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Adenosine Receptors: From Cell Biology to Human Diseases

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A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cell Signaling".

Deadline for manuscript submissions: closed (31 March 2020) | Viewed by 57663

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Dr. Katia Varani

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Department of Medical Sciences, University of Ferrara, 44121 Ferrara, Italy
Interests: G protein coupled receptors; drug discovery; cell signaling transduction; neurodegenerative disorders; chronic inflammatory diseases; cancer; clinical biophysics
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Special Issue Information

Dear Colleagues,

Adenosine is a ubiquitous molecule which is involved in the regulation of different functions in every organ and tissue through the interaction with four G protein coupled receptors named A₁, A_2A, A_2B, and A₃ adenosine receptors (ARs). Due to the wide distribution of ARs throughout the body, this purine nucleoside induces a variety of physiopathological effects primarily regulating central nervous and peripheral systems. Adenosine levels rise during conditions concerning increased metabolic demand and/or lack of oxygen occurring in several pathological states, like ischemia, stress, seizures, pain, chronic inflammation, fibrosis, organ damage, and cancer. These characteristics make ARs a potential and attractive target for drug development in some of the most widespread disorders.

This Special Issue aims to provide the state-of-the-art on the involvement of the cellular and molecular pathways triggered by ARs that could play a role in the different adenosine effects and in their implications in diseases. Based on these important scientific and clinical advances, purine scientists are definitely getting closer to identifying novel adenosine drugs with the ability to have a therapeutic effect in improving human health.

We look forward to your contributions.

Dr. Katia Varani
Guest Editor

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Keywords

adenosine receptors
drug discovery
cell signaling transduction
neurodegenerative disorders
chronic inflammatory diseases
fibrosis
cancer

Published Papers (13 papers)

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20 pages, 6753 KiB

Open AccessArticle

Adenosine Receptors as Neuroinflammation Modulators: Role of A₁ Agonists and A_2A Antagonists

by Aleix Martí Navia, Diego Dal Ben, Catia Lambertucci, Andrea Spinaci, Rosaria Volpini, Inês Marques-Morgado, Joana E. Coelho, Luísa V. Lopes, Gabriella Marucci and Michela Buccioni

Cells 2020, 9(7), 1739; https://doi.org/10.3390/cells9071739 - 21 Jul 2020

Cited by 26 | Viewed by 3591

Abstract

The pathological condition of neuroinflammation is caused by the activation of the neuroimmune cells astrocytes and microglia. The autacoid adenosine seems to be an important neuromodulator in this condition. Its main receptors involved in the neuroinflammation modulation are A₁AR and A_2AAR. Evidence suggests that A₁AR activation produces a neuroprotective effect and A_2AARs block prevents neuroinflammation. The aim of this work is to elucidate the effects of these receptors in neuroinflammation using the partial agonist 2′-dCCPA (2-chloro-N⁶-cyclopentyl-2′-deoxyadenosine) (C1 K_iA₁AR = 550 nM, K_iA_2AAR = 24,800 nM, and K_iA₃AR = 5560 nM, α = 0.70, EC₅₀A₁AR = 832 nM) and the newly synthesized in house compound 8-chloro-9-ethyl-2-phenethoxyadenine (C2 K_iA_2AAR = 0.75 nM; K_iA₁AR = 17 nM and K_iA₃AR = 227 nM, IC₅₀A_2AAR = 251 nM unpublished results). The experiments were performed in in vitro and in in vivo models of neuroinflammation. Results showed that C1 was able to prevent the inflammatory effect induced by cytokine cocktail (TNF-α, IL-1β, and IFN-γ) while C2 possess both anti-inflammatory and antioxidant properties, counteracting both neuroinflammation in mixed glial cells and in an animal model of neuroinflammation. In conclusion, C2 is a potential candidate for neuroinflammation therapy. Full article

(This article belongs to the Special Issue Adenosine Receptors: From Cell Biology to Human Diseases)

