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Parkinsons Dis. 2012; 2012: 489853.
Published online 2012 June 17. doi:  10.1155/2012/489853
PMCID: PMC3382949

A2A Receptor Antagonism and Dyskinesia in Parkinson's Disease

Abstract

Dyskinesia, a major complication of treatment of Parkinson's disease (PD), involves two phases: induction, which is responsible for dyskinesia onset, and expression, which underlies its clinical manifestation. The unique cellular and regional distribution of adenosine A2A receptors in basal ganglia areas that are richly innervated by dopamine, and their antagonistic role towards dopamine receptor stimulation, have positioned A2A receptor antagonists as an attractive nondopaminergic target to improve the motor deficits that characterize PD. In this paper, we describe the biochemical characteristics of A2A receptors and the effects of adenosine A2A antagonists in rodent and primate models of PD on L-DOPA-induced dyskinesia, together with relevant biomarker studies. We also review clinical trials of A2A antagonists as adjuncts to L-DOPA in PD patients with motor fluctuations. These studies have generally demonstrated that the addition of an A2A antagonist to a stable L-DOPA regimen reduces OFF time and mildly increases dyskinesia. However, limited clinical data suggest that the addition of an A2A antagonist along with a reduction of L-DOPA might maintain anti-Parkinsonian benefit and reduce dyskinesia. Whether A2A antagonists might reduce the development of dyskinesia has not yet been tested clinically.

1. Adenosine A2A Receptor Localization and Biochemistry

Adenosine A2A receptors are present in medium to high concentrations in several basal ganglia (BG) nuclei and may therefore be capable of influencing motor activity by acting at different BG levels. This feature renders A2A receptors particularly attractive for modulation of dopamine receptor functions in a disease such as Parkinson's disease (PD), which is caused by degeneration of dopaminergic neurons in the nigrostriatal pathway, but associated with changes at several receptor levels. An interesting peculiarity of A2A receptors is their selective localization in the indirect striatonigral GABAergic pathway, which contains enkephalin (ENK) and which is known to lead to inhibition of motor behavior [1, 2].

A2A receptors are positively coupled to adenylate cyclase and, either at the level of second messengers or through the formation of receptor heterodimers, negatively influence dopamine D2 receptor activity [36]. On the basis of this anatomical and functional organization, A2A receptors acting in concert with D2 and D1 receptors are capable of affecting planning and execution of movements [7, 8]. Moreover, the low levels of A2A receptors expressed in brain areas other than the BG are at the basis of the low incidence of nonmotor side effects observed in clinical trials so far performed [9]. A2A receptors, however, are expressed in some peripheral organs and blood cells, underlying the importance of evaluating these elements in clinical trials testing the efficacy of A2A receptor antagonists in PD [10, 11].

Interestingly, an abnormal increase in A2A signaling, in the striatum of 6-hydroxydopamine- (6-OHDA-) lesioned rats, and in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine- (MPTP-) treated primates, as well as in PD patients chronically treated with L-DOPA [1214], might produce a prevailing tone of A2A receptors, the activation of which inhibits motor activity. Therefore, blockade of the A2A receptor inhibitory tone could be one of the factors underlying the positive effects produced by A2A antagonists in PD.

2. Adenosine A2A Receptor Antagonists in Animal Models of Dyskinesia

2.1. Behavioral Studies

Preclinical behavioral investigations suggest that A2A antagonists may be of interest in the management of dyskinesia in PD. The first preclinical evidence suggesting that A2A antagonists may be utilized in patients rendered dyskinetic by L-DOPA was obtained in 6-OHDA unilaterally lesioned rats subchronically treated with L-DOPA [17]. In this paradigm, the repeated administration of L-DOPA causes a progressive, sensitized, increase in contraversive turning behavior, which is thought to reproduce some aspects of the abnormal motor responses induced by the prolonged treatment with L-DOPA [1719]. Of great interest, sensitization in contraversive turning behavior did not take place when L-DOPA was administered at a low dose in association with an A2A antagonist [17, 20]. Subsequent studies utilizing a full effective L-DOPA dose in rats with established dyskinesia [21] did not report any benefit, since L-DOPA treatment alone or in combination with an A2A antagonist presented the same degree of dyskinesia. These results demonstrated that A2A antagonists are not antidyskinetic drugs; however, in this model, they did not worsen existing dyskinesia while increasing the efficacy of L-DOPA on motor symptoms.

Studies in MPTP-treated primates, the best experimental model of PD and PD-associated dyskinesia, have confirmed the beneficial effects of blockade of A2A receptors. A2A antagonists were found not to be prodyskinetic drugs, since their administration to Parkinsonian primates with established dyskinesia induced by L-DOPA relieved motor impairment and did not worsen dyskinesia [2224]. Moreover, an attenuation of dyskinesia induced by long-term apomorphine was observed when the drug was administered in combination with an A2A antagonist [25], suggesting that A2A antagonists might lower the dyskinetic potential of dopamine-replacement therapy in specific conditions. The previous coadministration of an A2A antagonist was also found to delay the onset of severe dyskinesia when the same primates were maintained on apomorphine alone [25].

