Role Of Adenosine A2A Receptors Research Articles

Repeated caffeine intake suppresses cerebral grey matter responses to chronic sleep restriction in an A1 adenosine receptor-dependent manner: a double-blind randomized controlled study with PET-MRI

Evidence has shown that both sleep loss and daily caffeine intake can induce changes in grey matter (GM). Caffeine is frequently used to combat sleepiness and impaired performance caused by insufficient sleep. It is unclear (1) whether daily use of caffeine could prevent or exacerbate the GM alterations induced by 5-day sleep restriction (i.e. chronic sleep restriction, CSR), and (2) whether the potential impact on GM plasticity depends on individual differences in the availability of adenosine receptors, which are involved in mediating effects of caffeine on sleep and waking function. Thirty-six healthy adults participated in this double-blind, randomized, controlled study (age = 28.9 ± 5.2 y/; F:M = 15:21; habitual level of caffeine intake < 450 mg; 29 homozygous C/C allele carriers of rs5751876 of ADORA2A, an A2A adenosine receptor gene variant). Each participant underwent a 9-day laboratory visit consisting of one adaptation day, 2 baseline days (BL), 5-day sleep restriction (5 h time-in-bed), and a recovery day (REC) after an 8-h sleep opportunity. Nineteen participants received 300 mg caffeine in coffee through the 5 days of CSR (CAFF group), while 17 matched participants received decaffeinated coffee (DECAF group). We examined GM changes on the 2nd BL Day, 5th CSR Day, and REC Day using magnetic resonance imaging and voxel-based morphometry. Moreover, we used positron emission tomography with [18F]-CPFPX to quantify the baseline availability of A1 adenosine receptors (A1R) and its relation to the GM plasticity. The results from the voxel-wise multimodal whole-brain analysis on the Jacobian-modulated T1-weighted images controlled for variances of cerebral blood flow indicated a significant interaction effect between caffeine and CSR in four brain regions: (a) right temporal-occipital region, (b) right dorsomedial prefrontal cortex (DmPFC), (c) left dorsolateral prefrontal cortex (DLPFC), and (d) right thalamus. The post-hoc analyses on the signal intensity of these GM clusters indicated that, compared to BL, GM on the CSR day was increased in the DECAF group in all clusters but decreased in the thalamus, DmPFC, and DLPFC in the CAFF group. Furthermore, lower baseline subcortical A1R availability predicted a larger GM reduction in the CAFF group after CSR of all brain regions except for the thalamus. In conclusion, our data suggest an adaptive GM upregulation after 5-day CSR, while concomitant use of caffeine instead leads to a GM reduction. The lack of consistent association with individual A1R availability may suggest that CSR and caffeine affect thalamic GM plasticity predominantly by a different mechanism. Future studies on the role of adenosine A2A receptors in CSR-induced GM plasticity are warranted.

Berberine attenuates epithelial mesenchymal transition in bleomycin-induced pulmonary fibrosis in mice via activating A2aR and mitigating the SDF-1/CXCR4 signaling

AimsBerberine is endowed with anti-oxidant, anti-inflammatory and anti-fibrotic effects. This study explored the role of adenosine A2a receptor (A2aR) activation and SDF-1/CXCR4 signaling suppression in the protective effects of berberine in bleomycin-induced pulmonary fibrosis in mice. Main methodsPulmonary fibrosis was generated in mice by injecting bleomycin (40 U/kg, i.p.) on days 0, 3, 7, 10 and 14. Mice were treated with berberine (5 mg/kg, i.p.) from day 15 to day 28. Key findingsSevere lung fibrosis and increased collagen content were observed in the bleomycin-challenged mice. Pulmonary A2aR downregulation was documented in bleomycin-induced pulmonary fibrosis animals and was accompanied by enhanced expression of SDF-1/CXCR4. Moreover, TGF-β1elevation and pSmad2/3 overexpression were reported in parallel with enhanced epithelial mesenchymal transition (EMT) markers expression, vimentin and α-SMA. Besides, bleomycin significantly elevated the inflammatory and pro-fibrogenic mediator NF-κB p65, TNF-α and IL-6. Furthermore, bleomycin administration induced oxidative stress as depicted by decreased Nrf2, SOD, GSH and catalase levels. Interestingly, berberine administration markedly ameliorated the fibrotic changes in lungs by modulating the purinergic system through the inhibition of A2aR downregulation, mitigating EMT and effectively suppressing inflammation and oxidative stress. Strikingly, A2aR blockade by SCH 58261, impeded the pulmonary protective effect of berberine. SignificanceThese findings indicated that berberine could attenuate the pathological processes of bleomycin-induced pulmonary fibrosis at least partially via upregulating A2aR and mitigating the SDF-1/CXCR4 related pathway, suggesting A2aR as a potential therapeutic target for the management of pulmonary fibrosis.