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13 pages, 2786 KiB

Open AccessArticle

The Anti-Inflammatory and Pain-Relieving Effects of AR170, an Adenosine A₃ Receptor Agonist, in a Rat Model of Colitis

by Luca Antonioli, Elena Lucarini, Catia Lambertucci, Matteo Fornai, Carolina Pellegrini, Laura Benvenuti, Lorenzo Di Cesare Mannelli, Andrea Spinaci, Gabriella Marucci, Corrado Blandizzi, Carla Ghelardini, Rosaria Volpini and Diego Dal Ben

Cells 2020, 9(6), 1509; https://doi.org/10.3390/cells9061509 - 21 Jun 2020

Cited by 13 | Viewed by 2335

Abstract

The pharmacological activation of A₃ receptors has shown potential usefulness in the management of bowel inflammation. However, the role of these receptors in the control of visceral hypersensitivity in the presence of intestinal inflammation has not been investigated. The effects of AR170, a potent and selective A₃ receptor agonist, and dexamethasone (DEX) were tested in rats with 2,4-dinitrobenzene sulfonic acid (DNBS)-induced colitis to assess their tissue inflammatory parameters. The animals received AR170, DEX, or a vehicle intraperitoneally for 6 days, starting 1 day before the induction of colitis. Visceral pain was assessed by recording the abdominal responses to colorectal distension in animals with colitis. Colitis was associated with a decrease in body weight and an increase in spleen weight. The macroscopic damage score and tissue tumor necrosis factor (TNF), interleukin 1β (IL-1β), and myeloperoxidase (MPO) levels were also enhanced. AR170, but not DEX, improved body weight. Both drugs counteracted the increase in spleen weight, ameliorated macroscopic colonic damage, and decreased TNF, IL-1β, and MPO tissue levels. The enhanced visceromotor response (VMR) in rats with colitis was decreased via AR170 administration. In rats with colitis, AR170 counteracted colonic inflammatory cell infiltration and decreased pro-inflammatory cytokine levels, thereby relieving visceral hypersensitivity. Full article

(This article belongs to the Special Issue Adenosine Receptors: From Cell Biology to Human Diseases)

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18 pages, 3133 KiB

Open AccessArticle

Glial A_2B Adenosine Receptors Modulate Abnormal Tachykininergic Responses and Prevent Enteric Inflammation Associated with High Fat Diet-Induced Obesity

by Vanessa D’Antongiovanni, Laura Benvenuti, Matteo Fornai, Carolina Pellegrini, Renè van den Wijngaard, Silvia Cerantola, Maria Cecilia Giron, Valentina Caputi, Rocchina Colucci, Gyorgy Haskó, Zoltán H. Németh, Corrado Blandizzi and Luca Antonioli

Cells 2020, 9(5), 1245; https://doi.org/10.3390/cells9051245 - 18 May 2020

Cited by 23 | Viewed by 3212

Abstract

The role played by adenosine A_2B receptors (A_2BRs) in the regulation of enteric glial cell (EGC) functions remains unclear. This study was aimed at investigating the involvement of A_2BRs in the control of EGC functions in a model of obesity. C57BL/6 mice were fed with standard diet (SD) or high fat diet (HFD) for eight weeks. Colonic tachykininergic contractions were recorded in the presence of BAY60-6583 (A_2BRs agonist), MRS1754 (A_2BRs antagonist), and the gliotoxin fluorocitrate. Immunofluorescence distribution of HuC/D, S100β, and A_2BRs was assessed in whole mount preparations of colonic myenteric plexus. To mimic HFD, EGCs were incubated in vitro with palmitate (PA) and lipopolysaccharide (LPS), in the absence or in the presence of A_2BR ligands. Toll-like receptor 4 (TLR4) expression was assessed by Western blot analysis. Interleukin-1β (IL-1β), substance P (SP), and glial cell derived neurotrophic factor (GDNF) release were determined by enzyme-linked immunosorbent assay (ELISA) assays. MRS1754 enhanced electrically evoked tachykininergic contractions of colonic preparations from HFD mice. BAY60-6583 decreased the evoked tachykininergic contractions, with higher efficacy in HFD mice. Such effects were blunted upon incubation with fluorocitrate. In in vitro experiments on EGCs, PA and LPS increased TLR4 expression as well as IL-1β, GDNF, and SP release. Incubation with BAY60-6583 reduced TLR4 expression as well as IL-1β, GDNF, and SP release. Such effects were blunted by MRS1754. The present results suggest that A_2BRs, expressed on EGCs, participate in the modulation of enteric inflammation and altered tachykininergic responses associated with obesity, thus representing a potential therapeutic target. Full article

