Adenosine A(2A) receptors measured with [C]TMSX PET in the striata of Parkinson's disease patients (original) (raw)
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An Update on Adenosine A2A Receptors as Drug Target in Parkinson's Disease
CNS & Neurological Disorders - Drug Targets, 2011
Adenosine receptors are G protein-coupled receptors (GPCRs) that mediate the physiological functions of adenosine. In the central nervous system adenosine A 2A receptors (A 2A Rs) are highly enriched in striatopallidal neurons where they form functional oligomeric complexes with other GPCRs such us the dopamine D 2 receptor (D 2 R). Furthermore, it is assumed that the formation of balanced A 2A R/D 2 R receptor oligomers are essential for correct striatal function as the allosteric receptor-receptor interactions established within the oligomer are needed for properly sensing adenosine and dopamine. Interestingly, A 2A R activation reduces the affinity of striatal D 2 R for dopamine and the blockade of A 2A R with specific antagonists facilitates function of the D 2 R. Thus, it may be postulated that A 2A R antagonists are pro-dopaminergic agents.
Nuclear Medicine and Biology, 2011
Introduction-A 2A receptors are expressed in the basal ganglia, specifically in striatopallidal GABAergic neurons in the striatum (caudate-putamen). This brain region undergoes degeneration of pre-synaptic dopamine projections and depletion of dopamine in Parkinson's disease. We developed a 18 F-labeled A 2A analog radiotracer ([ 18 F]-MRS5425) for A 2A receptor imaging using positron emission tomography (PET). We hypothesized that this tracer could image A 2A receptor changes in the rat model for Parkinson disease, which is created following unilateral injection of the monoaminergic toxin, 6-hydroxydopamine (6-OHDA) into the substantia nigra.
Adenosine A 2A receptors, dopamine D 2 receptors and their interactions in Parkinson's disease
Movement Disorders, 2007
Future therapies in Parkinson's disease may substantially build on the existence of intra-membrane receptor-receptor interactions in DA receptor containing heteromeric receptor complexes. The A 2A /D 2 heteromer is of substantial interest in view of its specific location in cortico-striatal glutamate terminals and in striato-pallidal GABA neurons. Antagonistic A 2A /D 2 receptor interactions in this heteromer demonstrated at the cellular level, and at the level of the striato-pallidal GABA neuron and at the network level made it possible to suggest A 2A antagonists as anti-parkinsonian drugs. The major mechanism is an enhancement of D 2 signaling leading to attenuation of hypokinesia, tremor, and rigidity in models of Parkinson's disease with inspiring results in two clinical trials. Other interactions are antagonism at the level of the adenylyl cyclase; heterologous sensitization at the A 2A activated adenylyl cyclase by persistent D 2 activation and a compensatory up-regulation of A 2A receptors in response to intermittent Levodopa treatment. An increased dominance of A 2A homomers over D 2 homomers and A 2A /D 2 heteromers after intermittent Levodopa treatment may therefore contribute to development of Levodopa induced dyskinesias and to the wearing off of the therapeutic actions of Levodopa giving additional therapeutic roles of A 2A antagonists. Their neuroprotective actions may involve an increase in the retrograde trophic signaling in the nigrostriatal DA system.
Targeting adenosine A 2A receptors in Parkinson's disease
Trends in Neurosciences, 2006
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.
