A2A Receptor Research Articles

Targeting adenosine A2A receptors for early intervention of retinopathy of prematurity.

Retinopathy of prematurity (ROP) continues to pose a significant threat to the vision of numerous children worldwide, primarily owing to the increased survival rates of premature infants. The pathologies of ROP are mainly linked to impaired vascularization as a result of hyperoxia, leading to subsequent neovascularization. Existing treatments, including anti-vascular endothelial growth factor(VEGF) therapies, have thus far been limited to addressing pathological angiogenesis at advanced ROP stages, inevitably leading to adverse side effects. Intervention to promote physiological angiogenesis during the initial stages could hold the potential to prevent ROP. Adenosine A2A receptors (A2AR) have been identified in various ocular cell types, exhibiting distinct densities and functionally intricate connections with oxygen metabolism. In this review, we discuss experimental evidence that strongly underscores the pivotal role of A2AR in ROP. In particular, A2AR blockade may represent an effective treatment strategy, mitigating retinal vascular loss by reversing hyperoxia-mediated cellular proliferation inhibition and curtailing hypoxia-mediated neovascularization in oxygen-induced retinopathy (OIR). These effects stem from the interplay of endothelium, neuronal and glial cells, and novel molecular pathways (notably promoting TGF-β signaling) at the hyperoxia phase. We propose that pharmacological targeting of A2AR signaling may confer an early intervention for ROP with distinct therapeutic benefits and mechanisms than the anti-VEGF therapy.

Pharmacologic Management of Parkinsonism and Other Movement Disorders

Parkinsonism and other movement disorders constitute a diverse group of neurodegenerative conditions characterized by disturbances in motor control. This abstract provides an overview of the pharmacologic management strategies employed in the treatment of these disorders. Parkinson's disease, the most prevalent form of Parkinsonism, is primarily managed through dopaminergic therapies aimed at replenishing dopamine levels or enhancing its effects in the central nervous system. Levodopa, a precursor of dopamine, remains the gold standard, often combined with dopaminergic agonists or monoamine oxidase-B inhibitors for optimal efficacy.In addition to Parkinson's disease, other movement disorders such as essential tremor, dystonia, and chorea pose unique challenges. Beta-blockers and anticonvulsants, like primidone, are commonly prescribed for essential tremor, while dystonia may respond to anticholinergic agents or botulinum toxin injections. Huntington's disease, characterized by chorea, is managed through dopamine-depleting agents, tetrabenazine being a notable example.Recent advances in pharmacotherapy include the development of adenosine A2A receptor antagonists and glutamate receptor modulators, providing promising alternatives and adjuncts to traditional therapies. However, challenges such as medication-induced side effects, disease progression, and the need for personalized treatment plans persist.This abstract underscore the evolving landscape of pharmacologic interventions for managing Parkinsonism and other movement disorders. A comprehensive understanding of the underlying pathophysiology, coupled with ongoing research efforts, promises to enhance therapeutic options and improve the quality of life for individuals affected by these debilitating conditions.

Effects of the adenosine A2A receptor antagonist KW6002 on the dopaminergic system, motor performance, and neuroinflammation in a rat model of Parkinson's disease

Adenosine A2A-receptors (A2AR) and dopamine D2-receptors (D2R) are known to work together in a synergistic manner. Inhibiting A2ARs by genetic or pharmacological means can relief symptoms and have neuroprotective effects in certain conditions. We applied PET imaging to evaluate the impact of the A2AR antagonist KW6002 on D2R availability and neuroinflammation in an animal model of Parkinson's disease. Male Wistar rats with 6-hydroxydopamine-induced damage to the right striatum were given 3 mg/kg of KW6002 daily for 20 days. Motor function was assessed using the rotarod and cylinder tests, and neuroinflammation and dopamine receptor availability were measured using PET scans with the tracers [11C]PBR28 and [11C]raclopride, respectively. On day 7 and 22 following 6-OHDA injection, rats were sacrificed for postmortem analysis. PET scans revealed a peak in neuroinflammation on day 7. Chronic treatment with KW6002 significantly reduced [11C]PBR28 uptake in the ipsilateral striatum [normalized to contralateral striatum] and [11C]raclopride binding in both striata when compared to the vehicle group. These imaging findings were accompanied by an improvement in motor function. Postmortem analysis showed an 84% decrease in the number of Iba-1+ cells in the ipsilateral striatum [normalized to contralateral striatum] of KW6002-treated rats compared to vehicle rats on day 22 (p = 0.007), corroborating the PET findings. Analysis of tyrosine hydroxylase levels showed less dopaminergic neuron loss in the ipsilateral striatum of KW6002-treated rats compared to controls on day 7. These findings suggest that KW6002 reduces inflammation and dopaminergic neuron loss, leading to less motor symptoms in this animal model of Parkinson's disease.