(This article belongs to the Special Issue Adenosine Receptors: From Cell Biology to Human Diseases)

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16 pages, 2706 KiB

Open AccessArticle

The Detrimental Action of Adenosine on Glutamate-Induced Cytotoxicity in PC12 Cells Can Be Shifted towards a Neuroprotective Role through A₁AR Positive Allosteric Modulation

by Fabrizio Vincenzi, Silvia Pasquini, Stefania Gessi, Stefania Merighi, Romeo Romagnoli, Pier Andrea Borea and Katia Varani

Cells 2020, 9(5), 1242; https://doi.org/10.3390/cells9051242 - 18 May 2020

Cited by 12 | Viewed by 2755

Abstract

Glutamate cytotoxicity is implicated in neuronal death in different neurological disorders including stroke, traumatic brain injury, and neurodegenerative diseases. Adenosine is a nucleoside that plays an important role in modulating neuronal activity and its receptors have been identified as promising therapeutic targets for glutamate cytotoxicity. The purpose of this study is to elucidate the role of adenosine and its receptors on glutamate-induced injury in PC12 cells and to verify the protective effect of the novel A₁ adenosine receptor positive allosteric modulator, TRR469. Flow cytometry experiments to detect apoptosis revealed that adenosine has a dual role in glutamate cytotoxicity, with A_2A and A_2B adenosine receptor (AR) activation exacerbating and A₁ AR activation improving glutamate-induced cell injury. The overall effect of endogenous adenosine in PC12 cells resulted in a facilitating action on glutamate cytotoxicity, as demonstrated by the use of adenosine deaminase and selective antagonists. However, enhancing the action of endogenous adenosine on A₁ARs by TRR469 completely abrogated glutamate-mediated cell death, caspase 3/7 activation, ROS production, and mitochondrial membrane potential loss. Our results indicate a novel potential therapeutic strategy against glutamate cytotoxicity based on the positive allosteric modulation of A₁ARs. Full article

(This article belongs to the Special Issue Adenosine Receptors: From Cell Biology to Human Diseases)

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22 pages, 3672 KiB

Open AccessArticle

Allosteric Antagonism of the A_2A Adenosine Receptor by a Series of Bitopic Ligands

by Zhan-Guo Gao, Kiran S. Toti, Ryan Campbell, R. Rama Suresh, Huijun Yang and Kenneth A. Jacobson