Movement Disorders, 1997
We used ["C]raclopride (RACLO) and positron emission tomography (PET) to study longitudinally striatal dopamine D, receptor binding in nine patients with Parkinson's disease (PD) at an early drug-naive stage and 3-5 years later, when motor fluctuations had appeared in beven of them. Patients were treated with a combination of levodopa and dopamine agonists. Data were compared with 10 healthy controls in the same age range. Initially, patients with PD showed a significant increase of RACLO uptake in the putamen compared with controls (p < 0.04). The caudate nucleus revealed values in the normal range. After 3-5 years, RACLO binding was significantly reduced in the putamen (p < 0.03) and caudate nucleus (p < 0.03) compared with baseline. Values were now in the control range in the putamen and reduced in the caudate nucleus (p < 0.05). The clinical score at "off" had significantly worsened (p < 0.0005) compared with the first PET scan. The nine PD patients reported here had already been investigated 3-4 months after therapy began and at that time did not show a reduction of the initially increased RACLO binding capacity (data published previously). These results indicate long-term downregulation of striatal dopamine D, receptor binding in PD. Receptor changes in the striatum of patients with PD may be induced by chronic dopaminergic therapy or occur independently of treatment, as a result of structural adaptation of the postsynaptic dopaminergic system to the progressive decline of nigrostriatal neurons. Key Words: Positron emission tomography-["C]Raclopride-Dopamine D, receptors-Parkinson's disease. Fluctuations in motor performance are a common complication in the course of treatment of patients with Parkinson's disease (PD). Loss of dopaminergic nerveterminals and changes of the dopamine D, receptor system in the striatum may underlie these complications (1). Positron emission tomography (PET) studies have shown increased I ' 'Clraclopride (RACLO) binding capacity to dopamine D, receptors in the putamen of early-stage PD patients . Conversely, more advanced patients tend to show normal RACLO binding. We investigated RACLO binding to striatal dopamine D, receptors in 20 PD patients at Hoehn and Yahr (H&Y) stages I-IV and found that patients at H&Y stage I11 and IV had signifi-
Adenosine/dopamine interaction: implications for the treatment of Parkinson's disease
Parkinsonism & Related Disorders, 2001
Evidence for a role of dopaminergic neurotransmission in the motor effects of adenosine antagonists, such as caffeine, is reviewed, based on the existence of speci®c antagonistic interactions between speci®c subtypes of adenosine and dopamine receptors in the striatum. Both adenosine A 1 and adenosine A 2A receptor antagonists induce motor activation in rodents. At least a certain degree of dopaminergic activity is required to obtain adenosine antagonist-induced motor activation, with adenosine A 1 antagonists being the most sensitive and non-selective adenosine antagonists the most resistant to striatal dopamine depletion. When considering long-term treatment with adenosine antagonists concomitant administration of dopamine agonists might be required in order to obtain strong motor effects (cross-sensitization) and to avoid the development of telerance. q
Dopamine and adenosine receptor interaction as basis for the treatment of Parkinson's disease
Journal of The Neurological Sciences, 2006
Preclinical evidence strongly indicate that adenosine A2A receptor antagonists represent a promising class of drugs for the treatment of motor deficits associated to Parkinson's disease. The effects of adenosine A2A receptor antagonists were here assessed in a rat model of parkinsonian tremor induced by cholinomimetic drugs by evaluating the counteraction of tremulous jaw movements. Systemic administration of the A2A antagonist
European Journal of Neuroscience, 2000
It has been shown that striatal adenosine A 2A receptors can antagonistically interact with dopamine D 2 receptors at the membrane level leading to a decrease in the af®nity and ef®cacy of D 2 receptors. Extracellular recordings and rotational behaviour were employed to obtain a correlate to these ®ndings in an animal model of Parkinson's disease (PD). The recordings were performed in rats with unilateral 6-hydroxydopamine (6-OHDA)-induced catecholamine depletion. While recording in the dopamine-depleted striatum, local applications of the dopamine D 2 agonist quinpirole reduced neuronal activity. However, when the adenosine A 2A antagonist MSX-3 was applied simultaneously with quinpirole, the inhibition of neuronal ®ring seen after quinpirole alone was signi®cantly potentiated (P < 0.001, n = 11). In contrast, local application of CGS 21680 attenuated the effect of quinpirole. The doses of MSX-3 and CGS 21680 used to achieve the modulation of quinpirole action had no effect per se on striatal neuronal ®ring. Furthermore, rotational behaviour revealed that MSX-3 dose-dependently increased the number of turns when administrated together with a threshold dose of quinpirole while no enhancement was achieved when MSX-3 was combined with SKF 38393. MSX-3 alone did not induce rotational behaviour. In conclusion, this study shows that low ineffective doses of MSX-3 enhance the effect of quinpirole on striatal ®ring rate, while the A 2A agonist exerts the opposite action. This mechanism gives a therapeutic potential to A 2A antagonists in the treatment of PD by enhancing D 2 receptor function.