The adenosine modulation system mostly operates through inhibitory A1 (A1R) and facilitatory A2A receptors (A2AR) in the brain. The activity‐dependent release of adenosine acts as a brake of ...excitatory transmission through A1R, which are enriched in glutamatergic terminals. Adenosine sharpens salience of information encoding in neuronal circuits: high‐frequency stimulation triggers ATP release in the ‘activated’ synapse, which is locally converted by ecto‐nucleotidases into adenosine to selectively activate A2AR; A2AR switch off A1R and CB1 receptors, bolster glutamate release and NMDA receptors to assist increasing synaptic plasticity in the ‘activated’ synapse; the parallel engagement of the astrocytic syncytium releases adenosine further inhibiting neighboring synapses, thus sharpening the encoded plastic change. Brain insults trigger a large outflow of adenosine and ATP, as a danger signal. A1R are a hurdle for damage initiation, but they desensitize upon prolonged activation. However, if the insult is near‐threshold and/or of short‐duration, A1R trigger preconditioning, which may limit the spread of damage. Brain insults also up‐regulate A2AR, probably to bolster adaptive changes, but this heightens brain damage since A2AR blockade affords neuroprotection in models of epilepsy, depression, Alzheimer's, or Parkinson's disease. This initially involves a control of synaptotoxicity by neuronal A2AR, whereas astrocytic and microglia A2AR might control the spread of damage. The A2AR signaling mechanisms are largely unknown since A2AR are pleiotropic, coupling to different G proteins and non‐canonical pathways to control the viability of glutamatergic synapses, neuroinflammation, mitochondria function, and cytoskeleton dynamics. Thus, simultaneously bolstering A1R preconditioning and preventing excessive A2AR function might afford maximal neuroprotection.
The main physiological role of the adenosine modulation system is to sharp the salience of information encoding through a combined action of adenosine A2A receptors (A2AR) in the synapse undergoing an alteration of synaptic efficiency with an increased inhibitory action of A1R in all surrounding synapses. Brain insults trigger an up‐regulation of A2AR in an attempt to bolster adaptive plasticity together with adenosine release and A1R desensitization; this favors synaptotocity (increased A2AR) and decreases the hurdle to undergo degeneration (decreased A1R). Maximal neuroprotection is expected to result from a combined A2AR blockade and increased A1R activation.
This article is part of a mini review series: “Synaptic Function and Dysfunction in Brain Diseases”.
The main physiological role of the adenosine modulation system is to sharp the salience of information encoding through a combined action of adenosine A2A receptors (A2AR) in the synapse undergoing an alteration of synaptic efficiency with an increased inhibitory action of A1R in all surrounding synapses. Brain insults trigger an up‐regulation of A2AR in an attempt to bolster adaptive plasticity together with adenosine release and A1R desensitization; this favors synaptotocity (increased A2AR) and decreases the hurdle to undergo degeneration (decreased A1R). Maximal neuroprotection is expected to result from a combined A2AR blockade and increased A1R activation.
This article is part of a mini review series: “Synaptic Function and Dysfunction in Brain Diseases”.
Alzheimer's disease (AD) is the most common neurodegenerative disorder that affects the elderly. The increase of life-expectancy is transforming AD into a major health-care problem. AD is ...characterized by a progressive impairment of memory and other cognitive skills leading to dementia. The major pathogenic factor associated to AD seems to be amyloid-beta peptide (Aβ) oligomers that tend to accumulate extracellularly as amyloid deposits and are associated with reactive microglia and astrocytes as well as with degeneration of neuronal processes. The involvement of microglia and astrocytes in the onset and progress of neurodegenerative process in AD is becoming increasingly recognized, albeit it is commonly accepted that neuroinflammation and oxidative stress can have both detrimental and beneficial influences on the neural tissue. However, little is known about the interplay of microglia, astrocytes and neurons in response to Aβ, especially in the early phases of AD. This review discusses current knowledge about the involvement of neuroinflammation in AD pathogenesis, focusing on phenotypic and functional responses of microglia, astrocytes and neurons in this process. The abnormal production by glia cells of pro-inflammatory cytokines, chemokines and the complement system, as well as reactive oxygen and nitrogen species, can disrupt nerve terminals activity causing dysfunction and loss of synapses, which correlates with memory decline; these are phenomena preceding the neuronal death associated with late stages of AD. Thus, therapeutic strategies directed at controlling the activation of microglia and astrocytes and the excessive production of pro-inflammatory and pro-oxidant factors may be valuable to control neurodegeneration in dementia.