Role of adenosine A2a receptor in cancers and autoimmune diseases.

Adenosine receptors are P1 class of purinergic receptors that belong to G protein-coupled receptors. There are 4 subtypes of adenosine receptors, namely A1, A2A, A2B, and A3. A2AR has a high affinity for the ligand adenosine. Under pathological conditions or external stimuli, ATP is sequentially hydrolyzed to adenosine by CD39 and CD73. The combination of adenosine and A2AR can increase the concentration of cAMP and activate a series of downstream signaling pathways, and further playing the role of immunosuppression and promotion of tumor invasion. A2AR is expressed to some extent on various immune cells, where it is abnormally expressed on immune cells in cancers and autoimmune diseases. A2AR expression also correlates with disease progression. Inhibitors and agonists of A2AR may be potential new strategies for treatment of cancers and autoimmune diseases. We herein briefly reviewed the expression and distribution of A2AR, adenosine/A2AR signaling pathway, expression, and potential as a therapeutic target.

Role of adenosine A2A receptors in hot and cold cognition: Effects of single-dose istradefylline in healthy volunteers

The role of the adenosine neurochemical system in human cognition is under-studied, despite such receptors being distributed throughout the brain. The aim of this study was to shed light on the role of the adenosine A2A receptors in human cognition using single-dose istradefylline. Twenty healthy male participants, aged 19–49, received 20 mg istradefylline and placebo, in a randomized, double-blind, placebo-controlled cross-over design. Cognition was assessed using computerized cognitive tests, covering both cold (non-emotional) and hot (emotion-laden) domains. Cardiovascular data were recorded serially. Cognitive effects of istradefylline were explored using repeated measures analysis of variance and paired t-tests as appropriate. On the EMOTICOM battery, there was a significant effect of istradefylline versus placebo on the Social Information Preference task (t = 2.50, p = 0.02, d=-0.59), indicating that subjects on istradefylline interpreted social situations more positively. No other significant effects were observed on other cognitive tasks, nor in terms of cardiovascular measures (pulse and blood pressure). De-briefing indicated that blinding was successful, both for participants and the research team. Further exploration of the role of adenosine A2A receptors in emotional processing may be valuable, given that abnormalities in related cognitive functions are implicated in neuropsychiatric disorders. The role of adenosine systems in human cognition requires further clarification, including with different doses of istradefylline and over different schedules of administration.

Accumbal adenosine A2A receptor inactivation biases for large and costly rewards in the effort- but not delay-based decision making

The cost-benefit decision-making (CBDM) is critical to normal human activity and a diminished willingness to expend effort to obtain rewards is a prevalent/noted characteristic of neuropsychiatric disorders such as schizophrenia, Parkinson's disease. Numerous studies have identified nucleus accumbens (NAc) as an important locus for CBDM control but their neuromodulatory and behavioral mechanisms remain largely under-explored. Adenosine A2A receptors (A2ARs), which are highly concentrated in the striatopallidal neurons, can integrate glutamate and dopamine signals for controlling effort-related choice behaviors. While the involvement of A2ARs in effort-based decision making is well documented, the role of other decision variables (reward discrimination) in effort-based decision making and the role of A2AR in delay-based decision making are less clear. In this study, we have developed a well-controlled CBDM behavioral paradigm to manipulate effort/cost and reward independently or in combination, allowing a dissection of four behavioral elements: effort-based CBDM (E-CBDM), delay-based CBDM (D-CBDM), reward discrimination (RD), effort discrimination (ED), and determined the effect of genetic knockdown (KD) of NAc A2AR on the four behavioral elements. We found that A2AR KD in NAc increased the choice for larger, more costly reward in the E-CBDM, but not D-CBDM. Furthermore, this high-effort/high-reward bias was attributable to the increased willingness to engage in effort but not the effect of discrimination of reward magnitude. Our findings substantiate an important role of the NAc A2AR in control of E-CBDM and support that pharmacologically targeting NAc A2ARs would be a useful strategy for treating the aberrant effort-based decision making in neuropsychiatric disorders.