2.2. Biochemical Studies

Regarding the mechanisms underlying dyskinesia and the effects of A2A antagonists in experimental models of dyskinesia, it seems likely that these drugs interfere with the neuroplastic changes induced by dopamine-replacement therapy in the dopamine-denervated BG (Figure 1). Studies in 6-OHDA-lesioned rats demonstrate that striatal dopamine denervation is associated with persistent modifications in the levels of the neuropeptides dynorphin (DYN) and ENK, as well as the enzyme glutamic acid decarboxylase 67 (GAD-67) [21, 2628] (Figure 1). Moreover, it was observed that chronic treatment with L-DOPA, which induces a dyskinetic-like motor response, further contributes to these biochemical changes [21, 26, 27] (Figure 1). Importantly, the coadministration of an A2A antagonist, besides resulting in a stable motor response, attenuated the effects of chronic L-DOPA treatment on ENK and GAD-67 [21, 26, 27]. It has to be acknowledged that, as of today, no evidence supports a direct role of DYN, ENK, and GAD-67 in dyskinesia. Nevertheless, changes in the expression of neuropeptides are a marker of the activity of striatal neurons [26]. Therefore, it can be suggested that A2A antagonists modulate the effects of L-DOPA and mitigate the neuroplastic changes this drug induces in the striatum. These effects could arise from the opposite functional interactions involving adenosine A2A and dopamine D1 and D2 receptors [29]. These interactions, by amplifying dopaminergic signaling, would regulate the activity of striatal output neurons in conditions of dopamine denervation and nonphysiological stimulation of dopamine receptors (Figure 1).

Figure 1
Role of A2A receptors on modifications in the activity of the striatal efferent pathways. Under physiological conditions (a), striatal neurons receive dopaminergic inputs from the substantia nigra pars compacta (SNc). Endogenous dopamine (DA) activates ...

It has to be considered that A2A receptor antagonists, in addition to their potential effects on biochemical and functional changes induced by dopamine-replacement therapy, potentiate the motor-activating effects of L-DOPA and dopaminergic agonists, allowing their use at lower, nondyskinetic doses [7]. Hence, the sparing of dopaminomimetic drugs in combination with an A2A antagonist may contribute to the attenuation, or delay, of the maladaptive modifications in striatal function which underlie dyskinesia.

2.3. Role of Glutamate Transmission

Besides the facilitation of dopamine transmission, other mechanisms have been proposed to underlie, or at least participate in, the effects of A2A receptor antagonists observed in experimental models of dyskinesia. Neuroanatomical studies demonstrate that striatal A2A receptors are highly expressed at the postsynaptic level in asymmetric synapses, where they can interact with glutamate receptors [30]. Glutamate receptors are thought to participate in the pathophysiology of dyskinesia [31] and, interestingly, chronic administration of L-DOPA to 6-OHDA-lesioned rats was reported to induce a hyperphosphorylation state of the α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptor [25, 32]. This effect was found to be significantly attenuated when L-DOPA was administered in combination with an A2A antagonist [25, 32]. Evidence also exists that A2A receptors may regulate the conductance of N-methyl-D-aspartate (NMDA) receptors [33]. This may have important implications for dyskinesia, since NMDA receptors play a major role in neuroplasticity phenomena [34, 35], including those which take place in motor circuits, and may underlie abnormal motor responses to dopamine-replacement therapy used in PD.

Interactions between A2A receptors and type 5 metabotropic glutamate receptors (mGlu5) have also been reported [3638]. In the light of the evidence showing that antagonism of mGlu5 receptors may reduce dyskinesia in MPTP-lesioned primates treated with L-DOPA [39], it is possible to envision that combined antagonism on the two receptors might contribute to the beneficial effects of A2A antagonists on dyskinesia. Additional mechanisms involved in the modulation of therapy-induced abnormal motor responses by A2A antagonists could include interaction with nondopaminergic and nonglutamatergic receptors, such as cannabinoid and serotonin receptors, and regulation of neurotransmitter release [4042]. In this regard, it has to be recalled that A2A receptors powerfully modulate extracellular concentrations of glutamate [43, 44], the excessive increase of which plays a role in the abnormal functioning of BG existing in PD and in neuroplasticity phenomena.

3. Biomarkers and Neuroimaging Studies Involving the A2A Receptor

A crucial need in the translation from preclinical studies to clinical trials is the availability of reliable biomarkers, which would give the opportunity of monitoring the effects of the compound on its biological target—the adenosine receptor—in addition to evaluating its clinical efficacy. In this field, substantial contributions have been made by neuroimaging studies, while biological findings in peripheral tissues have opened interesting perspectives.

3.1. Neuroimaging Studies in Humans

Neuroimaging techniques, based on positron emission tomography (PET), have been recently used to analyze A2A receptor distribution in the human brain, either in normal subjects or in PD patients exposed to L-DOPA; in this latter case, the purpose was to draw potential in vivo correlations between changes in A2A receptor availability and the presence of L-DOPA-induced dyskinesias.