After more than two decades of preclinical and clinical studies, on August 27, 2019, the US Food and Drug Administration (FDA) approved the adenosine A
2A
receptor antagonist Nourianz® ...(istradefylline) developed by Kyowa Hakko Kirin Inc., Japan, as an add-on treatment to levodopa in Parkinson’s disease (PD) with “OFF” episodes. This milestone achievement is the culmination of the decade-long clinical studies of the effects of istradefylline in more than 4000 PD patients. Istradefylline is the first non-dopaminergic drug approved by FDA for PD in the last two decades. This approval also provides some important lessons to be remembered, namely, concerning disease-specific adenosine signaling and targeting subpopulation of PD patients. Importantly, this approval paves the way to foster entirely novel therapeutic opportunities for adenosine A
2A
receptor antagonists, such as neuroprotection or reversal of mood and cognitive deficits in PD and other neuropsychiatric diseases.
Adenosine modulation is considered both a paracrine signal coordinating different cells in a tissue and a stress signal. Both functions are ensured by 4 types of adenosine receptors (ARs), which have ...been studied individually. Mice with knockout of all ARs (quad-AR-KO) now allow enquiring the overall function of the adenosine modulation system. The observed "normal" physiology of quad-AR-KO mice indicates that ARs do not regulate homeostasis and are likely recruited to selectively control allostasis.
ATP is released in an activity-dependent manner from different cell types in the brain, fulfilling different roles as a neurotransmitter, neuromodulator, in astrocyte-to-neuron communication, ...propagating astrocytic responses and formatting microglia responses. This involves the activation of different ATP P2 receptors (P2R) as well as adenosine receptors upon extracellular ATP catabolism by ecto-nucleotidases. Notably, brain noxious stimuli trigger a sustained increase of extracellular ATP, which plays a key role as danger signal in the brain. This involves a combined action of extracellular ATP in different cell types, namely increasing the susceptibility of neurons to damage, promoting astrogliosis and recruiting and formatting microglia to mount neuroinflammatory responses. Such actions involve the activation of different receptors, as heralded by neuroprotective effects resulting from blockade mainly of P2X7R, P2Y1R and adenosine A2A receptors (A2AR), which hierarchy, cooperation and/or redundancy is still not resolved. These pleiotropic functions of ATP as a danger signal in brain damage prompt a therapeutic interest to multi-target different purinergic receptors to provide maximal opportunities for neuroprotection.
The health implications of acrylamide in food are a matter of concern based on toxicological studies in rodents, which showed that doses of acrylamide more than 100 times higher than those estimated ...to result from dietary exposure in humans are carcinogenic; however, the cancer types reported in rodents are species-specific, and whether these results can be extrapolated to humans is still in question. In fact, human epidemiological studies revealed a general lack of association between dietary acrylamide exposure and the incidence of different cancer types. Even occupational exposure to acrylamide, resulting in acrylamide exposure nearly 10 times higher than dietary exposure, did not increase tumor occurrence. Furthermore, the consumption of coffee, which is a main contributor of dietary acrylamide exposure, actually decreases the overall incidence of cancer in humans and afford global health benefits, increasing both lifespan and healthspan on ageing. This paradox clearly illustrates the risk of evaluating an individual molecule independently of its complete food matrix, which may have other components that completely override the effects of the considered molecule.
