with levodopa, istradefylline
Clinical trials with the A2A antagonist istradefylline
In a proof-of-concept study conducted in 15 PD patients [70], the acute effects of istradefylline were evaluated using levodopa infusions. Patients randomized to istradefylline (n = 11, plus 1 withdrawal) received placebo for 2 weeks, istradefylline 40 mg/day for 2 weeks, and then istradefylline 80 mg for 2 weeks; the other patients (n = 3) received placebo for 6 weeks. Patients were evaluated at the end of each 2-week period when study medication (istradefylline or placebo) was given (1)
Could adenosine A2A receptor antagonists be neuroprotective?
One of the most exciting prospective roles for A2A receptor antagonists as a novel therapy for PD is their potential to attenuate dopaminergic neurodegeneration, as suggested by convergent epidemiologic and experimental evidence. In a 30-year follow-up study of 8004 Japanese–American men in the Honolulu Heart Program, Ross and colleagues [77] reported an inverse relationship between consumption of the non-selective adenosine antagonist caffeine and the risk of developing PD 20 years later. The
Conclusions
The selective localization of A2A receptors to the basal ganglia and specifically to the indirect output pathway offers a unique opportunity to modulate the output from the striatum that is believed critical to the occurrence of motor components of PD. How A2A receptors can affect basal ganglia function is explained by the role of adenosine as a signalling molecule in the nervous system. This type of modulation forms a new concept for how basal ganglia function is controlled in normal
References (99)
- et al.
Projected number of people with Parkinson disease in the most populous nations, 2005 through 2030
Neurology
(2007) - et al.
Frequency of levodopa-related dyskinesias and motor fluctuations as estimated from the cumulative literature
Mov Disord
(2001) - et al.
Levodopa in the treatment of Parkinson's disease: current controversies
Mov Disord
(2004) - et al.
Deep brain stimulation for Parkinson's disease: patient selection and evaluation
Mov Disord
(2002) - et al.
Dopamine agonists in Parkinson's disease
Expert Rev Neurother
(2008) - et al.
Non-motor symptoms of Parkinson's disease: diagnosis and management
Lancet Neurol
(2006) - et al.
An algorithm (decision tree) for the management of Parkinson's disease: treatment guidelines
Neurology
(2001) - et al.
The origin of motor fluctuations in Parkinson's disease: importance of dopaminergic innervation and basal ganglia circuits
Neurology
(2004) - et al.
New pharmacologic horizons in the treatment of Parkinson disease
Neurology
(2006) Indirect-pathway neurons lose their spines in Parkinson disease
Nat Neurosci
(2006)
Adenosine A2A receptors and basal ganglia physiology
Prog Neurobiol
Striatal restricted adenosine A2 receptor (RDC8) is expressed by enkephalin but not by substance P neurons: an in situ hybridization histochemistry study
J Neurochem
Interaction of adenosine with adenosine-binding protein, S-adenylsyl homocysteine hydrolase
Adenosine, an endogenous distress signal, modulates tissue damage and repair
Cell Death Differ
Adenosine and brain function
Adenine nucleotides undergo rapid, quantitative conversion to adenosine in the extracellular space in rat hippocampus
J Neurosci
ATP and acetylcholine, equal brethren
Neurochem Int
Glial regulation of the cerebral microvasculature
Nat Neurosci
Adenosine is crucial for deep brain stimulation-mediated attenuation of tremor
Nat Med
International Union of Pharmacology. XXV. Nomenclature and classification of adenosine receptors
Pharmacol Rev
Comparison of the potency of adenosine as an agonist at human adenosine receptors expressed in Chinese hamster ovary cells
Biochem Pharmacol
Signaling via A2A adenosine receptor in four PC12 cell clones
Naunyn Schmiedebergs Arch Pharmacol