Cells 2020, 9(5), 1200; https://doi.org/10.3390/cells9051200 - 12 May 2020

Cited by 11 | Viewed by 3720

Abstract

Allosteric antagonism by bitopic ligands, as reported for many receptors, is a distinct modulatory mechanism. Although several bitopic A_2A adenosine receptor (A_2AAR) ligand classes were reported as pharmacological tools, their receptor binding and functional antagonism patterns, i.e., allosteric or competitive, were not well characterized. Therefore, here we systematically characterized A_2AAR binding and functional antagonism of two distinct antagonist chemical classes. i.e., fluorescent conjugates of xanthine amine congener (XAC) and SCH442416. Bitopic ligands were potent, weak, competitive or allosteric, based on the combination of pharmacophore, linker and fluorophore. Among antagonists tested, XAC, XAC245, XAC488, SCH442416, MRS7352 showed K_i binding values consistent with K_B values from functional antagonism. Interestingly, MRS7396, XAC-X-BY630 (XAC630) and 5-(N,N-hexamethylene)amiloride (HMA) were 9–100 times weaker in displacing fluorescent MRS7416 binding than radioligand binding. XAC245, XAC630, MRS7396, MRS7416 and MRS7322 behaved as allosteric A_2AAR antagonists, whereas XAC488 and MRS7395 antagonized competitively. Schild analysis showed antagonism slopes of 0.42 and 0.47 for MRS7396 and XAC630, respectively. Allosteric antagonists HMA and MRS7396 were more potent in displacing [³H]ZM241385 binding than MRS7416 binding. Sodium site D52N mutation increased and decreased affinity of HMA and MRS7396, respectively, suggesting possible preference for different A_2AAR conformations. The allosteric binding properties of some bitopic ligands were rationalized and analyzed using the Hall two-state allosteric model. Thus, fluorophore tethering to an orthosteric ligand is not neutral pharmacologically and may confer unexpected properties to the conjugate. Full article

(This article belongs to the Special Issue Adenosine Receptors: From Cell Biology to Human Diseases)

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16 pages, 2757 KiB

Open AccessArticle

Adenosine A_2A Receptor Antagonists Affects NMDA Glutamate Receptor Function. Potential to Address Neurodegeneration in Alzheimer’s Disease

by Rafael Franco, Rafael Rivas-Santisteban, Mireia Casanovas, Alejandro Lillo, Carlos A. Saura and Gemma Navarro

Cells 2020, 9(5), 1075; https://doi.org/10.3390/cells9051075 - 26 Apr 2020

Cited by 35 | Viewed by 5288

Abstract

(1) Background. N-methyl d-aspartate (NMDA) ionotropic glutamate receptor (NMDAR), which is one of the main targets to combat Alzheimer’s disease (AD), is expressed in both neurons and glial cells. The aim of this paper was to assess whether the adenosine A_2A receptor (A_2AR), which is a target in neurodegeneration, may affect NMDAR functionality. (2) Methods. Immuno-histo/cytochemical, biophysical, biochemical and signaling assays were performed in a heterologous cell expression system and in primary cultures of neurons and microglia (resting and activated) from control and the APP_Sw,Ind transgenic mice. (3) Results. On the one hand, NMDA and A_2A receptors were able to physically interact forming complexes, mainly in microglia. Furthermore, the amount of complexes was markedly enhanced in activated microglia. On the other hand, the interaction resulted in a novel functional entity that displayed a cross-antagonism, that could be useful to prevent the exacerbation of NMDAR function by using A_2AR antagonists. Interestingly, the amount of complexes was markedly higher in the hippocampal cells from the APP_Sw,Ind than from the control mice. In neurons, the number of complexes was lesser, probably due to NMDAR not interacting with the A_2AR. However, the activation of the A_2AR receptors resulted in higher NMDAR functionality in neurons, probably by indirect mechanisms. (4) Conclusions. A_2AR antagonists such as istradefylline, which is already approved for Parkinson’s disease (Nouriast^® in Japan and Nourianz^® in the US), have potential to afford neuroprotection in AD in a synergistic-like fashion. i.e., via both neurons and microglia. Full article

(This article belongs to the Special Issue Adenosine Receptors: From Cell Biology to Human Diseases)

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16 pages, 2901 KiB

Open AccessArticle

Adenosinergic System Involvement in Ischemic Stroke Patients’ Lymphocytes

by Silvia Pasquini, Fabrizio Vincenzi, Ilaria Casetta, Michele Laudisi, Stefania Merighi, Stefania Gessi, Pier Andrea Borea and Katia Varani

