The adenosine A2A receptor antagonist, istradefylline enhances anti-parkinsonian activity induced by combined treatment with low doses of L-DOPA and dopamine agonists in MPTP-treated common marmosets

Uchida, Shunya; Soshiroda, Kazuhiro; Okita, Eri; Kawai-Uchida, Mika; Mori, Akihisa; Jenner, Peter; Kanda, Tomoyuki

doi:10.1016/j.ejphar.2015.09.028

Cited by 33 publications

(22 citation statements)

References 25 publications

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“…The opposite pharmacological profile was obtained with KW 6002, which produced strong locomotor activation at doses that were ineffective at blocking glutamate release from cortical afferents in the striatum [32]. KW 6002 is thus a promising anti-parkinsonian agent and is already being successfully used for the treatment of Parkinson's disease [33][34][35].…”

Section: Introductionmentioning

confidence: 93%

Evidence for the heterotetrameric structure of the adenosine A2A–dopamine D2 receptor complex

Casadó-Anguera

Bonaventura

Moreno

et al. 2016

Biochemical Society Transactions

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Heteromers of G-protein-coupled receptors (GPCRs) have emerged as potential novel targets for drug development. Accumulating evidence indicates that GPCRs can form homodimers and heteromers, with homodimers being the predominant species and oligomeric receptors being formed as multiples of dimers. Recently, heterotetrameric structures have been proposed for dopamine D1receptor (D1R)-dopamine D3receptor (D3R) and adenosine A2Areceptor (A2AR)-dopamine D2receptor (D2R) heteromers. The structural model proposed for these complexes is a heteromer constituted by two receptor homodimers. The existence of GPCR homodimers and heteromers provides a structural basis for inter-protomer allosteric mechanisms that might account for a multiplicity of unique pharmacological properties. In this review, we focus on the A2AR-D2R heterotetramer as an example of an oligomeric structure that is key in the modulation of striatal neuronal function. We also review the interfaces involved in this and other recently reported heteromers of GPCRs. Furthermore, we discuss several published studies showing theex vivoexpression of A2AR-D2R heteromers. The ability of A2AR agonists to decrease the affinity of D2R agonists has been reported and, on the basis of this interaction, A2AR antagonists have been proposed as potential drugs for the treatment of Parkinson's disease. The heterotetrameric structure of the A2AR-D2R complex offers a novel model that can provide new clues about how to adjust the drug dosage to the expected levels of endogenous adenosine.

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Section: Introductionmentioning

confidence: 93%

Evidence for the heterotetrameric structure of the adenosine A2A–dopamine D2 receptor complex

Casadó-Anguera

Bonaventura

Moreno

et al. 2016

Biochemical Society Transactions

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“…for several weeks, ranging from 16 days to 8 weeks. KW-6002 as the A2A receptor antagonist was reported in four studies ( 12 , 20 , 21 , 27 ), ST1535 ( 22 , 23 ) in two, Caffeine ( 24 , 25 ) in two, and SCH 412348 ( 26 ) in one study. Meanwhile, total AIM score, locomotor activity, and motor disability were reported as a outcome measure in 5, 5, and 3 studies, respectively.…”

Section: Resultsmentioning

confidence: 99%

“…Another eight studies were excluded as the dyskinesia presented was not developed by long-term l -dopa. Ultimately, nine eligible studies were identified ( 12 , 20 – 27 ) (Figure 1 ).…”

Section: Resultsmentioning

confidence: 99%

A Meta-Analysis of Adenosine A2A Receptor Antagonists on Levodopa-Induced Dyskinesia In Vivo

Wang

Zhang

et al. 2017

Front. Neurol.