The role of purinergic signaling in acupuncture-mediated relief of neuropathic and inflammatory pain.

Acupuncture is a traditional medicinal practice in China that has been increasingly recognized in other countries in recent decades. Notably, several reports have demonstrated that acupuncture can effectively aid in pain management. However, the analgesic mechanisms through which acupuncture provides such benefits remain poorly understood. Purinergic signaling, which is mediated by purine nucleotides and purinergic receptors, has been proposed to play a central role in acupuncture analgesia. On the one hand, acupuncture affects the transmission of nociception by increasing adenosine triphosphate dephosphorylation and thereby decreasing downstream P2X3, P2X4, and P2X7 receptors signaling activity, regulating the levels of inflammatory factors, neurotrophic factors, and synapsin I. On the other hand, acupuncture exerts analgesic effects by promoting the production of adenosine, enhancing the expression of downstream adenosine A1 and A2A receptors, and regulating downstream inflammatory factors or synaptic plasticity. Together, this systematic overview of the field provides a sound, evidence-based foundation for future research focused on the application of acupuncture as a means of relieving pain.

Visualizing the structural dynamics of G protein-activated A2A adenosine receptor at the single-molecule level

Visualizing the structural dynamics of G protein-activated A2A adenosine receptor at the single-molecule level

The binary-switch model of the adenosine A2A receptor: A molecular dynamics study

The binary-switch model of the adenosine A2A receptor: A molecular dynamics study

Optical Control of Adenosine A2A Receptor Using Istradefylline Photosensitivity.

In recent years, there has been growing interest in the potential therapeutic use of inhibitors of adenosine A2A receptors (A2AR) for the treatment of neurodegenerative diseases and cancer. Nevertheless, the widespread expression of A2AR throughout the body emphasizes the importance of temporally and spatially selective ligands. Photopharmacology is an emerging strategy that utilizes photosensitive ligands to attain high spatiotemporal precision and regulate the function of biomolecules using light. In this study, we combined photochemistry and cellular and in vivo photopharmacology to investigate the light sensitivity of the FDA-approved antagonist istradefylline and its potential use as an A2AR photopharmacological tool. Our findings reveal that istradefylline exhibits rapid trans-to-cis isomerization under near-UV light, and prolonged exposure results in the formation of photocycloaddition products. We demonstrate that exposure to UV light triggers a time-dependent decrease in the antagonistic activity of istradefylline in A2AR-expressing cells and enables real-time optical control of A2AR signaling in living cells and zebrafish. Together, these data demonstrate that istradefylline is a photoinactivatable A2AR antagonist and that this property can be utilized to perform photopharmacological experiments in living cells and animals.

Glia-derived adenosine in the ventral hippocampus drives pain-related anxiodepression in a mouse model resembling trigeminal neuralgia