Mounting an effective immune response against cancer requires the activation of innate and adaptive immune cells. Metastatic melanoma is the most aggressive form of skin cancer. While immunotherapies ...have shown a remarkable success in melanoma treatment, patients develop resistance by mechanisms that include the establishment of an immune suppressive tumor microenvironment. Thus, understanding how metastatic melanoma cells suppress the immune system is vital to develop effective immunotherapies against this disease. In this study, we find that macrophages (MOs) and dendritic cells (DCs) are suppressed in metastatic melanoma and that the Ig-CDR-based peptide C36L1 is able to restore MOs and DCs' antitumorigenic and immunogenic functions and to inhibit metastatic growth in lungs. Specifically, C36L1 treatment is able to repolarize M2-like immunosuppressive MOs into M1-like antitumorigenic MOs, and increase the number of immunogenic DCs, and activated cytotoxic T cells, while reducing the number of regulatory T cells and monocytic myeloid-derived suppressor cells in metastatic lungs. Mechanistically, we find that C36L1 directly binds to the MIF receptor CD74 which is expressed on MOs and DCs, disturbing CD74 structural dynamics and inhibiting MIF signaling on these cells. Interfering with MIF-CD74 signaling on MOs and DCs leads to a decrease in the expression of immunosuppressive factors from MOs and an increase in the capacity of DCs to activate cytotoxic T cells. Our findings suggest that interfering with MIF-CD74 immunosuppressive signaling in MOs and DCs, using peptide-based immunotherapy can restore the antitumor immune response in metastatic melanoma. Our study provides the rationale for further development of peptide-based therapies to restore the antitumor immune response in metastatic melanoma.
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Caffeine is the most consumed psychoactive drug worldwide and its intake in moderate amounts prevents neurodegenerative disorders. However, the molecular targets of caffeine to ...modulate activity in brain circuits are ill-defined. By electrophysiologically recording synaptic transmission and plasticity in Schaffer fibers-CA1 pyramid synapses of mouse hippocampal slices, we characterized the impact of caffeine using a concentration reached in the brain parenchyma upon moderate caffeine consumption. Caffeine (50 µM) facilitated synaptic transmission by 40%, while decreasing paired-pulse facilitation, and also decreased by 35% the amplitude of long-term potentiation (LTP). Clearance of extracellular adenosine with adenosine deaminase (2 U/mL) blunted all the effects of caffeine on synaptic transmission and plasticity. The A1R antagonist DPCPX (100 nM) only eliminated caffeine-induced facilitation of synaptic transmission while not affecting caffeine-induced depression of LTP; conversely, the genetic (using A2AR knockout mice) or the pharmacological blockade (with SCH58261, 50 nM) of A2AR eliminated the effect of caffeine on LTP while not affecting caffeine-induced facilitation of synaptic transmission. Finally, blockade of GABAA or of ryanodine receptors with bicuculline (10 μM) or dantrolene (10 μM), respectively, did not affect the ability of caffeine to alter synaptic transmission or plasticity. These results show that the effects of caffeine on synaptic transmission and plasticity in the hippocampus are selectively mediated by antagonizing adenosine receptors, where A1R are responsible for the impact of caffeine on synaptic transmission and A2AR regulate the impact of caffeine on LTP.
This scientific commentary refers to ‘Exacerbation of C1q dysregulation, synaptic loss and memory deficits in tau pathology linked to neuronal adenosine A2A receptors’, by Carvalho et al. ...(doi:10.1093/brain/awz288).
Our previous International Union of Basic and Clinical Pharmacology report on the nomenclature and classification of adenosine receptors (2011) contained a number of emerging developments with ...respect to this G protein-coupled receptor subfamily, including protein structure, protein oligomerization, protein diversity, and allosteric modulation by small molecules. Since then, a wealth of new data and results has been added, allowing us to explore novel concepts such as target binding kinetics and biased signaling of adenosine receptors, to examine a multitude of receptor structures and novel ligands, to gauge new pharmacology, and to evaluate clinical trials with adenosine receptor ligands. This review should therefore be considered a further update of our previous reports from 2001 and 2011. SIGNIFICANCE STATEMENT: Adenosine receptors (ARs) are of continuing interest for future treatment of chronic and acute disease conditions, including inflammatory diseases, neurodegenerative afflictions, and cancer. The design of AR agonists ("biased" or not) and antagonists is largely structure based now, thanks to the tremendous progress in AR structural biology. The A
- and A
AR appear to modulate the immune response in tumor biology. Many clinical trials for this indication are ongoing, whereas an A
AR antagonist (istradefylline) has been approved as an anti-Parkinson agent.
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