Cells 2020, 9(5), 1072; https://doi.org/10.3390/cells9051072 - 25 Apr 2020

Cited by 7 | Viewed by 3192

Abstract

Adenosine modulates many physiological processes through the interaction with adenosine receptors (ARs) named as A₁, A_2A, A_2B, and A₃ARs. During ischemic stroke, adenosine mediates neuroprotective and anti-inflammatory effects through ARs activation. One of the dominant pathways generating extracellular adenosine involves the dephosphorylation of ATP by ecto-nucleotidases CD39 and CD73, which efficiently hydrolyze extracellular ATP to adenosine. The aim of the study is to assess the presence of ARs in lymphocytes from ischemic stroke patients compared to healthy subjects and to analyze changes in CD39 and CD73 expression in CD4⁺ and CD8⁺ lymphocytes. Saturation binding experiments revealed that A_2AARs affinity and density were significantly increased in ischemic stroke patients whilst no differences were found in A₁, A_2B, and A₃ARs. These results were also confirmed in reverse transcription (RT)-polymerase chain reaction (PCR) assays where A_2AAR mRNA levels of ischemic stroke patients were higher than in control subjects. In flow cytometry experiments, the percentage of CD73⁺ cells was significantly decreased in lymphocytes and in T-lymphocyte subclasses CD4⁺ and CD8⁺ obtained from ischemic stroke patients in comparison with healthy individuals. These data corroborate the importance of the adenosinergic system in ischemic stroke and could open the way to more targeted therapeutic approaches and biomarker development for ischemic stroke. Full article

(This article belongs to the Special Issue Adenosine Receptors: From Cell Biology to Human Diseases)

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16 pages, 2741 KiB

Open AccessArticle

Adenosine A₁-A_2A Receptor-Receptor Interaction: Contribution to Guanosine-Mediated Effects

by Débora Lanznaster, Caio M. Massari, Vendula Marková, Tereza Šimková, Romain Duroux, Kenneth A. Jacobson, Víctor Fernández-Dueñas, Carla I. Tasca and Francisco Ciruela

Cells 2019, 8(12), 1630; https://doi.org/10.3390/cells8121630 - 13 Dec 2019

Cited by 25 | Viewed by 3492

Abstract

Guanosine, a guanine-based purine nucleoside, has been described as a neuromodulator that exerts neuroprotective effects in animal and cellular ischemia models. However, guanosine’s exact mechanism of action and molecular targets have not yet been identified. Here, we aimed to elucidate a role of adenosine receptors (ARs) in mediating guanosine effects. We investigated the neuroprotective effects of guanosine in hippocampal slices from A_2AR-deficient mice (A_2AR^−/−) subjected to oxygen/glucose deprivation (OGD). Next, we assessed guanosine binding at ARs taking advantage of a fluorescent-selective A_2AR antagonist (MRS7396) which could engage in a bioluminescence resonance energy transfer (BRET) process with NanoLuc-tagged A_2AR. Next, we evaluated functional AR activation by determining cAMP and calcium accumulation. Finally, we assessed the impact of A₁R and A_2AR co-expression in guanosine-mediated impedance responses in living cells. Guanosine prevented the reduction of cellular viability and increased reactive oxygen species generation induced by OGD in hippocampal slices from wild-type, but not from A_2AR^−/− mice. Notably, while guanosine was not able to modify MRS7396 binding to A_2AR-expressing cells, a partial blockade was observed in cells co-expressing A₁R and A_2AR. The relevance of the A₁R and A_2AR interaction in guanosine effects was further substantiated by means of functional assays (i.e., cAMP and calcium determinations), since guanosine only blocked A_2AR agonist-mediated effects in doubly expressing A₁R and A_2AR cells. Interestingly, while guanosine did not affect A₁R/A_2AR heteromer formation, it reduced A_2AR agonist-mediated cell impedance responses. Our results indicate that guanosine-induced effects may require both A₁R and A_2AR co-expression, thus identifying a molecular substrate that may allow fine tuning of guanosine-mediated responses. Full article

(This article belongs to the Special Issue Adenosine Receptors: From Cell Biology to Human Diseases)

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Review

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25 pages, 1124 KiB

Open AccessReview

Adenosine A_2AReceptors in Substance Use Disorders: A Focus on Cocaine

by Karolina Wydra, Dawid Gawliński, Kinga Gawlińska, Małgorzata Frankowska, Dasiel O. Borroto-Escuela, Kjell Fuxe and Małgorzata Filip

