Adenosine A2A Receptors Measured with [11C]TMSX PET in the Striata of Parkinson's Disease Patients

Masahiro Mishina,Kenji Ishii,Masahiko Suzuki,Keiichi Oda,Yuichi Kimura,Muneyuki Sakata,Kenji Ishibashi,Shiro Kobayashi,Mika Naganawa,Makoto Hamamoto,Masaya Hashimoto,Shin Kitamura,Kiichi Ishiwata,Yasuo Katayama

doi:10.1371/journal.pone.0017338

Abstract

Adenosine A2A receptors (A2ARs) are thought to interact negatively with the dopamine D2 receptor (D2R), so selective A2AR antagonists have attracted attention as novel treatments for Parkinson's disease (PD). However, no information about the receptor in living patients with PD is available. The purpose of this study was to investigate the relationship between A2ARs and the dopaminergic system in the striata of drug-naïve PD patients and PD patients with dyskinesia, and alteration of these receptors after antiparkinsonian therapy. We measured binding ability of striatal A2ARs using positron emission tomography (PET) with [7-methyl-11C]-(E)-8-(3,4,5-trimethoxystyryl)-1,3,7-trimethylxanthine ([11C]TMSX) in nine drug-naïve patients with PD, seven PD patients with mild dyskinesia and six elderly control subjects using PET. The patients and eight normal control subjects were also examined for binding ability of dopamine transporters and D2Rs. Seven of the drug-naïve patients underwent a second series of PET scans following therapy. We found that the distribution volume ratio of A2ARs in the putamen were larger in the dyskinesic patients than in the control subjects (p<0.05, Tukey-Kramer post hoc test). In the drug-naïve patients, the binding ability of the A2ARs in the putamen, but not in the head of caudate nucleus, was significantly lower on the more affected side than on the less affected side (p<0.05, paired t-test). In addition, the A2ARs were significantly increased after antiparkinsonian therapy in the bilateral putamen of the drug-naïve patients (p<0.05, paired t-test) but not in the bilateral head of caudate nucleus. Our study demonstrated that the A2ARs in the putamen were increased in the PD patients with dyskinesia, and also suggest that the A2ARs in the putamen compensate for the asymmetrical decrease of dopamine in drug-naïve PD patients and that antiparkinsonian therapy increases the A2ARs in the putamen. The A2ARs may play an important role in regulation of parkinsonism in PD.

Highlights

Parkinson’s disease (PD) is a progressive degenerative neurological disorder characterized clinically by resting tremor, bradykinesia, cogwheel rigidity, and postural instability [1]
As previous stidies reported [13,14,23], our positron emission tomography (PET) study demonstrates that the putaminal binding ability of A2A receptors (A2ARs) was increased in the PD patients with dyskinesia, and that there was no significant difference in the striatal binding ability of A2ARs between drug-naıve PD patients and normal controls
In drawing attention to the asymmetrical symptoms in drug-naıve PD, our study suggests that A2ARs were asymmetrically downregulated in the putamen but not in the head of the caudate nucleus

Summary

Introduction

Parkinson’s disease (PD) is a progressive degenerative neurological disorder characterized clinically by resting tremor, bradykinesia, cogwheel rigidity, and postural instability [1]. These symptoms result primarily from the loss of dopaminergic neurons in the substantia nigra and can be reduced by levodopa, which replenishes dopamine, and dopamine agonists. Adenosine A1 receptors (A1Rs) are widely distributed throughout the entire brain, while adenosine A2A receptors (A2ARs) are enriched in the basal ganglia [4,5]. The A2AR is known to stimulate adenylyl cyclase and interacts with the dopamine D2 receptor (D2R). The A1R is known to inhibit adenylyl cyclase

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