Glial activation and dysregulation of adenosine triphosphate (ATP)/adenosine are involved in the neuropathology of several neuropsychiatric illnesses. The ventral hippocampus (vHPC) has attracted considerable attention in relation to its role in emotional regulation. However, it is not yet clear how vHPC glia and their derived adenosine regulate the anxiodepressive-like consequences of chronic pain. Here, we report that chronic cheek pain elevates vHPC extracellular ATP/adenosine in a mouse model resembling trigeminal neuralgia (rTN), which mediates pain-related anxiodepression, through a mechanism that involves synergistic effects of astrocytes and microglia. We found that rTN resulted in robust activation of astrocytes and microglia in the CA1 area of the vHPC (vCA1). Genetic or pharmacological inhibition of astrocytes and connexin 43, a hemichannel mainly distributed in astrocytes, completely attenuated rTN-induced extracellular ATP/adenosine elevation and anxiodepressive-like behaviors. Moreover, inhibiting microglia and CD39, an enzyme primarily expressed in microglia that degrades ATP into adenosine, significantly suppressed the increase in extracellular adenosine and anxiodepressive-like behaviors. Blockade of the adenosine A2A receptor (A2AR) alleviated rTN-induced anxiodepressive-like behaviors. Furthermore, interleukin (IL)-17A, a pro-inflammatory cytokine probably released by activated microglia, markedly increased intracellular calcium in vCA1 astrocytes and triggered ATP/adenosine release. The astrocytic metabolic inhibitor fluorocitrate and the CD39 inhibitor ARL 67156, attenuated IL-17A-induced increases in extracellular ATP and adenosine, respectively. In addition, astrocytes, microglia, CD39, and A2AR inhibitors all reversed rTN-induced hyperexcitability of pyramidal neurons in the vCA1. Taken together, these findings suggest that activation of astrocytes and microglia in the vCA1 increases extracellular adenosine, which leads to pain-related anxiodepression via A2AR activation. Approaches targeting astrocytes, microglia, and adenosine signaling may serve as novel therapies for pain-related anxiety and depression.

Hippocampal-derived extracellular vesicle synergistically deliver active adenosine hippocampus targeting to promote cognitive recovery after stroke

Ischemic stroke is a neurological disease that leads to brain damage and severe cognitive impairment. In this study, extracellular vesicles(Ev) derived from mouse hippocampal cells (HT22) were used as carriers, and adenosine (Ad) was encapsulated to construct Ev-Ad to target the damaged hippocampus. The results showed that, Ev-Ad had significant antioxidant effect and inhibited apoptosis. In vivo, Ev-Ad reduced cell death and reversed inflammation in hippocampus of ischemic mice, and improved long-term memory and learning impairment by regulating the expression of the A1 receptor and the A2A receptor in the CA1 region. Thus, the developmental approach based on natural carriers that encapsulating Ad not only successfully restored nerves after ischemic stroke, but also improved cognitive impairment in the later stage of ischemic stroke convalescence. The development and design of therapeutic drugs provides a new concept and method for the treatment of cognitive impairment in the convalescent phase after ischemic stroke.

Population Pharmacokinetics of the Novel Adenosine A2A Antagonist/Inverse Agonist KW-6356 and Its Active Metabolite Following Single and Multiple Oral Administration in Healthy Individuals and Patients with Parkinson's Disease.

KW-6356 is a selective antagonist and inverse agonist of the adenosine A2A receptor. The primary aim of the present analysis was to characterize the pharmacokinetics (PK) of KW-6356 and its active metabolite M6 in healthy subjects and patients with Parkinson's disease (PD). We pooled concentration-time data from healthy subjects and patients with PD who were administered KW-6356. Using these data, we developed a population PK model by sequentially fitting the KW-6356 parameters followed by the M6 parameters. A first-order absorption with a 1-compartment model for KW-6356 and a 1-compartment model for M6 best described the profiles. The covariates included in the final models were food status (fed/fasted/unknown) on first-order absorption rate constant, baseline serum albumin level on apparent clearance of KW-6356, and baseline body weight on apparent volume of distribution of KW-6356 and apparent clearance of M6. No covariate had a clinically meaningful impact on KW-6356 or M6 exposure.

Highly Sensitive Real-Time Monitoring of Adenosine Receptor Activities in Nonsmall Cell Lung Cancer Cells Using Carbon Nanotube Field-Effect Transistors.

Adenosine metabolism through adenosine receptors plays a critical role in lung cancer biology. Although recent studies showed the potential of targeting adenosine receptors as drug targets for lung cancer treatment, conventional methods for investigating receptor activities often suffer from various drawbacks, including low sensitivity and slow analysis speed. In this study, adenosine receptor activities in nonsmall cell lung cancer (NSCLC) cells were monitored in real time with high sensitivity through a carbon nanotube field-effect transistor (CNT-FET). In this method, we hybridized a CNT-FET with NSCLC cells expressing A2A and A2B adenosine receptors to construct a hybrid platform. This platform could detect adenosine, an endogenous ligand of adenosine receptors, down to 1 fM in real time and sensitively discriminate adenosine among other nucleosides. Furthermore, we could also utilize the platform to detect adenosine in complicated environments, such as human serum. Notably, our hybrid platform allowed us to monitor pharmacological effects between adenosine and other drugs, including dipyridamole and theophylline, even in human serum samples. These results indicate that the NSCLC cell-hybridized CNT-FET can be a practical tool for biomedical applications, such as the evaluation and screening of drug-candidate substances.