In 2007, Mishina et al. examined the distribution of A2A receptors in the brain of 5 normal subjects using PET tracer [7-methyl-11C]-(E)-8-(3,4,5-trimethoxystyryl)-1,3,7-trimethylxanthine ([11C]TMSX) [45]. Various brain regions were examined, including the cerebellum, brainstem, thalamus, head of caudate nucleus, anterior and posterior putamen, frontal lobe, temporal lobe, parietal lobe, occipital lobe, and posterior cingulate gyrus. Results showed the highest levels of A2A receptor binding in the putamen, followed by the caudate nucleus and thalamus, while the lowest levels were detected in the cerebral cortex. Using a different A2A receptor-specific radiotracer, [11C]SCH442416, Brooks et al. assessed binding of vipadenant (3-(4-amino-3-methylbenzyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine), a selective nonxanthine A2A receptor antagonist synthesized by Vernalis Plc (also known as BIIB014 or V2006) [15]. Displacement of the PET tracer by increasing doses of vipadenant (2.5–100 mg/day for 10 or 11 days) was investigated in various brain regions—including the putamen, caudate nucleus, nucleus accumbens, thalamus of both hemispheres, and cerebellum—of 15 healthy volunteers. The estimated receptor occupancy of vipadenant in the brain varied from 74% to 94% at the lowest daily dose (2.5 mg), with the highest value being observed in the putamen and the lowest value in the cerebellum. Saturation was reached in all regions at the highest dose administered (100 mg). It is noteworthy that double-blind, placebo-controlled, phase 2 clinical trials with vipadenant have been conducted in PD patients, showing modest anti-PD activity, until a review of preclinical toxicology studies, conducted by Vernalis Plc, led to discontinuation of this drug in July 2010 (http://www.vernalis.com/media-centre/latest-releases/2010-releases/584/).

Recently, Mishina et al., using PET with [11C]TMSX, measured the binding ability of striatal A2A receptors in 9 untreated PD patients, 7 PD patients with dyskinesia, and 6 age-matched control subjects [16]. They found that the distribution volume ratio of A2A receptors in the putamen was larger in patients with L-DOPA-induced dyskinesias than in control subjects and that L-DOPA treatment tended to increase the presence of A2A receptors in the putamen.

Further information on the relationship between A2A receptors and L-DOPA-induced dyskinesias has been provided by Ramlackhansingh et al., who investigated adenosine A2A receptor availability in the caudate and putamen of PD patients with (n = 6) and without L-DOPA-induced dyskinesias (n = 6) and in age-matched healthy controls (n = 6) [46]. In line with previous studies [12], they found that A2A receptor binding was higher in the caudate and putamen of PD patients with L-DOPA-induced dyskinesias, with respect to both PD patients without L-DOPA-induced dyskinesias and controls, thereby lending further support to the view that A2A antagonists may prove beneficial in the management of motor complications associated with L-DOPA treatment. It is worth mentioning that although their cohort was small and the power was probably too limited to detect a difference, Ramlackhansingh et al. did not find a correlation between striatal [11C]SCH442416 uptake and dyskinesia severity.

An additional study tested the hypothesis that blockade of striatal A2A receptors, caused by the selective antagonist SYN115, a benzothiazole derivative, may reduce the inhibitory output of the striatofugal indirect pathway [47]. For this purpose, the authors used a perfusion magnetic resonance imaging (MRI) technique, which gives a functional measure of the cerebral blood flow (CBF) reflecting neuronal activity. The study was conducted during a randomized, double-blind, placebo-controlled, crossover study with SYN115 in 21 PD patients on L-DOPA. The results showed that SYN115 produced a dose-dependent decrease in thalamic CBF, which the authors deemed consistent with reduced pallid-thalamic inhibition via the indirect pathway [47].

3.2. Peripheral Expression of Adenosine Receptors

To our knowledge, only one paper has reported the characterization of adenosine receptors in peripheral tissues (peripheral blood cells) of human Parkinsonian subjects [48]. In this study, Varani et al. investigated affinity and density of A1, A2A, A2B, and A3A receptors in lymphocyte and neutrophil membranes from PD patients and healthy control subjects; they also analyzed A2A receptors density in autoptic samples of putamen from PD patients and control subjects. They found that A2A receptors were significantly different between PD patients and controls, in terms of affinity and density, while no changes seemed to affect A1, A2B, or A3A receptors. In particular, increased density of A2A receptors, coupled with decreased affinity, was detected in lymphocyte and neutrophil membranes of PD patients, with respect to control subjects. This finding was associated with a reduction in the mRNA of A2A receptors, while no changes were observed in the mRNAs of the other adenosine receptor subtypes investigated. The postmortem study confirmed this result, showing increased A2A receptor density in the putamen of PD patients [48].

