A2A Adenosine Receptor Antagonists in Neurodegenerative Diseases

2021 ◽  
Vol 28 ◽  
Author(s):  
Stefania Merighi ◽  
Pier Andrea Borea ◽  
Katia Varani ◽  
Fabrizio Vincenzi ◽  
Kenneth A. Jacobson ◽  
...  
Keyword(s):  
Adenosine Receptor ◽  
Rational Design ◽  
Symptomatic Relief ◽  
Clinical Signs ◽  
Receptor Activation ◽  
Amyloid Peptide ◽  
Receptor Antagonists ◽  
A2a Adenosine Receptor ◽  
A2a Adenosine Receptors ◽  
A2a Receptor

Background: Alzheimer's disease (AD) is the most common form of dementia worldwide, with approximately 6 million American cases in 2020. The clinical signs of AD include cognitive dysfunction, apathy, anxiety and neuropsychiatric signs, and pathogenetic mechanisms that involve amyloid peptide-β extracellular accumulation and tau hyperphosphorylation. Unfortunately, current drugs to treat AD can provide only symptomatic relief but are not disease-modifying molecules able to revert AD progression. The endogenous modulator adenosine, through A2A receptor activation, plays a role in synaptic loss and neuroinflammation, which are crucial for cognitive impairment and memory damage. Objective: In this review, recent advances covering A2A adenosine receptor antagonists will be extensively reviewed, providing a base for the rational design of future A2A inhibitors. Method: Herein, the literature on A2A adenosine receptors and their role in synaptic plasticity and neuroinflammation as well as the effects of A2A antagonism in animal models of AD and in humans are reviewed. Furthermore, current chemical and structure-based strategies are presented. Results : Caffeine, the most widely consumed natural product stimulant and an A2A antagonist, improves human memory. Similarly, synthetic A2A receptor antagonists, as described in this review, may provide a means to fight AD. Conclusion: This review highlights the clinical potential of A2A adenosine receptor antagonists as a novel approach to treat patients with AD.

scholarly journals A2A adenosine receptors and C/EBPβ are crucially required for IL-10 production by macrophages exposed to Escherichia coli

Blood ◽  
2007 ◽  
Vol 110 (7) ◽  
pp. 2685-2695 ◽  
Author(s):  
Balázs Csóka ◽  
Zoltán H. Németh ◽  
László Virág ◽  
Pál Gergely ◽  
S. Joseph Leibovich ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Adenosine Receptor ◽  
Molecular Mechanisms ◽  
Receptor Activation ◽  
Site Directed Mutagenesis ◽  
Nuclear Accumulation ◽  
Minor Role ◽  
E Coli ◽  
A2a Adenosine Receptors ◽  
A2a Receptor

We recently showed that A2A adenosine receptor activation by endogenous adenosine contributes to interleukin-10 (IL-10) production in polymicrobial sepsis. Here we investigated the molecular mechanisms underpinning this interaction between adenosine receptor signaling and infection by exposing macrophages to Escherichia coli. We demonstrated using receptor knockout mice that A2A receptor activation is critically required for the stimulatory effect of adenosine on IL-10 production by E coli–challenged macrophages, whereas A2B receptors have a minor role. The stimulatory effect of adenosine on E coli–induced IL-10 production did not require toll-like receptor 4 (TLR4) or MyD88, but was blocked by p38 inhibition. Using shRNA we demonstrated that TRAF6 impairs the potentiating effect of adenosine. Measuring IL-10 mRNA abundance and transfection with an IL-10 promoter-luciferase construct indicated that E coli and adenosine synergistically activate IL-10 transcription. Sequential deletion analysis and site-directed mutagenesis of the IL-10 promoter revealed that a region harboring C/EBP binding elements was responsible for the stimulatory effect of adenosine on E coli–induced IL-10 promoter activity. Adenosine augmented E coli–induced nuclear accumulation and DNA binding of C/EBPβ. C/EBPβ-deficient macrophages failed to produce IL-10 in response to adenosine and E coli. Our results suggest that the A2A receptor–C/EBPβ axis is critical for IL-10 production after bacterial infection.

scholarly journals A2A Adenosine Receptor as a Potential Biomarker and a Possible Therapeutic Target in Alzheimer’s Disease

