Budget Amount *help |
¥3,810,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥210,000)
Fiscal Year 2007: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
Fiscal Year 2006: ¥800,000 (Direct Cost: ¥800,000)
Fiscal Year 2005: ¥2,100,000 (Direct Cost: ¥2,100,000)
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Research Abstract |
Parkinson's disease (PD) is a progressive degenerative neurological disorder characterized clinically by resting tremor, bradykinesia, cogwheel rigidity, and postural instability. These symptoms result primarily from the loss of dopaminergic neurons in the substantia nigra. Adenosine is produced by conversion of intra- and extracellular adenine nucleotides, and plays a role as an endogenous modulator of synaptic functions in the central nervous system. The effects are mediated by at least four receptor subtypes: A_1, A_<2A>, A_<2B>, and A_3. The adenosine A_<2A> receptors are enriched in dopamine-rich areas of the brain, such as the basal ganglia, and would interact with dopamine D_2 receptor negatively: at the level of second messengers and beyond. A selective adenosine A_<2A> receptor antagonist provides an antiparkinsonian benefit without causing and worsening dyskinesia that is one of the most inconvenient side effects of dopaminergic therapy. A postmortem study suggested that aden
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osine A_<2A> receptors were increased in the patients with dyskinesia following long-term levodopa therapy. Therefore, adenosine A_<2A> receptors may be involved with the appearance of the side effects of the antiparkinsonian agents. Although adenosine A_<2A> receptor has attracted much attention, little information was available about the receptor in the living human brain until quite recently. However, we developed a PET ligand, [7-methyl^<-11>C]- (E) -8- (3,4,5-trimethoxystyryl) -1,3,7-trimethylxanthine ([^<11>C]TMSX) , for mapping the adenosine A_<2A> receptors, and we have successfully visualized the receptors in a living human brain using [^<11>C]TMSX PET (Mishina M, et. Al. Synapse 2007) . Then, we studied seven drug naive patients with PD (Mishina M, et. al., Movement Disorder, supple, 2006). The BP was significantly lower on the more affected side than the less affected side of the putamen in PD patients (paired t test, p<0.05). Release of dopamine is reduced asymmetrically in the putamen of early PD, and dopamine D_2 receptors are up-regulated as compensation for the decrease of dopamine. Our data showed that reaction of the adenosine A_<2A> receptor was opposite to the dopamine D_2 receptor. We also studied six patients with PD after antiparkinsonian therapy for 15.7 ± 2.7 months (Mishina M, et. al., Movement Disorder, supple, 2008 in press). The BP of [^<11>C]TMSX was increased after dopaminergic therapy in the putamen of four patients, but was decreased in that of two patients. Dopamine D_2 receptors are up-regulated and adenosine A_<2A> receptors are down-regulated as compensation for the decrease of dopamine in the drug naive PD. However, the reaction of adenosine A_<2A> receptors to the anti-parkinsonian therapy varied in each PD patient. The variety of the reaction may be involved in the existence of the side effect of antiparkinsonian agents, such as dyskinesia and sleep attack. Less
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