4. Clinical Trials of A2A Receptor Antagonists

4.1. Istradefylline

Clinical trials of A2A antagonists in patients with motor complications have focused on reductions in OFF time rather than changes in dyskinesia. Istradefylline was the first A2A receptor antagonist to enter clinical trials seeking an indication in PD. Bara-Jimenez et al. conducted an early proof-of-principle study using intravenous L-DOPA infusions in 15 moderate to advanced PD patients with motor fluctuations, 6 of whom had L-DOPA-induced peak-dose dyskinesia [49]. Twelve subjects were randomized to istradefylline, 3 to placebo, and 1 dropped out. Istradefylline 40 or 80 mg had no effect on Parkinsonian signs or dyskinesia when added to an optimal L-DOPA infusion. However, when added to a low-dose L-DOPA infusion, istradefylline 40 mg improved Unified Parkinson's Disease Rating Scale (UPDRS) motor scores by 24% (P < 0.05) and istradefylline 80 mg improved motor scores by 36% (P < 0.05). The anti-Parkinsonian response to a low-dose L-DOPA infusion plus istradefylline 80 mg was similar to an optimal-dose L-DOPA infusion. Notably, the severity of dyskinesia with a low-dose L-DOPA infusion plus istradefylline 80 mg was 45% less (P < 0.05) than with an optimal-dose L-DOPA infusion. This suggests that by lowering the L-DOPA dose and adding istradefylline, one might be able to maintain anti-Parkinsonian benefit and reduce dyskinesia, a paradigm that has not been studied in clinical trials using oral L-DOPA preparations.

Istradefylline was then studied in a 12-week, randomized, placebo-controlled exploratory trial in which patients with both motor fluctuations and dyskinesia were randomized to the addition of placebo (n = 29), istradefylline in ascending doses up to 20 mg/day (n = 26), or istradefylline in ascending doses up to 40 mg/day (n = 28) [50]. Anti-Parkinsonian medications were kept unchanged except that the total daily L-DOPA dose could be reduced, if necessary, to ameliorate L-DOPA-related adverse events. Over the course of the study, there were no significant changes in daily L-DOPA doses comparing istradefylline and placebo groups (P = 0.96). Diary results showed that the combined istradefylline groups experienced a reduction in OFF time of 1.2 hours, whereas the placebo group experienced an increase in OFF time of 0.5 hours (P < 0.004). Multiple assessments of change in dyskinesia did not demonstrate significant differences between the placebo and istradefylline groups, including Goetz dyskinesia scale scores (−0.2 versus −0.1, P = 0.3), Parkinson dyskinesia scale scores (−1.4 versus −1.3, P = 0.9), and UPDRS items 32–34 (−0.03 versus −0.4, P = 0.8). However, diary results indicated that ON time with dyskinesia was significantly more increased with istradefylline than placebo (0.6 hours versus −1.5 hours, P = 0.001). Troublesome dyskinesia was not included as a diary category in this study. As an adverse event, increased dyskinesia was reported by 13.8% of placebo patients and 16.7% of istradefylline patients.

This is an important study in that it is the largest study of an A2A receptor antagonist in a population of patients, all of whom have L-DOPA-induced dyskinesia. In addition, dyskinesia was most thoroughly assessed by multiple scales. Clearly, the addition of istradefylline to a stable antiparkinson regimen did not reduce dyskinesia, nor was there a very substantial increase. Perhaps the most parsimonious interpretation is that overall severity of dyskinesia was essentially unchanged, but much or all of the reduction in OFF time was replaced by an increase in ON time with dyskinesia.

Subsequent trials in moderate to advanced PD patients all included subjects with motor fluctuations, some of whom had dyskinesia and some of whom did not. These included two phase 2 istradefylline trials. In one, istradefylline 40 mg/day reduced OFF time compared with placebo by 1.2 hours (P = 0.005) [51]. ON time with dyskinesia increased by 1.0 hour more in the istradefylline group than the placebo group (P = 0.035). Of this differential increase in ON time with dyskinesia, approximately 0.8 hours were ON time with nontroublesome dyskinesia (P = 0.065), and 0.2 hours were ON time with troublesome dyskinesia (P = 0.347). Dyskinesia was reported as an adverse event in 15.2% of placebo subjects and 30.2% of istradefylline subjects. In the other phase 2 study [52], istradefylline 20 mg/day reduced OFF time by 0.64 hours, and istradefylline 60 mg/day reduced OFF time by 0.77 hours (overall P value = 0.065). Compared with placebo, istradefylline 20 mg/day increased ON time with dyskinesia by 0.54 hours, and ON time with troublesome dyskinesia by 0.06 hours; istradefylline 60 mg/day increased ON time with dyskinesia by 0.23 hours and ON time with troublesome dyskinesia by 0.04 hours. Dyskinesia was reported as an adverse event in 14.3% of placebo subjects, 23.9% of istradefylline 20 mg/day subjects, and 22.6% of istradefylline 60 mg/day subjects.

In a phase 3 study, istradefylline 20 mg/day reduced OFF time compared with placebo 0.7 hours (P = 0.03) [53]. Increases in dyskinesia were similar in placebo and istradefylline groups (ON time with dyskinesia: 0.5 versus 0.7 hours, P = 0.57; ON time with nontroublesome dyskinesia: 0.4 versus 0.4 hours, P = 0.82; ON time with troublesome dyskinesia: 0.2 versus 0.3 hours, P = 0.48). However, dyskinesia was reported as an adverse event in 22.6% of istradefylline subjects compared with 12.2% of placebo subjects.