Adenosine-A2A Receptor Signaling Plays a Crucial Role in Sudden Unexpected Death in Epilepsy.

Adenosinergic activities are suggested to participate in SUDEP pathophysiology; this study aimed to evaluate the adenosine hypothesis of SUDEP and specifically the role of adenosine A2A receptor (A2AR) in the development of a SUDEP mouse model with relevant clinical features. Using a combined paradigm of intrahippocampal and intraperitoneal administration of kainic acid (KA), we developed a boosted-KA model of SUDEP in genetically modified adenosine kinase (ADK) knockdown (Adk+/-) mice, which has reduced ADK in the brain. Seizure activity was monitored using video-EEG methods, and in vivo recording of local field potential (LFP) was used to evaluate neuronal activity within the nucleus tractus solitarius (NTS). Our boosted-KA model of SUDEP was characterized by a delayed, postictal sudden death in epileptic mice. We demonstrated a higher incidence of SUDEP in Adk+/- mice (34.8%) vs. WTs (8.0%), and the ADK inhibitor, 5-Iodotubercidin, further increased SUDEP in Adk+/- mice (46.7%). We revealed that the NTS level of ADK was significantly increased in epileptic WTs, but not in epileptic Adk+/- mutants, while the A2AR level in NTS was increased in epileptic (WT and Adk+/-) mice vs. non-epileptic controls. The A2AR antagonist, SCH58261, significantly reduced SUDEP events in Adk+/- mice. LFP data showed that SCH58261 partially restored KA injection-induced suppression of gamma oscillation in the NTS of epileptic WT mice, whereas SCH58261 increased theta and beta oscillations in Adk+/- mutants after KA injection, albeit with no change in gamma oscillations. These LFP findings suggest that SCH58261 and KA induced changes in local neuronal activities in the NTS of epileptic mice. We revealed a crucial role for NTS A2AR in SUDEP pathophysiology suggesting A2AR as a potential therapeutic target for SUDEP risk prevention.

Allosteric Modulation of Adenosine A2A Receptors as a New Therapeutic Avenue.

The therapeutic potential of targeting adenosine A2A receptors (A2ARs) is immense due to their broad expression in the body and central nervous system. The role of A2ARs in cardiovascular function, inflammation, sleep/wake behaviors, cognition, and other primary nervous system functions has been extensively studied. Numerous A2AR agonist and antagonist molecules are reported, many of which are currently in clinical trials or have already been approved for treatment. Allosteric modulators can selectively elicit a physiologic response only where and when the orthosteric ligand is released, which reduces the risk of an adverse effect resulting from A2AR activation. Thus, these allosteric modulators have a potential therapeutic advantage over classical agonist and antagonist molecules. This review focuses on the recent developments regarding allosteric A2AR modulation, which is a promising area for future pharmaceutical research because the list of existing allosteric A2AR modulators and their physiologic effects is still short.

A maestro role of adenosine A2A receptors in GABAergic synapses stabilization during postnatal neuronal maturation.

A maestro role of adenosine A2A receptors in GABAergic synapses stabilization during postnatal neuronal maturation.

A major role for adenosine A2A receptor in the interaction between astrocytes and myelinated neurons: possible implications for the therapy of neurodegenerative disorders.

A major role for adenosine A2A receptor in the interaction between astrocytes and myelinated neurons: possible implications for the therapy of neurodegenerative disorders.

Adenosine A2A Receptor in Bone Marrow-Derived Cells Mediated Macrophages M2 Polarization via PPARγ-P65 Pathway in Chronic Hypoperfusion Situation.

