An Update on Adenosine A2A Receptors as Drug Target in Parkinson's Disease

Vallano, Antonio; Fernández-Dueñas, Víctor; Pedrós, Consuelo; Arnau, Josep Maria; Ciruela, Francisco

doi:10.2174/187152711797247803

Cited by 22 publications

(22 citation statements)

References 67 publications

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“…Our transcriptomics data indicated over‐expression of ADORA2A, the adenosine A2A receptor, which associates with D2 dopamine receptor (Vallano et al . ). Since activated A2A receptor reduces the affinity of striatal D2 receptors to dopamine leading to decreased dopamine‐mediated signaling, A2A antagonists are potential drug candidates for PD and A2A receptor could serve a potential marker of early events in manganism.…”

Section: Discussionmentioning

confidence: 97%

Manganese‐ and 1‐methyl‐4‐phenylpyridinium‐induced neurotoxicity display differences in morphological, electrophysiological and genome‐wide alterations: implications for idiopathic Parkinson's disease

Mythri

Raghunath

Narwade

et al. 2017

Journal of Neurochemistry

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Idiopathic Parkinson's disease and manganese-induced atypical parkinsonism are characterized by movement disorder and nigrostriatal pathology. Although clinical features, brain region involved and responsiveness to levodopa distinguish both, differences at the neuronal level are largely unknown. We studied the morphological, neurophysiological and molecular differences in dopaminergic neurons exposed to the Parkinson's disease toxin 1-methyl-4-phenylpyridinium ion (MPP ) and manganese (Mn), followed by validation in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and Mn mouse models. Morphological analysis highlighted loss of neuronal processes in the MPP and not the Mn model. Cellular network dynamics of dopaminergic neurons characterized by spike frequency and inter-spike intervals indicated major neuronal population (~ 93%) with slow discharge rates (0-5 Hz). While MPP exposure suppressed the firing of these neurons, Mn neither suppressed nor elevated the neuronal activity. High-throughput transcriptomic analysis revealed up-regulation of 694 and 603 genes and down-regulation of 428 and 255 genes in the MPP and Mn models respectively. Many differentially expressed genes were unique to either models and contributed to neuroinflammation, metabolic/mitochondrial function, apoptosis and nuclear function, synaptic plasticity, neurotransmission and cytoskeleton. Analysis of the Janus kinase-signal transducer and activator of transcription pathway with implications for neuritogenesis and neuronal proliferation revealed contrasting profile in both models. Genome-wide DNA methylomics revealed differences between both models and substantiated the epigenetic basis of the difference in the Janus kinase-signal transducer and activator of transcription pathway. We conclude that idiopathic Parkinson's disease and atypical parkinsonism have divergent neurotoxicological manifestation at the dopaminergic neuronal level with implications for pathobiology and evolution of novel therapeutics. Cover Image for this issue: doi. 10.1111/jnc.13821.

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Section: Discussionmentioning

confidence: 97%

Manganese‐ and 1‐methyl‐4‐phenylpyridinium‐induced neurotoxicity display differences in morphological, electrophysiological and genome‐wide alterations: implications for idiopathic Parkinson's disease

Mythri

Raghunath

Narwade

et al. 2017

Journal of Neurochemistry

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“…3). In fact, it has been reported that A 2A Rs functionally interact with mGlu 5 receptors to modulate several downstream mGlu 5 receptor-mediated effects (for review see [64] Overall, all this data provide a rationale for using A 2A R and mGlu 5 receptor antagonists in PD [81,82]. Furthermore, these non-dopaminergic-based PD therapies may also offer some advantages over dopamine medications, for instance by reducing side effects [83].…”

Section: Glutamatergic Neurotransmission and Parkinson's Diseasementioning

confidence: 99%

Targeting Striatal Metabotropic Glutamate Receptor Type 5 in Parkinson`s Disease: Bridging Molecular Studies and Clinical Trials

Vallano¹,

Fernández-Dueñas²,

García-Negredo³

et al. 2013

CNSNDDT

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“…Striatal A2A receptor levels are increased in PD [22–24], even at early stages of the disease, and they are possibly regulated, in part, by miR‐34b [25]. Therefore, A2A receptor antagonists are potential therapeutic agents to increase dopamine uptake in the PD striatum, thereby improving dopamine availability [26–28].…”

Section: Introductionmentioning

confidence: 99%

Purine metabolism gene deregulation in Parkinson's disease

Garcia‐Esparcia

Hernández‐Ortega

Ansoleaga

et al. 2015

Neuropathology Appl Neurobio

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Gene down-regulation in the substantia nigra may be interpreted as a consequence of dopaminergic cell death as ENTPD3, NME1, NME7, AK1 and PNP1 are mainly expressed in neurons. Yet ENTPD1 and NT5E, also down-regulated in the substantia nigra, are expressed in astrocytes, probably pericytes and microglia, respectively. In contrast, gene up-regulation in the frontal cortex area 8 at advanced stages of the disease suggests a primary manifestation or a compensation of altered purine metabolism in this region.

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An Update on Adenosine A2A Receptors as Drug Target in Parkinson's Disease

Cited by 22 publications

References 67 publications

Manganese‐ and 1‐methyl‐4‐phenylpyridinium‐induced neurotoxicity display differences in morphological, electrophysiological and genome‐wide alterations: implications for idiopathic Parkinson's disease

Manganese‐ and 1‐methyl‐4‐phenylpyridinium‐induced neurotoxicity display differences in morphological, electrophysiological and genome‐wide alterations: implications for idiopathic Parkinson's disease

Targeting Striatal Metabotropic Glutamate Receptor Type 5 in Parkinson`s Disease: Bridging Molecular Studies and Clinical Trials

Purine metabolism gene deregulation in Parkinson's disease

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