In a phase 3 study in Japan [54], istradefylline 20 mg/day reduced OFF time compared with placebo by 0.65 hours (P = 0.013) and 40 mg reduced OFF time compared with placebo by 0.92 hours (P < 0.001). Compared with placebo, istradefylline 40 mg/day significantly increased ON time with troublesome dyskinesia (0.35 hours, P = 0.011). As an adverse event, dyskinesia was reported in 2.5% of placebo subjects, 8.5% of istradefylline 20 mg/day subjects, and 6.4% of istradefylline 40 mg/day subjects.

Thus, in most of the clinical trials, the addition of istradefylline was associated with some increase in ON time with dyskinesia, and dyskinesia was reported as an adverse event more commonly in istradefylline- than placebo-treated subjects.

A recent population pharmacokinetic-pharmacodynamic study analyzed data from 1798 patients participating in 6 phase 2/3 istradefylline trials [55]. The analysis predicted a maximum probability of experiencing dyskinesia as an adverse event sometime during a study as 15.4% for placebo, 22.5% for istradefylline 20 mg/day, 24.1% for istradefylline 40 mg/day, and 24.3% for istradefylline 60 mg/day.

Thus, clinical data to date do not provide evidence for an antidyskinetic effect of istradefylline but rather suggest that istradefylline mildly increases dyskinesia in a dose-dependent fashion. Results vary slightly from trial to trial and may depend, in part, on the percentage of subjects with dyskinesia at baseline and the severity of their dyskinesia. Other potential factors may include concomitant medications such as amantadine and dietary intake of caffeine, a nonspecific adenosine antagonist, although these factors have not been systematically evaluated.

4.2. Preladenant

Preladenant was evaluated in a phase 2, 12-week, dose-finding study of PD patients experiencing motor fluctuations [56]. In this study, patients were randomized to preladenant 1, 2, 5, or 10 mg twice daily (BID) or matching placebo. OFF time was significantly reduced compared with placebo in subjects randomized to preladenant 5 mg BID (1.0 hours, P = 0.0486) and preladenant 10 mg BID (1.2 hours, P = 0.019). In the 5 mg BID group, compared with placebo, ON time with dyskinesia was increased 0.9 hours (P = 0.185), ON time with nontroublesome dyskinesia was increased by 1.0 hour (P = 0.064), and ON time with troublesome dyskinesia was decreased by 0.1 hours (P = 0.812). In the preladenant 10 mg BID group, compared with placebo, ON time with dyskinesia was increased by 1.3 hours (P = 0.054), ON time with nontroublesome dyskinesia was increased by 1.1 hours (P = 0.047), and ON time with troublesome dyskinesia was increased by 0.2 hours (P = 0.540). These results appear to be similar to some of the istradefylline findings in which much of the reduction in OFF time was replaced by ON time with nontroublesome dyskinesia. Dyskinesia was reported as an adverse event by 13% of placebo subjects, by 9% of preladenant 5 mg BID subjects, and by 13% of preladenant 10 mg BID subjects. This result may be different from what has been observed with istradefylline where dyskinesia was rather consistently reported more frequently as an adverse event in istradefylline-compared with placebo-treated groups. Thus, preliminary results suggest that like istradefylline, preladenant does not reduce dyskinesia, but it remains to be seen whether preladenant causes less dyskinesia than istradefylline, as suggested by these adverse event results.

To our knowledge, there have been no clinical trials evaluating whether an A2A receptor antagonist can reduce the development of dyskinesia when administered in early disease concomitant with the introduction of dopaminergic therapy. Based on animal model data, this remains an important avenue for future investigation. Similarly, we are not aware of clinical trials of patients with L-DOPA-induced dyskinesia to determine whether lowering the L-DOPA dose and adding an A2A receptor antagonist will allow maintenance of the anti-Parkinsonian response with reduction of dyskinesia.

5. Conclusions

The management of PD is most complex in the treatment of late, complicated PD, when the response to L-DOPA is associated with dyskinesia. From the studies described in the present paper, it is suggested that the management of the first (uncomplicated) phase has important consequences on the induction of dyskinesia that characterize the second (complicated) phase.

Preclinical studies suggest that A2A antagonists might reduce the development of dyskinesia, but this has not yet been tested clinically. In PD patients, once dyskinesias are established, adding an A2A antagonist to a stable dopaminergic therapeutic regimen does not appear to provide an antidyskinetic response, and most clinical trials have suggested a mild increase in dyskinesia in association with a reduction in OFF time. Limited clinical data suggest the possibility that in PD patients with established dyskinesia, one might be able to maintain the anti-Parkinsonian response and reduce dyskinesia by adding an A2A antagonist and lowering the L-DOPA dose, but this remains to be proven. Thus, critical aspects of the potential benefits of A2A antagonists with regard to dyskinesia are yet to be evaluated.

Acknowledgment

Dr. N. Simola is supported by Regione Autonoma della Sardegna (Project Master and Back, code PR-MAB-A2009-614).