Cells 2020, 9(6), 1372; https://doi.org/10.3390/cells9061372 - 01 Jun 2020

Cited by 15 | Viewed by 3498

Abstract

Several psychoactive drugs can evoke substance use disorders (SUD) in humans and animals, and these include psychostimulants, opioids, cannabinoids (CB), nicotine, and alcohol. The etiology, mechanistic processes, and the therapeutic options to deal with SUD are not well understood. The common feature of all abused drugs is that they increase dopamine (DA) neurotransmission within the mesocorticolimbic circuitry of the brain followed by the activation of DA receptors. D₂ receptors were proposed as important molecular targets for SUD. The findings showed that D₂ receptors formed heteromeric complexes with other GPCRs, which forced the addiction research area in new directions. In this review, we updated the view on the brain D₂ receptor complexes with adenosine (A)2A receptors (A_2AR) and discussed the role of A_2AR in different aspects of addiction phenotypes in laboratory animal procedures that permit the highly complex syndrome of human drug addiction. We presented the current knowledge on the neurochemical in vivo and ex vivo mechanisms related to cocaine use disorder (CUD) and discussed future research directions for A_2AR heteromeric complexes in SUD. Full article

(This article belongs to the Special Issue Adenosine Receptors: From Cell Biology to Human Diseases)

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12 pages, 1046 KiB

Open AccessReview

Multiple Adenosine-Dopamine (A2A-D2 Like) Heteroreceptor Complexes in the Brain and Their Role in Schizophrenia

by Dasiel O. Borroto-Escuela, Luca Ferraro, Manuel Narvaez, Sergio Tanganelli, Sarah Beggiato, Fang Liu, Alicia Rivera and Kjell Fuxe

Cells 2020, 9(5), 1077; https://doi.org/10.3390/cells9051077 - 27 Apr 2020

Cited by 19 | Viewed by 4812

Abstract

In the 1980s and 1990s, the concept was introduced that molecular integration in the Central Nervous System could develop through allosteric receptor–receptor interactions in heteroreceptor complexes presents in neurons. A number of adenosine–dopamine heteroreceptor complexes were identified that lead to the A_2A-D₂ heteromer hypothesis of schizophrenia. The hypothesis is based on strong antagonistic A_2A-D₂ receptor–receptor interactions and their presence in the ventral striato-pallidal GABA anti-reward neurons leading to reduction of positive symptoms. Other types of adenosine A_2A heteroreceptor complexes are also discussed in relation to this disease, such as A_2A-D₃ and A_2A-D₄ heteroreceptor complexes as well as higher order A_2A-D₂-mGluR5 and A_2A-D₂-Sigma1R heteroreceptor complexes. The A_2A receptor protomer can likely modulate the function of the D₄ receptors of relevance for understanding cognitive dysfunction in schizophrenia. A_2A-D₂-mGluR5 complex is of interest since upon A_2A/mGluR5 coactivation they appear to synergize in producing strong inhibition of the D2 receptor protomer. For understanding the future of the schizophrenia treatment, the vulnerability of the current A_2A-D₂like receptor complexes will be tested in animal models of schizophrenia. A_2A-D₂-Simag1R complexes hold the highest promise through Sigma1R enhancement of inhibition of D2R function. In line with this work, Lara proposed a highly relevant role of adenosine for neurobiology of schizophrenia. Full article

(This article belongs to the Special Issue Adenosine Receptors: From Cell Biology to Human Diseases)