Background: The role of adenosine A2A receptor (A2AR) in the ischemic white matter damage induced by chronic cerebral hypoperfusion remains obscure. Here we investigated the role of A2AR in the process of macrophage polarizations in the white matter damage induced by chronic cerebral hypoperfusion and explored the involved signaling pathways.Methods: We combined mouse model and macrophage cell line for our study. White matter lesions were induced in A2AR knockout mice, wild-type mice, and chimeric mice generated by bone marrow cells transplantation through bilateral common carotid artery stenosis. Microglial/macrophage polarization in the corpus callosum was detected by immunofluorescence. For the cell line experiments, RAW264.7 macrophages were treated with the A2AR agonist CHS21680 or A2AR antagonist SCH58261 for 30 min and cultured under low-glucose and hypoxic conditions. Macrophage polarization was examined by immunofluorescence. The expression of peroxisome proliferator activated receptor gamma (PPARγ) and transcription factor P65 was examined by western blotting and real-time polymerase chain reaction (RT-PCR). Inflammatory cytokine factors were assessed by enzyme-linked immunosorbent assay (ELISA) and RT-PCR.Results: Both global A2AR knockout and inactivation of A2AR in bone marrow-derived cells enhanced M1 marker expression in chronic ischemic white matter lesions. Under low-glucose and hypoxic conditions, CGS21680 treatment promoted macrophage M2 polarization, increased the expression of PPARγ, P65, and interleukin-10 (IL-10) and suppressed the expression of tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β). The CGS21680-induced upregulation of P65 and IL-10 was abolished in macrophages upon PPARγ knockdown. The downregulation of TNF-α and IL-1β by CGS21680 was less affected by PPARγ knockdown.Conclusions: In the cerebral hypoperfusion induced white matter damage, A2AR signaling in bone marrow-derived cells induces macrophage M2 polarization and increases the expression of the anti-inflammatory factor IL-10 via the PPARγ-P65 pathway, both of which might explain its neuroprotective effect.

A2A Adenosine Receptor as a Potential Biomarker and a Possible Therapeutic Target in Alzheimer's Disease.

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.

SCH58261, the antagonist of adenosine A2A receptor, alleviates cadmium-induced preeclampsia via sirtiun-1/hypoxia-inducible factor-1α pathway in rats.

To identify the role of adenosine A2A receptor (A2AR) in cadmium-induced preeclampsia (PE) rats and the potential molecular mechanism. The expression of A2AR in placentae obtained from PE women and normal pregnant (NP) women were measured. The pregnant rats were randomly divided into four groups, including NP rats, PE rats, SCH+NP rats, and SCH+PE rats. The 0.125 mg/kg/d CdCl2 was used to establish a PE rat model in PE and SCH+PE rats. SCH58261 was used as the specific antagonist of A2AR with a concentration of 0.2 mg/kg in SCH+NP and SCH+PE rats. The conditions of mother, foetus, and placenta were tested. The placental expression of A2AR, sirtuin-1 (sirt1), and Hypoxia-Inducible Factor-1α (HIF-1α) was measured by Western blot (WB) and immunohistochemistry (IHC) staining. A2AR and HIF-1α increased, and sirt1 decreased in placenta in both PE women and cadmium-induced PE rats. After treatment with SCH58261, the sirt1 increased and HIF-1a decreased in cadmium-induced PE rats along with the amelioration of maternal outcomes, foetal and placental growth. This paper firstly revealed that placental A2AR mediated cadmium-induced PE, and A2AR suppression could attenuate placental impairment by acting on the expression of sirt1 and sirt1-mediated regulation of HIF-1α.