Abbreviations

AMPA:
α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid
BG:
Basal ganglia
BID:
Bis in die, twice a day
CBF:
Cerebral blood flow
PD:
Parkinson's disease
6-OHDA:
6-Hydroxydopamine
MPTP:
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
DYN:
Dynorphin
ENK:
Enkephalin
GAD-67:
Glutamic acid decarboxylase 67
mGLU5:
Type 5 metabotropic glutamate receptors 5
MRI:
Magnetic resonance imaging
NMDA:
N-Methyl-D-aspartate
PET:
Positron emission tomography
UPDRS:
Unified Parkinson's disease rating scale.

References

1. Fink JS, Weaver DR, Rivkees SA, et al. Molecular cloning of the rat A2 adenosine receptor: selective co-expression with D2 dopamine receptors in rat striatum. Molecular Brain Research. 1992;14(3):186–195. [PubMed]
2. Schiffmann SN, Libert F, Vassart G, Vanderhaeghen JJ. Distribution of adenosine A2 receptor mRNA in the human brain. Neuroscience Letters. 1991;130(2):177–181. [PubMed]
3. Canals M, Marcellino D, Fanelli F, et al. Adenosine A2A-dopamine D2 receptor-receptor heteromerization: qualitative and quantitative assessment by fluorescence and bioluminescence energy transfer. Journal of Biological Chemistry. 2003;278(47):46741–46749. [PubMed]
4. Fuxe K, Agnati LF, Jacobsen K, et al. Receptor heteromerization in adenosine A2A receptor signaling: relevance for striatal function and Parkinson’s disease. Neurology. 2003;61(11):S19–S23. [PubMed]
5. Hillion J, Canals M, Torvinen M, et al. Coaggregation, cointernalization, and codesensitization of adenosine A2A receptors and dopamine D2 receptors. Journal of Biological Chemistry. 2002;277(20):18091–18097. [PubMed]
6. Short JL, Ledent C, Borrelli E, Drago J, Lawrence AJ. Genetic interdependence of adenosine and dopamine receptors: evidence from receptor knockout mice. Neuroscience. 2006;139(2):661–670. [PubMed]
7. Morelli M, Di Paolo T, Wardas J, Calon F, Xiao D, Schwarzschild MA. Role of adenosine A2A receptors in parkinsonian motor impairment and l-DOPA-induced motor complications. Progress in Neurobiology. 2007;83(5):293–309. [PubMed]
8. Pinna A, Pontis S, Borsini F, Morelli M. Adenosine A2A receptor antagonists improve deficits in initiation of movement and sensory motor integration in the unilateral 6-hydroxydopamine rat model of Parkinson’s disease. Synapse. 2007;61(8):606–614. [PubMed]
9. Hauser RA, Schwarzschild MA. Adenosine A2A receptor antagonists for Parkinson’s disease rationale, therapeutic potential and clinical experience. Drugs and Aging. 2005;22(6):471–482. [PubMed]
10. Adair TH. Growth regulation of the vascular system: an emerging role for adenosine. American Journal of Physiology. 2005;289(2):R283–R296. [PubMed]
11. Lukashev D, Ohta A, Apasov S, Chen JF, Sitkovsky M. Cutting edge: physiologic attenuation of proinflammatory transcription by the Gs protein-coupled A2A adenosine receptor in vivo. Journal of Immunology. 2004;173(1):21–24. [PubMed]
12. Calon F, Dridi M, Hornykiewicz O, Bédard PJ, Rajput AH, Di Paolo T. Increased adenosine A2A receptors in the brain of Parkinson’s disease patients with dyskinesias. Brain. 2004;127(5):1075–1084. [PubMed]
13. Pinna A, Corsi C, Carta AR, Valentini V, Pedata F, Morelli M. Modification of adenosine extracellular levels and adenosine A2A receptor mRNA by dopamine denervation. European Journal of Pharmacology. 2002;446(1-3):75–82. [PubMed]
14. Tomiyama M, Kimura T, Maeda T, Tanaka H, Kannari K, Baba MA. Upregulation of Striatal Adenosine A2A Receptor mRNA in 6-Hydroxydopamine-Lesioned Rats Intermittently Treated with L-DOPA. Synapse. 2004;52(3):218–222. [PubMed]
15. Brooks DJ, Papapetropoulos S, Vandenhende F, et al. An open-label, positron emission tomography study to assess adenosine A2A brain receptor occupancy of vipadenant (BIIB014) at steady-state levels in healthy male volunteers. Clinical Neuropharmacology. 2010;33(2):55–60. [PubMed]
16. Mishina M, Ishiwata K, Naganawa M, et al. Adenosine A2A receptors measured with [11C]TMSX pet in the striata of parkinson’s disease patients. PLoS ONE. 2011;6(2) Article ID e17338. [PMC free article] [PubMed]
17. Pinna A, Fenu S, Morelli M. Motor stimulant effects of the adenosine A2A receptor antagonist SCH 58261 do not develop tolerance after repeated treatment in 6-hydroxydopamine-lesioned rats. Synapse. 2001;39(3):233–238. [PubMed]