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20 pages, 3345 KiB

Open AccessFeature PaperReview

by Kenneth A. Jacobson and Marc L. Reitman

Cells 2020, 9(4), 956; https://doi.org/10.3390/cells9040956 - 13 Apr 2020

Cited by 16 | Viewed by 6452

Abstract

Many ligands directly target adenosine receptors (ARs). Here we review the effects of noncanonical AR drugs on adenosinergic signaling. Non-AR mechanisms include raising adenosine levels by inhibiting adenosine transport (e.g., ticagrelor, ethanol, and cannabidiol), affecting intracellular metabolic pathways (e.g., methotrexate, nicotinamide riboside, salicylate, and 5-aminoimidazole-4-carboxamide riboside), or undetermined means (e.g., acupuncture). However, other compounds bind ARs in addition to their canonical ‘on-target’ activity (e.g., mefloquine). The strength of experimental support for an adenosine-related role in a drug’s effects varies widely. AR knockout mice are the ‘gold standard’ method for investigating an AR role, but few drugs have been tested on these mice. Given the interest in AR modulation for treatment of cancer, CNS, immune, metabolic, cardiovascular, and musculoskeletal conditions, it is informative to consider AR and non-AR adenosinergic effects of approved drugs and conventional treatments. Full article

(This article belongs to the Special Issue Adenosine Receptors: From Cell Biology to Human Diseases)

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36 pages, 1549 KiB

Open AccessReview

Focusing on Adenosine Receptors as a Potential Targeted Therapy in Human Diseases

by Wiwin Is Effendi, Tatsuya Nagano, Kazuyuki Kobayashi and Yoshihiro Nishimura

Cells 2020, 9(3), 785; https://doi.org/10.3390/cells9030785 - 24 Mar 2020

Cited by 88 | Viewed by 10635

Abstract

Adenosine is involved in a range of physiological and pathological effects through membrane-bound receptors linked to G proteins. There are four subtypes of adenosine receptors, described as A₁AR, A_2AAR, A_2BAR, and A₃AR, which are the center of cAMP signal pathway-based drug development. Several types of agonists, partial agonists or antagonists, and allosteric substances have been synthesized from these receptors as new therapeutic drug candidates. Research efforts surrounding A₁AR and A_2AAR are perhaps the most enticing because of their concentration and affinity; however, as a consequence of distressing conditions, both A_2BAR and A₃AR levels might accumulate. This review focuses on the biological features of each adenosine receptor as the basis of ligand production and describes clinical studies of adenosine receptor-associated pharmaceuticals in human diseases. Full article

(This article belongs to the Special Issue Adenosine Receptors: From Cell Biology to Human Diseases)

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15 pages, 3691 KiB

Open AccessBrief Report

Inhibition of the Adenosine A_2A Receptor Mitigates Excitotoxic Injury in Organotypic Tissue Cultures of the Rat Cochlea

by Belinda RX Han, Shelly CY Lin, Kristan Espinosa, Peter R Thorne and Srdjan M Vlajkovic

Cells 2019, 8(8), 877; https://doi.org/10.3390/cells8080877 - 12 Aug 2019

Cited by 12 | Viewed by 4012

Abstract

The primary loss of cochlear glutamatergic afferent nerve synapses due to noise or ageing (cochlear neuropathy) often presents as difficulties in speech discrimination in noisy conditions (hidden hearing loss (HHL)). Currently, there is no treatment for this condition. Our previous studies in mice with genetic deletion of the adenosine A_2A receptor (A_2AR) have demonstrated better preservation of cochlear afferent synapses and spiral ganglion neurons after noise exposure compared to wildtype mice. This has informed our current targeted approach to cochlear neuroprotection based on pharmacological inhibition of the A_2AR. Here, we have used organotypic tissue culture of the Wistar rat cochlea at postnatal day 6 (P6) to model excitotoxic injury induced by N-methyl-d-aspartate (NMDA)/kainic acid (NK) treatment for 2 h. The excitotoxic injury was characterised by a reduction in the density of neural processes immediately after NK treatment and loss of afferent synapses in the presence of intact sensory hair cells. The administration of istradefylline (a clinically approved A_2AR antagonist) reduced deafferentation of inner hair cells and improved the survival of afferent synapses after excitotoxic injury. This study thus provides evidence that A_2AR inhibition promotes cochlear recovery from excitotoxic injury, and may have implications for the treatment of cochlear neuropathy and prevention of HHL. Full article

(This article belongs to the Special Issue Adenosine Receptors: From Cell Biology to Human Diseases)

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