Cells ◽  
2021 ◽  
Vol 10 (9) ◽  
pp. 2344
Author(s):  
Stefania Gessi ◽  
Tino Emanuele Poloni ◽  
Giulia Negro ◽  
Katia Varani ◽  
Silvia Pasquini ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Adenosine Receptor ◽  
Therapeutic Target ◽  
Calcium Influx ◽  
Glutamate Release ◽  
Receptor Activation ◽  
A2a Adenosine Receptor ◽  
Potential Biomarker ◽  
A2a Receptor

Alzheimer’s disease (AD) is one of the most common neurodegenerative pathologies. Its incidence is in dramatic growth in Western societies and there is a need of both biomarkers to support the clinical diagnosis and drugs for the treatment of AD. The diagnostic criteria of AD are based on clinical data. However, it is necessary to develop biomarkers considering the neuropathology of AD. The A2A receptor, a G-protein coupled member of the P1 family of adenosine receptors, has different functions crucial for neurodegeneration. Its activation in the hippocampal region regulates synaptic plasticity and in particular glutamate release, NMDA receptor activation and calcium influx. Additionally, it exerts effects in neuroinflammation, regulating the secretion of pro-inflammatory cytokines. In AD patients, its expression is increased in the hippocampus/entorhinal cortex more than in the frontal cortex, a phenomenon not observed in age-matched control brains, indicating an association with AD pathology. It is upregulated in peripheral blood cells of patients affected by AD, thus reflecting its increase at central neuronal level. This review offers an overview on the main AD biomarkers and the potential role of A2A adenosine receptor as a new marker and therapeutic target.

Ligand-Based Virtual Screening Using Tailored Ensembles: A Prioritization Tool for Dual A2A Adenosine Receptor Antagonists / Monoamine Oxidase B Inhibitors

2016 ◽  
Vol 22 (21) ◽  
pp. 3082-3096 ◽  
Author(s):  
Aliuska Morales Helguera ◽  
Yunierkis Perez-Castillo ◽  
M. Natália D.S. Cordeiro ◽  
Eduardo Tejera ◽  
César Paz-y-Miño ◽  
...  
Keyword(s):  
Virtual Screening ◽  
Monoamine Oxidase ◽  
Adenosine Receptor ◽  
Monoamine Oxidase B ◽  
Receptor Antagonists ◽  
A2a Adenosine Receptor

scholarly journals Immunosuppression via adenosine receptor activation by adenosine monophosphate released from apoptotic cells

eLife ◽  
2014 ◽  
Vol 3 ◽  
Author(s):  
Hiroshi Yamaguchi ◽  
Toshihiko Maruyama ◽  
Yoshihiro Urade ◽  
Shigekazu Nagata
Keyword(s):  
Adenosine Receptor ◽  
Molecular Mechanisms ◽  
Apoptotic Cell ◽  
Adenosine Monophosphate ◽  
Receptor Activation ◽  
Death Process ◽  
Apoptotic Cells ◽  
Dependent Manner ◽  
A2a Adenosine Receptor ◽  
Anti Inflammatory

Apoptosis is coupled with recruitment of macrophages for engulfment of dead cells, and with compensatory proliferation of neighboring cells. Yet, this death process is silent, and it does not cause inflammation. The molecular mechanisms underlying anti-inflammatory nature of the apoptotic process remains poorly understood. In this study, we found that the culture supernatant of apoptotic cells activated the macrophages to express anti-inflammatory genes such as Nr4a and Thbs1. A high level of AMP accumulated in the apoptotic cell supernatant in a Pannexin1-dependent manner. A nucleotidase inhibitor and A2a adenosine receptor antagonist inhibited the apoptotic supernatant-induced gene expression, suggesting AMP was metabolized to adenosine by an ecto-5’-nucleotidase expressed on macrophages, to activate the macrophage A2a adenosine receptor. Intraperitoneal injection of zymosan into Adora2a- or Panx1-deficient mice produced high, sustained levels of inflammatory mediators in the peritoneal lavage. These results indicated that AMP from apoptotic cells suppresses inflammation as a ‘calm down’ signal.