18. Henry B, Crossman AR, Brotchie JM. Characterization of enhanced behavioral responses to L-DOPA following repeated administration in the 6-hydroxydopamine-lesioned rat model of Parkinson’s disease. Experimental Neurology. 1998;151(2):334–342. [PubMed]
19. Pinna A, Pontis S, Morelli M. Expression of dyskinetic movements and turning behaviour in subchronic l-DOPA 6-hydroxydopamine-treated rats is influenced by the testing environment. Behavioural Brain Research. 2006;171(1):175–178. [PubMed]
20. Tronci E, Simola N, Borsini F, et al. Characterization of the antiparkinsonian effects of the new adenosine A2A receptor antagonist ST1535: acute and subchronic studies in rats. European Journal of Pharmacology. 2007;566(1–3):94–102. [PubMed]
21. Lundblad M, Vaudano E, Cenci MA. Cellular and behavioural effects of the adenosine A2A receptor antagonist KW-6002 in a rat model of L-DOPA-induced dyskinesia. Journal of Neurochemistry. 2003;84(6):1398–1410. [PubMed]
22. Grondin R, Bédard PJ, Tahar AH, Grégoire L, Mori A, Kase H. Antiparkinsonian effect of a new selective adenosine A(2A) receptor antagonist in MPTP-treated monkeys. Neurology. 1999;52(8):1673–1677. [PubMed]
23. Hodgson RA, Bedard PJ, Varty GB, et al. Preladenant, a selective A2A receptor antagonist, is active in primate models of movement disorders. Experimental Neurology. 2010;225(2):384–390. [PubMed]
24. Kanda T, Jackson MJ, Smith LA, et al. Combined use of the adenosine A2A antagonist KW-6002 with L-DOPA or with selective D1 or D2 dopamine agonists increases antiparkinsonian activity but not dyskinesia in MPTP-treated monkeys. Experimental Neurology. 2000;162(2):321–327. [PubMed]
25. Bibbiani F, Oh JD, Petzer JP, et al. A2A antagonist prevents dopamine agonist-induced motor complications in animal models of Parkinson’s disease. Experimental Neurology. 2003;184(1):285–294. [PubMed]
26. Gerfen CR, Engber TM, Mahan LC, et al. D1 and D2 dopamine receptor-regulated gene expression of striatonigral and striatopallidal neurons. Science. 1990;250(4986):1429–1432. [PubMed]
27. Carta AR, Pinna A, Cauli O, Morelli M. Differential regulation of GAD67, enkephalin and dynorphin mRNAs by chronic-intermittent L-dopa and A2A receptor blockade plus L-dopa in dopamine-denervated rats. Synapse. 2002;44(3):166–174. [PubMed]
28. Zeng BY, Pearce RKB, MacKenzie GM, Jenner P. Alterations in preproenkephalin and adenosine-2a receptor mRNA, but not preprotachykinin mRNA correlate with occurrence of dyskinesia in normal monkeys chronically treated with L-DOPA. European Journal of Neuroscience. 2000;12(3):1096–1104. [PubMed]
29. Ferré S, Fredholm BB, Morelli M, Popoli P, Fuxe K. Adenosine-dopamine receptor-receptor interactions as an integrative mechanism in the basal ganglia. Trends in Neurosciences. 1997;20(10):482–487. [PubMed]
30. Rosin DL, Hettinger BD, Lee A, Linden J. Anatomy of adenosine A2A receptors in brain: morphological substrates for integration of striatal function. Neurology. 2003;61(11):S12–S18. [PubMed]
31. Gardoni F, Ghiglieri V, Luca MD, Calabresi P. Assemblies of glutamate receptor subunits with post-synaptic density proteins and their alterations in Parkinson’s disease. Progress in Brain Research. 2010;183(C):169–182. [PubMed]
32. Chase TN, Bibbiani F, Bara-Jimenez W, Dimitrova T, Oh-Lee JD. Translating A2A antagonist KW6002 from animal models to parkinsonian patients. Neurology. 2003;61(11):S107–S111. [PubMed]
33. Wirkner K, Gerevich Z, Krause T, et al. Adenosine A2A receptor-induced inhibition of NMDA and GABA A receptor-mediated synaptic currents in a subpopulation of rat striatal neurons. Neuropharmacology. 2004;46(7):994–1007. [PubMed]
34. Calabresi P, Galletti F, Saggese E, Ghiglieri V, Picconi B. Neuronal networks and synaptic plasticity in Parkinson’s disease: beyond motor deficits. Parkinsonism and Related Disorders. 2007;13(3):S259–S262. [PubMed]
35. Kelley AE, Andrzejewski ME, Baldwin AE, Hernandez PJ, Pratt WE. Glutamate-mediated plasticity in corticostriatal networks: role in adaptive motor learning. Annals of the New York Academy of Sciences. 2003;1003:159–168. [PubMed]
36. Ferré S, Karcz-Kubicha M, Hope BT, et al. Synergistic interaction between adenosine A2A and glutamate mGlu5 receptors: implications for striatal neuronal function. Proceedings of the National Academy of Sciences of the United States of America. 2002;99(18):11940–11945. [PubMed]