The Essential Role of Angiogenesis in Adenosine 2A Receptor Deficiency-mediated Impairment of Wound Healing Involving c-Ski via the ERK/CREB Pathways.

Adenosine receptor-mediated signaling, especially adenosine A2A receptor (A2AR) signaling, has been implicated in wound healing. However, the role of endothelial cells (ECs) in A2AR-mediated wound healing and the mechanism underlying this effect are still unclear. Here, we showed that the expression of A2AR substantially increased after wounding and was especially prominent in granulation tissue. The delaying effects of A2AR knockout (KO) on wound healing are due mainly to the effect of A2AR on endothelial cells, as shown with A2AR-KO and EC-A2AR-KO mice. Moreover, the expression of c-Ski, which is especially prominent in CD31-positive cells in granulation tissue, increased after wounding and was decreased by both EC-A2AR KO and A2AR KO. In human microvascular ECs (HMECs), A2AR activation induced EC proliferation, migration, tubule formation and c-Ski expression, whereas c-Ski depletion by RNAi abolished these effects. Mechanistically, A2AR activation promotes the expression of c-Ski through an ERK/CREB-dependent pathway. Thus, A2AR-mediated angiogenesis plays a critical role in wound healing, and c-Ski is involved mainly in the regulation of angiogenesis by A2AR via the ERK/CREB pathway. These findings identify A2AR as a therapeutic target in wound repair and other angiogenesis-dependent tissue repair processes.

The adenosine A2A receptor in human sperm: its role in sperm motility and association with in vitro fertilization outcomes.

The involvement of ATP and cAMP in sperm function has been extensively documented, but the understanding of the role of adenosine and adenosine receptors remains incomplete. This study aimed to examine the presence of adenosine A2A receptor (A2AR) and study the functional role of A2AR in human sperm. The presence and localization of A2AR in human sperm were examined by western blotting and immunofluorescence assays. The functional role of A2AR in sperm was assessed by incubating human sperm with an A2AR agonist (regadenoson) and an A2AR antagonist (SCH58261). The sperm level of A2AR was examined by western blotting in normozoospermic and asthenozoospermic men to evaluate the association of A2AR with sperm motility and in vitro fertilization (IVF) outcomes. A2AR with a molecular weight of 43 kDa was detected in the tail of human sperm. SCH58261 decreased the motility, penetration ability, intracellular Ca2+ concentration, and CatSper current of human sperm. Although regadenoson did not affect these sperm parameters, it alleviated the adverse effects of SCH58261 on these parameters. In addition, the mean level of A2AR in sperm from asthenozoospermic men was lower than that in sperm from normozoospermic men. The sperm level of A2AR was positively correlated with progressive motility. Furthermore, the fertilization rate during IVF was lower in men with decreased sperm level of A2AR than in men with normal sperm level of A2AR. These results indicate that A2AR is important for human sperm motility and is associated with IVF outcome.

Adenosine A2a Receptor Polymorphisms and Susceptibility to Anxiety Disorders.

Anxiety disorders (ADs) are a group of mental disorders characterized by feelings of tension, fear, and excessive worrying in the face of life experiences. Aberrant signaling of adenosine A2a receptor (ADORA2A) is believed to be involved in the pathogenesis of ADs. Polymorphisms in the ADORA2A gene were shown to be associated with some of the patterns presented by ADs. The results of these studies have been inconsistent, making it hard to draw definitive conclusions. Therefore, this study performed a systematic review to clarify the associations between ADORA2A gene polymorphisms and ADs susceptibility. PubMed/Medline, Web of Science, and Scopus database using appropriate keywords, then screened for separation of suitable studies based on inclusion/exclusion criteria. Collectively, rs5751876 (1976T>C or previously 1083C>T) and rs35060421 (2592C>Tins) polymorphisms of ADORA2A were associated with an increased susceptibility to ADs. Moreover, rs2298383 TT genotype may be the causal regulatory factor, and ADORA2A T/C (rs2298383/rs3761422) haplotypes have significant susceptibility to ADs development. Additional research is needed to further define the role of ADORA2A gene polymorphisms in the pathogenesis of ADs.

