Istradefylline, an adenosine A2A receptor antagonist, for patients with Parkinson's Disease: A meta-analysis

Chen, Wanqiang; Wang, Hongquan; Wei, Hongtao; Gu, Shuli; Wei, Haiping

doi:10.1016/j.jns.2012.08.030

Cited by 40 publications

(16 citation statements)

References 22 publications

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“…A2a antagonism/inverse agonism is clearly a promising target in the treatment of human Parkinson's disease (41), as both caffeine intake (42) and genetic polymorphisms of the Adora2a gene (43) contribute to the risk of contracting the disease. Furthermore, in the study of Parkinson's disease, promising results have been obtained with istradefylline, an inverse agonist specific to A2a (44). Thus, cyclic dinucleotides constitute a potential novel class of A2a inverse agonist, with pharmacokinetics, pharmacodynamics, and safety profiles distinctive from those of istradefylline.…”

Section: Discussionmentioning

confidence: 99%

Human Monocyte Recognition of Adenosine-Based Cyclic Dinucleotides Unveils the A2a G_αsProtein-Coupled Receptor Tonic Inhibition of Mitochondrially Induced Cell Death

Tosolini

Pont

Bétous

et al. 2015

Molecular and Cellular Biology

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Cyclic dinucleotides are important messengers for bacteria and protozoa and are well-characterized immunity alarmins for infected mammalian cells through intracellular binding to STING receptors. We sought to investigate their unknown extracellular effects by adding cyclic dinucleotides to the culture medium of freshly isolated human blood cells in vitro. Here we report that adenosine-containing cyclic dinucleotides induce the selective apoptosis of monocytes through a novel apoptotic pathway. We demonstrate that these compounds are inverse agonist ligands of A2a, a G ␣s -coupled adenosine receptor selectively expressed by monocytes. Inhibition of monocyte A2a by these ligands induces apoptosis through a mechanism independent of that of the STING receptors. The blockade of basal (adenosine-free) signaling from A2a inhibits protein kinase A (PKA) activity, thereby recruiting cytosolic p53, which opens the mitochondrial permeability transition pore and impairs mitochondrial respiration, resulting in apoptosis. A2a antagonists and inverse agonist ligands induce apoptosis of human monocytes, while A2a agonists are antiapoptotic. In vivo, we used a mock developing human hematopoietic system through NSG mice transplanted with human CD34؉ cells. Treatment with cyclic di-AMP selectively depleted A2a-expressing monocytes and their precursors via apoptosis. Thus, monocyte recognition of cyclic dinucleotides unravels a novel proapoptotic pathway: the A2a G ␣s protein-coupled receptor (GPCR)-driven tonic inhibitory signaling of mitochondrion-induced cell death. P urine and pyrimidine-based signaling is a fundamental and conserved mode of intercellular communication. In the body, mononucleotides are the major mediators of tissue protection and regeneration, for example, adenosine, which is released from damaged cells. In contrast, microorganisms use cyclic dinucleotides, such as cyclic di-AMP (c-di-AMP) and cyclic di-GMP (cdi-GMP), which are secreted by bacteria and protozoa, respectively (1, 2). As a defense mechanism, mammalian cells have evolved a means to sense cyclic dinucleotides. When infected with retroviruses (3) or carrying cytosolic DNA (4), cells assemble an endogenous 2=,3= cyclic GMP-AMP (cGAMP) dinucleotide which is recognized by the intracellular protein STING to induce type I interferon (IFN) responses (5). In this way, intracellular cyclic dinucleotides represent important alarmins in immunity.Extracellular cyclic dinucleotides are released from infected dying cells or damaged tissues and also represent important signals, but whether and how mammalian cells can detect these and respond is presently unknown. We hypothesized that human peripheral blood cells might be capable of detecting extracellular cyclic dinucleotides. We found that the extracellular 3=,5= cyclic dinucleotides c-di-AMP and cGAMP are specifically recognized by human monocytes expressing the A2a adenosine receptor and can selectively induce their apoptosis. Analysis of the role of A2a in this apoptotic response showed that it controls the s...

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Section: Discussionmentioning

confidence: 99%

Human Monocyte Recognition of Adenosine-Based Cyclic Dinucleotides Unveils the A2a G_αsProtein-Coupled Receptor Tonic Inhibition of Mitochondrially Induced Cell Death

Tosolini

Pont

Bétous

et al. 2015

Molecular and Cellular Biology

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“…As in AD, there is also solid evidence for a role of A 2A R in the control of PD, as testified by the recent introduction of A 2A R antagonists as coadjuvants in the management of PD [121]. Thus, A 2A R antagonists improve PD symptoms in different rodent and primate models of the disease and also in PD patients enrolled in clinical trials (for a review see [122]).…”

Section: Introductionmentioning

confidence: 99%

Role of Microglia Adenosine A_2AReceptors in Retinal and Brain Neurodegenerative Diseases