Activation of adenosine A2a receptor accelerates and A2a receptor antagonist reduces intermittent hypoxia induced PC12 cell injury via PKC-KATP pathway

Obstructive sleep apnea hypopnea syndrome (OSAHS) is associated with multiple system diseases. Neurocognitive dysfunction resulting from central nervous system complications has been reported, especially in children with OSAHS. Chronic intermittent hypoxia is accepted to be the major pathophysiological mechanism of OSAHS. Adenosine plays an important role in cellular function via interactions with its receptors. A2a receptor has been recognized as a factor involved in neuroprotection. However, the role of adenosine A2a receptor in intermittent hypoxia induced cellular injury is not completely understood. In this study, we aim to investigate the underlying mechanisms of A2a receptor mediated cellular damage caused by intermittent hypoxia in PC12 cells. We found that activated A2a receptor by CGS21680 decreased cellular viability, increased PKC as well as ATP-sensitive potassium channel (KATP) subunits expression Kir6.2 and SUR1. Inhibition of A2a receptor by SCH58261 increased cellular viability, suppressed PKC and SUR1 expression level, ultimately showing a protective role in PC12 cells. Moreover, we observed that CHE, which is an antagonist of PKC, downregulated Kir6.2 and SUR1 expression and increased cellular viability. Additionally, we found that A2a receptor activation induced cell injury was associated with increased Cleaved-Caspase 3 expression, which can be decreased by inhibition of A2a receptor or PKC. In conclusion, our findings indicate that A2a receptor induced KATP expression by PKC activation and plays a role in accelerating PC12 cells injury induced by intermittent hypoxia exposure via A2a-PKC-KATP signal pathway mediated apoptosis.

Adenosine A2A Receptor Mediates Inhibition of Synovitis and Osteoclastogenesis after Electroacupuncture in Rats with Collagen-Induced Arthritis.

Background This study was to investigate the role of adenosine A2A receptors (A2AR) in inhibiting the effect of electroacupuncture (EA) on osteoclastogenesis in collagen-induced arthritis (CIA). Methods Wistar rats were divided into four groups: sham-control group, CIA-control group, CIA-EA group, and CIA-EA-SCH58261 (A2AR antagonist) group. We detected tumor necrosis factor-α (TNF-α), nuclear transcription factor-κB (NF-κB), receptor activator of NF-κB ligand (RANKL), protein kinase A (PKA), and extracellular regulatory protein kinase 1/2 (ERK1/2) in peripheral blood by ELISA. PKA, ERK1/2, and NF-κB in ankle joints were determined by western blotting. We evaluated the arthritis damage by histological examination and determined the number of osteoclasts by tartrate-resistant acid phosphatase (TRAP) staining. Results EA treatment downregulated the expression of TNF-α, RANKL, PKA, ERK1/2, and NF-κB in peripheral blood but increased the levels of PKA and ERK1/2 in ankle joints. Importantly, EA treatment reduced bone erosion as evidenced by the histological findings and inhibited osteoclastogenesis as revealed by TRAP staining. All these effects of the EA treatment were reversed by combining EA treatment with the A2AR antagonist SCH58261. Conclusion Our data suggest that EA treatment activated A2AR. The effects of the A2AR antagonist SCH58261 suggest that the inhibition of osteoclast formation, the inhibition of TNF-α, RANKL, and NF-κB expression, and the increase of ERK1/2 are all dependent on this EA-induced A2AR activation. It is therefore likely that these pathways with clearly defined roles in inflammation and bone erosion are at least partially involved in the mediation of the inhibition of synovitis and osteoclast formation induced by EA.

Adenosine A2A Receptor Stimulation Inhibits TCR-Induced Notch1 Activation in CD8+T-Cells.

Notch receptors signaling is required for optimal T-cell activation and function. T-cell receptor (TCR) engagement can activate Notch receptors in T-cells in a ligand-independent fashion. In this study, we examined the role of adenosine A2A receptor (A2AR) signaling pathway in regulating the activity of Notch1 induced by TCR stimulation in CD8+T-cells. A selective A2AR agonist decreased Notch1 protein expression and Notch1 cleavage, and reduced transcripts of Notch1-target genes Hes1 and Myc in activated CD8+T-cells. Inhibition of TCR-induced Notch1 expression by an A2AR agonist was accompanied by increased cAMP concentration and mimicked by forskolin. This effect was associated with reduced IFN-γ and granzyme B production. The effect of an A2AR agonist was abrogated by a selective A2AR antagonist and absent in CD8+T-cells harvested from A2AR−/− mice. Stimulation of A2AR reduced Notch1 receptor levels by inhibiting upstream TCR signals, including ZAP70 phosphorylation, in turn impairing the generation of the active Notch1 intracellular domain (N1ICD). Direct activation of PKC with PMA and ionomycin bypassed A2AR-induced Notch1 inhibition. Overexpression of N1ICD in CD8+T-cells prevented the suppressive effects of an A2AR agonist on proliferation and cytokine release during activation. Our results identify the A2AR signaling pathway as an important regulator of TCR-induced Notch1 receptor activation in CD8+T-cells, and Notch as an important target of the immune suppressive effects of A2AR. We propose a mechanism whereby A2AR impairs CD8 T-cells function through inhibition of Notch1 receptor activation.