37. Kachroo A, Orlando LR, Grandy DK, Chen JF, Young AB, Schwarzschild MA. Interactions between metabotropic glutamate 5 and adenosine A2A receptors in normal and parkinsonian mice. Journal of Neuroscience. 2005;25(45):10414–10419. [PubMed]
38. Lopez S, Turle-Lorenzo N, Johnston TH, et al. Functional interaction between adenosine A2A and group III metabotropic glutamate receptors to reduce parkinsonian symptoms in rats. Neuropharmacology. 2008;55(4):483–490. [PubMed]
39. Johnston TH, Fox SH, McIldowie MJ, Piggott MJ, Brotchie JM. Reduction of L-DOPA-induced dyskinesia by the selective metabotropic glutamate receptor 5 antagonist 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned macaque model of Parkinson’s disease. Journal of Pharmacology and Experimental Therapeutics. 2010;333(3):865–873. [PubMed]
40. Carriba P, Ortiz O, Patkar K, et al. Striatal adenosine A2A and cannabinoid CB1 receptors form functional heteromeric complexes that mediate the motor effects of cannabinoids. Neuropsychopharmacology. 2007;32(11):2249–2259. [PubMed]
41. Ferré S, Lluís C, Justinova Z, et al. Adenosine-cannabinoid receptor interactions. Implications for striatal function. British Journal of Pharmacology. 2010;160(3):443–453. [PubMed]
42. Łukasiewicz S, Błasiak E, Faron-Górecka A, et al. Fluorescence studies of homooligomerization of adenosine A2A and serotonin 5-HT1A receptors reveal the specificity of receptor interactions in the plasma membrane. Pharmacological Reports. 2007;59(4):379–392. [PubMed]
43. Ciruela F, Casadó V, Rodrigues RJ, et al. Presynaptic control of striatal glutamatergic neurotransmission by adenosine A1-A2A receptor heteromers. Journal of Neuroscience. 2006;26(7):2080–2087. [PubMed]
44. Popoli P, Frank C, Tebano MT, et al. Modulation of glutamate release and excitotoxicity by adenosine A2A receptors. Neurology. 2003;61(11):S69–S71. [PubMed]
45. Mishina M, Ishiwata K, Kimura Y, et al. Evaluation of distribution of adenosine A2A receptors in normal human brain measured with [11C]TMSX PET. Synapse. 2007;61(9):778–784. [PubMed]
46. Ramlackhansingh AF, Bose SK, Ahmed I, Turkheimer FE, Pavese N, Brooks DJ. Adenosine 2A receptor availability in dyskinetic and nondyskinetic patients with Parkinson disease. Neurology. 2011;76(21):1811–1816. [PMC free article] [PubMed]
47. Black KJ, Koller JM, Campbell MC, Gusnard DA, Bandak SI. Quantification of indirect pathway inhibition by the adenosine A2A antagonist SYN115 in Parkinson disease. Journal of Neuroscience. 2010;30(48):16284–16292. [PMC free article] [PubMed]
48. Varani K, Vincenzi F, Tosi A, et al. A2A adenosine receptor overexpression and functionality, as well as TNF-α levels, correlate with motor symptoms in Parkinson’s disease. FASEB Journal. 2010;24(2):587–598. [PubMed]
49. Bara-Jimenez W, Sherzai A, Dimitrova T, et al. Adenosine A2A receptor antagonist treatment of Parkinson’s disease. Neurology. 2003;61(3):293–296. [PubMed]
50. Hauser RA, Hubble JP, Truong DD. Randomized trial of the adenosine A2A receptor antagonist istradefylline in advanced PD. Neurology. 2003;61(3):297–303. [PubMed]
51. LeWitt PA, Guttman M, Tetrud JW, et al. Adenosine A2A receptor antagonist istradefylline (KW-6002) reduces off time in Parkinson’s disease: a double-blind, randomized, multicenter clinical trial (6002-US-005) Annals of Neurology. 2008;63(3):295–302. [PubMed]
52. Stacy M, Silver D, Mendis T, et al. A 12-week, placebo-controlled study (6002-US-006) of istradefylline in Parkinson disease. Neurology. 2008;70(23):2233–2240. [PubMed]
53. Hauser RA, Shulman LM, Trugman JM, et al. Study of istradefylline in patients with Parkinson’s disease on levodopa with motor fluctuations. Movement Disorders. 2008;23(15):2177–2185. [PubMed]
54. Mizuno Y, Hasegawa K, Kondo T, et al. Clinical efficacy of istradefylline (KW-6002) in Parkinson’s disease: a randomized, controlled study. Movement Disorders. 2010;25(10):1437–1443. [PubMed]
55. Knebel W, Rao N, Uchimura T, et al. Population pharmacokinetic analysis of istradefylline in healthy subjects and in patients with parkinson’s disease. Journal of Clinical Pharmacology. 2011;51(1):40–52. [PubMed]
56. Hauser RA, Cantillon M, Pourcher E, et al. Preladenant in patients with Parkinson’s disease and motor fluctuations: a phase 2, double-blind, randomised trial. The Lancet Neurology. 2011;10(3):221–229. [PubMed]

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