Santiago

Baptista

Santos

et al. 2014

Mediators of Inflammation

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Neuroinflammation mediated by microglial cells in the brain has been commonly associated with neurodegenerative diseases. Whether this microglia-mediated neuroinflammation is cause or consequence of neurodegeneration is still a matter of controversy. However, it is unequivocal that chronic neuroinflammation plays a role in disease progression and halting that process represents a potential therapeutic strategy. The neuromodulator adenosine emerges as a promising targeting candidate based on its ability to regulate microglial proliferation, chemotaxis, and reactivity through the activation of its G protein coupled A2A receptor (A2AR). This is in striking agreement with the ability of A2AR blockade to control several brain diseases. Retinal degenerative diseases have been also associated with microglia-mediated neuroinflammation, but the role of A2AR has been scarcely explored. This review aims to compare inflammatory features of Parkinson's and Alzheimer's diseases with glaucoma and diabetic retinopathy, discussing the therapeutic potential of A2AR in these degenerative conditions.

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“…As a result of this direct A 2A R-D 2 R interaction [29], antagonists for A 2A R have emerged as new targets for non-dopaminergic antiparkinsonian treatments [30]. Indeed, several clinical trials have shown that the administration of istradefylline (or KW-6002), an A 2A R antagonist, ameliorates the dyskinesias induced by chronic levodopa treatment of PD patients [31][32][33][34][35][36][37][38]. Similarly, since A 2A R levels have been shown to be increased in the putamen of some PD patients [5][6][7][8][9], it seems likely that ADORA2A repression would be an alternative therapy to reduce A 2A R activity.…”

Section: Resultsmentioning

confidence: 99%

Striatal adenosine A2A receptor expression is controlled by S-adenosyl-L-methionine-mediated methylation

Villar-Menéndez

Núñez

Díaz-Sánchez

et al. 2014

Purinergic Signalling

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Adenosine A 2A receptor (A 2A R) is a G proteincoupled receptor enriched in the striatum for which an increased expression has been demonstrated in certain neurological diseases. Interestingly, previous in vitro studies demonstrated that A 2A R expression levels are reduced after treatment with S-adenosyl-L-methionine (SAM), a methyl donor molecule involved in the methylation of important biological structures such as DNA, proteins, and lipids. However, the in vivo effects of SAM treatment on A 2A R expression are still obscure. Here, we demonstrated that 2 weeks of SAM treatment produced a significant reduction in the rat striatal A 2A R messenger RNA (mRNA) and protein content as well as A 2A R-mediated signaling. Furthermore, when the content of 5-methylcytosine levels in the 5′UTR region of ADORA2A was analyzed, this was significantly increased in the striatum of SAM-treated animals; thus, an unambiguous correlation between SAM-mediated methylation and striatal A 2A R expression could be established. Overall, we concluded that striatal A 2A R functionality can be controlled by SAM treatment, an issue that might be relevant for the management of these neurological conditions that course with increased A 2A R expression.

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Istradefylline, an adenosine A2A receptor antagonist, for patients with Parkinson's Disease: A meta-analysis

Cited by 40 publications

References 22 publications

Human Monocyte Recognition of Adenosine-Based Cyclic Dinucleotides Unveils the A2a G_αsProtein-Coupled Receptor Tonic Inhibition of Mitochondrially Induced Cell Death

Human Monocyte Recognition of Adenosine-Based Cyclic Dinucleotides Unveils the A2a G_αsProtein-Coupled Receptor Tonic Inhibition of Mitochondrially Induced Cell Death

Role of Microglia Adenosine A_2AReceptors in Retinal and Brain Neurodegenerative Diseases

Striatal adenosine A2A receptor expression is controlled by S-adenosyl-L-methionine-mediated methylation

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Istradefylline, an adenosine A2A receptor antagonist, for patients with Parkinson's Disease: A meta-analysis

Cited by 40 publications

References 22 publications

Human Monocyte Recognition of Adenosine-Based Cyclic Dinucleotides Unveils the A2a GαsProtein-Coupled Receptor Tonic Inhibition of Mitochondrially Induced Cell Death

Human Monocyte Recognition of Adenosine-Based Cyclic Dinucleotides Unveils the A2a GαsProtein-Coupled Receptor Tonic Inhibition of Mitochondrially Induced Cell Death

Role of Microglia Adenosine A2AReceptors in Retinal and Brain Neurodegenerative Diseases

Striatal adenosine A2A receptor expression is controlled by S-adenosyl-L-methionine-mediated methylation

Contact Info

Product

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Human Monocyte Recognition of Adenosine-Based Cyclic Dinucleotides Unveils the A2a G_αsProtein-Coupled Receptor Tonic Inhibition of Mitochondrially Induced Cell Death

Human Monocyte Recognition of Adenosine-Based Cyclic Dinucleotides Unveils the A2a G_αsProtein-Coupled Receptor Tonic Inhibition of Mitochondrially Induced Cell Death

Role of Microglia Adenosine A_2AReceptors in Retinal and Brain Neurodegenerative Diseases