Ischemia postconditioning protects dermal microvascular endothelial cells of rabbit epigastric skin flaps against apoptosis via adenosine A2a receptors

Background: It has been shown that endogenous adenosine-induced by ischemia postconditioning attenuates apoptosis in recent studies; however, they focus only on parenchymal cells. The detailed mechanism has not been clearly clarified in any research and the subtype of adenosine receptors involved remains unknown. In our study, dermal microvascular endothelial cells (DMECs) are used to explore the role of adenosine A2a receptor in the anti-apoptotic effects of ischemic postconditioning.Material and methods: The epigastric skin flaps of rabbits were elevated. After 4 h of ischemia, the flaps were either abruptly reperfused or postconditioned by six cycles of brief reperfusion (15s) and re-ischemia (15s). Adenosine A2a receptor agonist (CGS-21680) and antagonist (ZM-241385) were used separately in other groups. The apoptosis-related proteins and adenosine A2a receptors were determined by immunohistochemical staining. Then apoptosis index was calculated by TUNEL.Results: Ischemia/reperfusion caused severe damages in DMECs of flaps as demonstrated by an increase in apoptosis index and an increase in expressions of apoptosis-related proteins, which can be significantly attenuated by IPC treatment or exposure to a selective adenosine A2a receptor agonist (all p values <.05). Meanwhile, the anti-apoptosis effects of IPC can be blocked by a selective adenosine A2a receptor antagonist. Statistical analysis revealed that the increase of apoptosis index closely correlated inversely with the relative increase of adenosine A2a receptors (p < .0001).Conclusions: Ischemia postconditioning protects DMECs of rabbit skin flap against apoptosis via activation of adenosine A2a receptors.

Putative role of adenosine A2A receptors in promoting remyelination through adult oligodendrogenesis in the EAE Model