Adenosine A2A receptor as a potential regulator of Mycobacterium leprae survival mechanisms: new insights into leprosy neural damage.

Leprosy is a chronic infectious disease caused by Mycobacterium leprae, which can lead to a disabling neurodegenerative condition. M. leprae preferentially infects skin macrophages and Schwann cells-glial cells of the peripheral nervous system. The infection modifies the host cell lipid metabolism, subverting it in favor of the formation of cholesterol-rich lipid droplets (LD) that are essential for bacterial survival. Although researchers have made progress in understanding leprosy pathogenesis, many aspects of the molecular and cellular mechanisms of host-pathogen interaction still require clarification. The purinergic system utilizes extracellular ATP and adenosine as critical signaling molecules and plays several roles in pathophysiological processes. Furthermore, nucleoside surface receptors such as the adenosine receptor A2AR involved in neuroimmune response, lipid metabolism, and neuron-glia interaction are targets for the treatment of different diseases. Despite the importance of this system, nothing has been described about its role in leprosy, particularly adenosinergic signaling (AdoS) during M. leprae-Schwann cell interaction. M. leprae was purified from the hind footpad of athymic nu/nu mice. ST88-14 human cells were infected with M. leprae in the presence or absence of specific agonists or antagonists of AdoS. Enzymatic activity assays, fluorescence microscopy, Western blotting, and RT-qPCR analysis were performed. M. leprae viability was investigated by RT-qPCR, and cytokines were evaluated by enzyme-linked immunosorbent assay. We demonstrated that M. leprae-infected Schwann cells upregulated CD73 and ADA and downregulated A2AR expression and the phosphorylation of the transcription factor CREB (p-CREB). On the other hand, activation of A2AR with its selective agonist, CGS21680, resulted in: 1) reduced lipid droplets accumulation and pro-lipogenic gene expression; 2) reduced production of IL-6 and IL-8; 3) reduced intracellular M. leprae viability; 4) increased levels of p-CREB. These findings suggest the involvement of the AdoS in leprosy neuropathogenesis and support the idea that M. leprae, by downmodulating the expression and activity of A2AR in Schwann cells, decreases A2AR downstream signaling, contributing to the maintenance of LD accumulation and intracellular viability of the bacillus.

Expression of Concern: Adenosine A2A Receptor: A Target for Regulating Renal Interstitial Fibrosis in Obstructive Nephropathy.

Expression of Concern: Adenosine A2A Receptor: A Target for Regulating Renal Interstitial Fibrosis in Obstructive Nephropathy.

Unlocking the adenosine receptor mechanism of the tumour immune microenvironment.

The suppressive tumour microenvironment significantly hinders the efficacy of immunotherapy in treating solid tumors. In this context, stromal cells, such as tumour-associated fibroblasts, undergo changes that include an increase in the number and function of immunosuppressive cells. Adenosine, a factor that promotes tumour growth, is produced from ATP breakdown and is markedly elevated in the tumour microenvironment. It acts through specific binding to adenosine receptors, with A2A and A2B adenosine receptor being primary drivers of immunosuppression. This paper presents the roles of various adenosine receptors in different tumour microenvironments. This review focus on the function of adenosine receptors in the stromal cells and non-cellular components of the tumour microenvironment. Additionally, we summarize and discuss recent advances and potential trends in using adenosine receptor antagonists combined with immunotherapy.

A2A adenosine receptor stimulation ameliorated diabetic-induced osteoporosis in rats.