Hyperalgesia, anxiety, and decreased hypoxic neuroprotection in mice lacking the adenosine A1 receptor
Proc Natl Acad Sci U S A
Distribution, biochemistry and function of striatal adenosine A2A receptors
Prog Neurobiol
Actions of adenosine at its receptors in the CNS: insights from knockouts and drugs
Annu Rev Pharmacol Toxicol
Adenosine in tissue protection and tissue regeneration
Mol Pharmacol
The role of adenosine in the regulation of coronary blood flow
Circ Res
Growth regulation of the vascular system: an emerging role for adenosine
Am J Physiol Regul Integr Comp Physiol
Adenosine 5′-triphosphate and adenosine as endogenous signaling molecules in immunity and inflammation
Pharmacol Ther
Recent progress in the development of adenosine receptor ligands as antiinflammatory drugs
Curr Top Med Chem
Purines and neutrophil leukocytes
Gen Pharmacol
Role of G-protein-coupled adenosine receptors in downregulation of inflammation and protection from tissue damage
Nature
A2A adenosine receptor induction inhibits IFN-gamma production in murine CD4+ T cells
J Immunol
Adenosine A2a receptor mRNA is expressed by enkephalin cells but not by somatostatin cells in rat striatum: a co-expression study
Brain Res Mol Brain Res
Cellular distribution of adenosine A2A receptor mRNA in the primate striatum
J Comp Neurol
Ultrastructural localization of adenosine A2A receptors suggests multiple cellular sites for modulation of GABAergic neurons in rat striatum
J Comp Neurol
Selective elimination of glutamatergic synapses on striatopallidal neurons in Parkinson disease models
Nat Neurosci
Adenosine A2a receptor-mediated modulation of striatal acetylcholine release in vivo
J Neurochem
Increased adenosine A2A receptors in the brain of Parkinson's disease patients with dyskinesias
Brain
Distribution of adenosine A2 receptor mRNA in the human brain
Neurosci Lett
Positron emission tomography analysis of [11C]KW-6002 binding to human and rat adenosine A2A receptors in the brain
Synapse
Actions of adenosine A2A receptor antagonist KW-6002 on drug-induced catalepsy and hypokinesia caused by reserpine or MPTP
Psychopharmacology (Berl)
Catalepsy induced by a blockade of dopamine D1 or D2 receptors was reversed by a concomitant blockade of adenosine A(2A) receptors in the caudate-putamen of rats
Eur J Neurosci
Adenosine A2A receptor antagonism potentiates L-DOPA-induced turning behaviour and c-fos expression in 6-hydroxydopamine-lesioned rats
Eur J Pharmacol
Adenosine A(2A) receptor antagonists KF17837 and KW-6002 potentiate rotation induced by dopaminergic drugs in hemi-parkinsonian rats
Eur J Pharmacol
The novel adenosine A2a antagonist ST1535 potentiates the effects of a threshold dose of l-dopa in unilaterally 6-OHDA-lesioned rats
Brain Res
A2A antagonists as novel non-dopaminergic therapy for motor dysfunction in PD
Neurology
Cellular and behavioural effects of the adenosine A2a receptor antagonist KW-6002 in a rat model of l-DOPA-induced dyskinesia
J Neurochem
Systemic administration of adenosine A(2A) receptor antagonist reverses increased GABA release in the globus pallidus of unilateral 6-hydroxydopamine-lesioned rats: a microdialysis study
Neuroscience
Cited by (187)
Targeting the adenosine A<inf>2A</inf> receptor for neuroprotection and cognitive improvement in traumatic brain injury and Parkinson's disease
2023, Chinese Journal of Traumatology - English EditionThe adenosine A<inf>2A</inf> receptor in the basal ganglia: Expression, heteromerization, functional selectivity and signalling
2023, International Review of NeurobiologyClinical Studies and Therapies in Parkinson’s Disease: Translations from Preclinical Models
2021, Clinical Studies and Therapies in Parkinson's Disease: Translations from Preclinical ModelsHow do adenosine A<inf>2A</inf> receptors regulate motor function?
2020, Parkinsonism and Related Disorders