Event Abstract Back to Event Putative role of adenosine A2A receptors in promoting remyelination through adult oligodendrogenesis in the EAE Model Marta A. Gomes1, 2, Joana M. Mateus1, 2, Ana M. Sebastião1, 2 and Sara Xapelli1, 2* 1 Institute of Pharmacology and Neurosciences, Faculty of Medicine, University of Lisbon, Portugal 2 Institute of Molecular Medicine, Faculty of Medicine, University of Lisbon, Portugal Multiple Sclerosis (MS) is a chronic neuroinflammatory autoimmune demyelinating disease of the central nervous system (CNS). MS pathogenesis begins with an exacerbated inflammatory response that deteriorates the myelin sheath, produced by oligodendrocytes (OLGs) in the CNS, which insulates neuronal axons. Myelinating OLGs result from the differentiation of oligodendrocyte progenitor cells (OPCs) present in the brain parenchyma but also from neural stem cells (NSCs) of the subventricular zone (SVZ) neurogenic niche. Previous studies have reported a spontaneous phenomenon of remyelination in MS, through the migration of OLGs to demyelinated areas. Furthermore, adenosine A2A Receptors (A2AR) have been shown to have a protective role against inflammation in Experimental Autoimmune Encephalomyelitis (EAE), an animal model of MS, attenuating the phenotype of the disease. However, A2AR role in modulating adult oligodendrogenesis under EAE pathogenesis has never been studied. Thus, this project aimed to assess the role of A2AR in promoting OLGs differentiation and myelination under EAE pathogenesis. Female C57BL/6 mice were immunized with MOG35-55 and injected with Pertussis toxin to induce EAE. EAE mice were administered in the lateral ventricle with vehicle or with A2AR agonist (CGS21680, 100 nM) for 26 days using micro-osmotic pumps. Behavioural tests were performed to evaluate EAE model progression, along with cellular and molecular analyses to assess A2AR agonist influence on inflammation, OLG differentiation and de- and remyelination. Overall, EAE disease incidence was of only 40% which constrained the significance of the results. EAE animals showed impaired performance in behavioral tests as EAE phenotype was progressing, although no differences were observed between the vehicle and the CGS21680 groups. Moreover, no tendencies for changes were observed at the molecular level, regarding either inflammatory and cell differentiation signaling pathways. Regarding demyelination, both luxol fast blue assay and immunohistochemical staining for myelin proteins showed that myelin amounts in both EAE vehicle and CGS21680 animals were similar to control animals. Taken together, EAE induction protocol and CGS21680 dose should be optimized to allow further conclusions on A2AR relevance for regenerative therapies in MS. Keywords: Multiple Sclerosis, EAE (experimental autoimmune encephalomyelitis), Adenosine A2A receptor (A2AR), Adult Oligodendrogenesis, remyelination Conference: XVI Meeting of the Portuguese Society for Neuroscience (SPN2019), Lisboa, Portugal, 30 May - 1 Jun, 2019. Presentation Type: Poster presentation Topic: Glia / Neuroinflammation Citation: Gomes MA, Mateus JM, Sebastião AM and Xapelli S (2019). Putative role of adenosine A2A receptors in promoting remyelination through adult oligodendrogenesis in the EAE Model. Front. Cell. Neurosci. Conference Abstract: XVI Meeting of the Portuguese Society for Neuroscience (SPN2019). doi: 10.3389/conf.fncel.2019.01.00008 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 27 Feb 2019; Published Online: 27 Sep 2019. * Correspondence: Dr. Sara Xapelli, Institute of Pharmacology and Neurosciences, Faculty of Medicine, University of Lisbon, Lisbon, Portugal, sxapelli@medicina.ulisboa.pt Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Marta A Gomes Joana M Mateus Ana M Sebastião Sara Xapelli Google Marta A Gomes Joana M Mateus Ana M Sebastião Sara Xapelli Google Scholar Marta A Gomes Joana M Mateus Ana M Sebastião Sara Xapelli PubMed Marta A Gomes Joana M Mateus Ana M Sebastião Sara Xapelli Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

A2a adenosine receptor agonist improves endoplasmic reticulum stress in MIN6 cell line through protein kinase A/ protein kinase B/ Cyclic adenosine monophosphate response element-binding protein/ and Growth Arrest And DNA-Damage-Inducible 34/ eukaryotic Initiation Factor 2α pathways.

Endoplasmic reticulum (ER) stress is one of the main molecular events underlying pancreatic beta cell (PBC) failure, apoptosis, and a decrease in insulin secretion. Recent studies have highlighted the fundamental role of A2a adenosine receptor (A2aR) in potentiation of insulin secretion and proliferation of PBCs. However, possible protective effects of A2aR signaling against ER stress have not been elucidated yet. Thus, in the present study, we aimed to investigate the effects of A2aR activation in MIN6 beta cells undergoing tunicamycin (TM)-mediated ER stress. A2aR expression and activity were evaluated using real-time polymerase chain reaction and measurement of the cyclic adenosine monophosphate (cAMP), protein kinase A (PKA), phospho-protein kinase B or Akt (p-Akt)/Akt, and phospho-Cyclic adenosine monophosphate response element-binding protein/CREB levels in response to a specific agonist (CGS 21680). Survival and proliferation in TM and CGS 21680 cotreated cells were evaluated using 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), annexin V-fluorescein isothiocyanate (FITC)/propidium iodide staining, colony formation, and 5-bromo-2'-deoxyuridine (Brdu) assays. In addition, the effects of A2aR stimulation on insulin secretion were evaluated using the enzyme-linked immunosorbent assay. B-cell lymphoma 2 (Bcl-2), phospho-eukaryotic Initiation Factor 2α (p-eIF2α)/eIF2α, growth arrest and DNA-damage-inducible 34 (GADD34), X-box binding protein 1 (XBP-1), spliced X-box binding protein 1 (XBP-1s), immunoglobulin heavy-chain-binding protein (BIP), and CCAAT-enhancer-binding protein homologous protein (CHOP) levels were evaluated using western blotting. Our results showed a decrease in A2aR expression and p-Akt/Akt and p-CREB/CREB levels in TM-pretreated cells. We also mentioned that CGS 21680 effectively increased cell survival, proliferation, and insulin secretion in TM-treated cells. The antiapoptotic effects were possibly mediated through Bcl-2 upregulation. Our western blotting results indicated that A2aR effectively downregulated p-eIF2α/eIF2α, XBP-1, XBP-1s, BIP, and CHOP levels, whereas GADD34 was upregulated. Altogether, the present study revealed that A2aR signaling through PKA/Akt/CREB mediators alleviated TM cytotoxicity effects in MIN6 beta cells. Thus, the stimulation of this receptor was seen as a new approach to control ER stress in the PBC cells.