Diabetic osteoporosis is a common health problem that is associated with a disruption in bone metabolism. A2A adenosine receptor (A2AAR) signaling seems to play a critical role in bone homeostasis. This study aimed to evaluate the effect of A2AAR stimulation on the treatment of diabetic-induced osteoporosis versus insulin treatment. Forty adult male rats were allocated into control (C), untreated diabetic-induced osteoporosis (DIO), insulin-treated DIO (I-DIO), and A2AAR agonist-treated DIO (A-DIO) groups. Both insulin and A2AAR agonist treatments significantly increased serum insulin level, glutathione peroxidase (GPx) activity, bone expression of osteoprotegerin (Opg) and β-catenin (Ctnnb1), and cortical and trabecular bone thickness, whereas they decreased serum fasting glucose, malondialdehyde (MDA), tumor necrosis factor α (TNF-α), bone expression of receptor activator of nuclear factor kappa-B ligand (Rankl), runt-related transcription factor-2 (Runx2), and sclerostin (Sost) versus the untreated DIO groups. A2AAR agonist treatment was more effective than insulin in ameliorating diabetic osteoporosis. This might be attributed to the upregulation of β-catenin gene expression, enhancing its anabolic effect on bone, in addition to the A2AAR agonist's anti-oxidative, anti-inflammatory, and anti-diabetic effects.

A novel A2a adenosine receptor inhibitor effectively mitigates hepatic fibrosis in a metabolic dysfunction-associated steatohepatitis mouse model.

Hepatic fibrosis exacerbates mortality and complications in progressive metabolic dysfunction-associated steatohepatitis (MASH). The role of the adenosine 2A receptor (A2aAR) in hepatic fibrosis within the context of MASH remains uncertain. This study aims to elucidate the involvement of the A2aAR signaling pathway and the efficacy of a novel potent A2aAR antagonist in treating hepatic fibrosis in MASH-induced mice fed a chlorine-deficient, L-amino acid-defined, high fat diet (CDAHFD). A2aAR overexpression in LX-2 cells increased fibrosis markers, whereas the known A2aAR antagonist, ZM241385, decreased these markers. A novel A2aAR antagonist, RAD11, not only attenuated fibrosis progression but also exhibited greater inhibition of the A2aAR signaling pathway compared to ZM241385 in mice with MASH, activated primary hepatocytes, and LX-2 cells. RAD11 exhibited a dual antifibrotic mechanism by targeting both activated HSCs and hepatocytes. Its superior antifibrotic efficacy over ZM241385 in the MASH condition stems from its ability to suppress A2aAR-mediated signaling, inhibit HSC activation, reduce hepatic lipogenesis in hepatocytes, and mitigate lipid accumulation-induced oxidative stress-mediated liver damage. This study has shed light on the relationship between A2aAR signaling and hepatic fibrosis, presenting RAD11 as a potent therapeutic agent for managing MASH and hepatic fibrosis.

Adenosine A2A Receptor Agonist, Polydeoxyribonucleotide Treatment Improves Locomotor Function and Thermal Hyperalgesia Following Neuropathic Pain in Rats.

Lithotomy position has been widely used in the various urologic surgery. Occasionally sensory and motor problems of the lower extremities are occurred due to the lithotomy position and these deficits may be related with sciatic nerve injury (SNI). Inflammatory process is a factor to induce functional impairment after SNI. Therefore, we evaluated the role of adenosine A2A receptor agonists, polydeoxyribonucleotide (PDRN) showing anti-inflammatory effect on locomotor function following SNI in rats. Sciatic nerve was compressed with surgical clips for 1 minute after exposing of right sciatic nerve. After 3 days of SNI, PDRN (2, 4, and 8 mg/kg) was applied to the damaged area of sciatic nerve once daily for 10 days. Walking track analysis was conducted for locomotor function and plantar test was performed for thermal pain sensitivity. Level of cyclic adenosine-3´,5´-monophosphate (cAMP) were measured using enzyme-linked immunosorbent assay. Western blot analysis was performed for tumor necrosis factor (TNF)-α, interleukin (IL)-1β, cAMP response element binding protein (CREP), vascular endothelial growth factor (VEGF). Immunofluorescence for neurofilament was also conducted. Locomotor function was decreased and thermal pain sensitivity was increased by SNI. SNI enhanced proinflammatory cytokines' production, such as TNF-α and IL-1β, while suppressed CREP phosphorylation and cAMP level. SNI also reduced the expression of VEGF and neurofilaments. However, treatment with PDRN inhibited proinflammatory cytokines' production and upregulated CREP phosphorylation and cAMP expression. PDRN also enhanced the expression of VEGF and neurofilaments. As a result, PDRN improved locomotor function and alleviated thermal hyperalgesia after SNI. PDRN has shown potential to be used as an effective treatment for neuropathic pain.