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BackgroundLong-term use of levodopa (l-dopa) is inevitably complicated with highly disabling fluctuations and drug-induced dyskinesias, which pose major challenges to the existing drug therapy of Parkinson’s disease.MethodsIn this study, we conducted a systematic review and meta-analysis to assess the efficacy of A2A receptor antagonists on reducing l-dopa-induced dyskinesias (LID).ResultsNine studies with a total of 152 animals were included in this meta-analysis. Total abnormal involuntary movements (AIM) score, locomotor activity, and motor disability were reported as outcome measures in 5, 5, and 3 studies, respectively. Combined standardized mean difference (SMD) estimates were calculated using a random-effects model. We pooled the whole data and found that, when compared to l-dopa alone, A2A receptor antagonists plus l-dopa treatment showed no effect on locomotor activity (SMD −0.00, 95% confidence interval (CI): −2.52 to 2.52, p = 1.0), superiority in improvement of motor disability (SMD −5.06, 95% CI: −9.25 to −0.87, p = 0.02) and more effective in control of AIM (SMD −1.82, 95% CI: −3.38 to −0.25, p = 0.02).ConclusionTo sum up, these results demonstrated that A2A receptor antagonists appear to have efficacy in animal models of LID. However, large randomized clinical trials testing the effects of A2A receptor antagonists in LID patients are always warranted.

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“…Reductions to A 1 R and A 2A R protein expression Neural Plasticity could contribute to reduced efficacy of adenosine-mediated inhibition of dopamine activity in the striatum, which should be followed up in more detail by future studies. Indeed, changes in A 1 Rs and A 2A Rs that are dependent on physical activity status could affect therapeutic approaches for psychiatric and neurological diseases that involve abnormal dopamine signaling in the striatum, including addiction, depression, Parkinson's disease, and Huntington's disease, among many others [94][95][96][97][98][99][100][101][102][103][104]. Therefore, the current findings could be of importance for understanding the mechanisms contributing to exercise-improved cognitive function, as well as the prevention and treatment of mental health and neurobiological disorders that involve the striatum.…”

Section: Neural Plasticitymentioning

confidence: 99%

Exercise-Induced Adaptations to the Mouse Striatal Adenosine System

2020

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Adenosine acts as a key regulator of striatum activity, in part, through the antagonistic modulation of dopamine activity. Exercise can increase adenosine activity in the brain, which may impair dopaminergic functions in the striatum. Therefore, long-term repeated bouts of exercise may subsequently generate plasticity in striatal adenosine systems in a manner that promotes dopaminergic activity. This study investigated the effects of long-term voluntary wheel running on adenosine 1 (A1R), adenosine 2A (A2AR), dopamine 1 (D1R), and dopamine 2 (D2R) receptor protein expression in adult mouse dorsal and ventral striatum structures using immunohistochemistry. In addition, equilibrative nucleoside transporter 1 (ENT1) protein expression was examined after wheel running, as ENT1 regulates the bidirectional flux of adenosine between intra- and extracellular space. The results suggest that eight weeks of running wheel access spared age-related increases of A1R and A2AR protein concentrations across the dorsal and ventral striatal structures. Wheel running mildly reduced ENT1 protein levels in ventral striatum subregions. Moreover, wheel running mildly increased D2R protein density within striatal subregions in the dorsal medial striatum, nucleus accumbens core, and the nucleus accumbens shell. However, D1R protein expression in the striatum was unchanged by wheel running. These data suggest that exercise promotes adaptations to striatal adenosine systems. Exercise-reduced A1R and A2AR and exercise-increased D2R protein levels may contribute to improved dopaminergic signaling in the striatum. These findings may have implications for cognitive and behavioral processes, as well as motor and psychiatric diseases that involve the striatum.

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The adenosine A2A receptor antagonist, istradefylline enhances anti-parkinsonian activity induced by combined treatment with low doses of L-DOPA and dopamine agonists in MPTP-treated common marmosets

Cited by 33 publications

References 25 publications

Evidence for the heterotetrameric structure of the adenosine A2A–dopamine D2 receptor complex

Evidence for the heterotetrameric structure of the adenosine A2A–dopamine D2 receptor complex

A Meta-Analysis of Adenosine A2A Receptor Antagonists on Levodopa-Induced Dyskinesia In Vivo

Exercise-Induced Adaptations to the Mouse Striatal Adenosine System

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