Role of adenosine A2A receptors in motor control: relevance to Parkinson's disease and dyskinesia.

Adenosine is an endogenous purine nucleoside that regulates several physiological functions, at the central and peripheral levels. Besides, adenosine has emerged as a major player in the regulation of motor behavior. In fact, adenosine receptors of the A2A subtype are highly enriched in the caudate-putamen, which is richly innervated by dopamine. Moreover, several studies in experimental animals have consistently demonstrated that the pharmacological antagonism of A2A receptors has a facilitatory influence on motor behavior. Taken together, these findings have envisaged A2A receptors as a promising target for symptomatic therapies aimed at ameliorating motor deficits. Accordingly, A2A receptor antagonists have been extensively studied as new agents for the treatment of Parkinson's disease (PD), the epitome of motor disorders. In this review, we provide an overview of the effects that adenosine A2A receptor antagonists elicit in rodent and primate experimental models of PD, with regard to the counteraction of motor deficits as well as to manifestation of dyskinesia and motor fluctuations. Moreover, we briefly present the results of clinical trials of A2A receptor antagonists in PD patients experiencing motor fluctuations, with particular regard to dyskinesia. Finally, we discuss the interaction between A2A receptor antagonists and serotonin receptor agonists, since combined administration of these drugs has recently emerged as a new potential therapeutic strategy in the treatment of dyskinesia.

Impaired autophagic flux is associated with the severity of trauma and the role of A2AR in brain cells after traumatic brain injury

Recent studies have shown that after traumatic brain injury (TBI), the number of autophagosomes is markedly increased in brain cells surrounding the wound; however, whether autophagy is enhanced or suppressed by TBI remains controversial. In our study, we used a controlled cortical impact system to establish models of mild, moderate and severe TBI. In the mild TBI model, the levels of autophagy-related protein 6 (Beclin1) and autophagy-related protein 12 (ATG12)-autophagy-related protein 5 (ATG5) conjugates were increased, indicating the enhanced initiation of autophagy. Furthermore, the level of the autophagic substrate sequestosome 1 (SQSTM1) was decreased in the ipsilateral cortex. This result, together with the results observed in tandem mRFP-GFP-LC3 adeno-associated virus (AAV)-infected mice, indicates that autophagosome clearance was also increased after mild TBI. Conversely, following moderate and severe TBI, there was no change in the initiation of autophagy, and autophagosome accumulation was observed. Next, we used chloroquine (CQ) to artificially impair autophagic flux in the injured cortex of the mild TBI model and found that the severity of trauma was obviously exacerbated. In addition, autophagic flux and trauma severity were significantly improved in adenosine A2A receptor (A2AR) knockout (KO) mice subjected to moderate TBI. Thus, A2AR may be involved in regulating the impairment of autophagic flux in response to brain injury. Our findings suggest that whether autophagy is increased after TBI is associated with whether autophagic flux is impaired, and the impairment of autophagic flux exacerbates the severity of trauma. Furthermore, A2AR may be a target for alleviating the impairment in autophagic flux after TBI.