Cardiac effects of adenosine in A2A receptor knockout hearts: uncovering A2B receptors

2002 ◽  
Vol 282 (2) ◽  
pp. H437-H444 ◽  
Author(s):  
R. Ray Morrison ◽  
M. A. Hassan Talukder ◽  
Catherine Ledent ◽  
S. Jamal Mustafa
Keyword(s):  
Adenosine Receptor ◽  
Coronary Flow ◽  
Receptor Activation ◽  
Receptor Subtypes ◽  
Functional Responses ◽  
Response Curves ◽  
Cgs 21680 ◽  
A2a Receptor ◽  
Developed Pressure ◽  
Adenosine Receptor Activation

To clarify the relative roles of A2 adenosine receptor subtypes in the regulation of coronary flow and myocardial contractility, coronary vascular and functional responses to adenosine and its analogs were examined in isolated wild-type (WT) and A2A receptor knockout (A2AKO) mouse hearts. Nonselective agonists adenosine and 5′- N-ethyl-carboxamido-adenosine (NECA) increased coronary flow in A2AKO hearts, albeit with a rightward shift of concentration-response curves and decreased maximal vasodilation compared with WT hearts. 2- p-(2-Carboxy-ethyl)phenethylamino-5′- N-ethyl-carboxamidoadenosine (CGS-21680, a selective A2A receptor agonist) increased coronary flow in WT hearts but did not affect A2AKO hearts. Adenosine and NECA each elicited equal maximal increases in developed pressure in WT and A2AKO hearts, whereas CGS-21680 did not affect developed pressure in A2AKO hearts. Alloxazine, a selective A2B receptor antagonist, attenuated NECA-induced coronary vasodilation (from 202 ± 14% to 128 ± 9% of baseline, P < 0.05) and NECA-induced increases in developed pressure (from 133 ± 8% to 112 ± 7% of baseline, P < 0.05) in A2AKO hearts. Together, these findings support the conclusion that A2Badenosine receptor activation increases coronary flow and developed pressure in isolated murine hearts.

Adenosine receptor gene expression in rat kidney

1992 ◽  
Vol 263 (6) ◽  
pp. F991-F995 ◽  
Author(s):  
D. R. Weaver ◽  
S. M. Reppert
Keyword(s):  
Adenosine Receptor ◽  
Rat Kidney ◽  
Renin Secretion ◽  
A1 Adenosine Receptor ◽  
A2a Adenosine Receptor ◽  
Excretory Function ◽  
A2a Adenosine Receptors ◽  
Receptor Mrna ◽  
Collecting Ducts ◽  
Receptor Mrnas

Adenosine is an important modulator of renal function. Adenosine produced and released within the kidney is thought to participate in the metabolic regulation of glomerular filtration (tubuloglomerular feedback), as well as in regulating renal excretory function and renin secretion. The recent cloning of cDNAs encoding the A1 and A2a adenosine receptors from rat brain allows direct examination of potential sites of adenosine action within the rat kidney. Northern blot analysis of rat kidney poly(A)+ RNA revealed that A1 adenosine receptor mRNA was more abundant in kidney than the A2a adenosine receptor transcript. In situ hybridization with 35S-labeled cRNA probes was used to localize A1 and A2a adenosine receptor mRNAs within the kidney. A1 adenosine receptor mRNA was most abundant in the collecting ducts of the papilla and inner medulla. Collecting ducts in the outermost portion of the inner stripe of the outer medulla and cells of the juxtaglomerular apparatus also expressed A1 adenosine receptor mRNA. A2a adenosine receptor mRNA was localized to the renal papilla. The distribution of A1 and A2a adenosine receptor mRNAs within the rat kidney supports previously postulated roles for adenosine in the regulation of renal hemodynamics, excretory function, and renin secretion.

Synthesis of 4-amino-6-(hetero)arylalkylamino-1,2,4-triazolo[4,3-a]quinoxalin-1-one derivatives as potent A2A adenosine receptor antagonists

2003 ◽  
Vol 11 (24) ◽  
pp. 5509-5518 ◽  
Author(s):  
Vittoria Colotta ◽  
Daniela Catarzi ◽  
Flavia Varano ◽  
Guido Filacchioni ◽  
Claudia Martini ◽  
...  
Keyword(s):  
Adenosine Receptor ◽  
Receptor Antagonists ◽  
A2a Adenosine Receptor
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