Prog Neurobiol. 1999 Dec;59(6):663-90.
Trophic effects of purines in neurons and glial cells.
Rathbone MP, Middlemiss PJ, Gysbers JW, Andrew C, Herman MA, Reed JK, Ciccarelli R, Di Iorio P, Caciagli F.
SourceDepartment of Medicine, McMaster University, Hamilton, Ontario, Canada.
Abstract
In addition to their well known roles within cells, purine nucleotides such as adenosine 5′ triphosphate (ATP) and guanosine 5′ triphosphate (GTP), nucleosides such as adenosine and guanosine and bases, such as adenine and guanine and their metabolic products xanthine and hypoxanthine are released into the extracellular space where they act as intercellular signaling molecules. In the nervous system they mediate both immediate effects, such as neurotransmission, and trophic effects which induce changes in cell metabolism, structure and function and therefore have a longer time course. Some trophic effects of purines are mediated via purinergic cell surface receptors, whereas others require uptake of purines by the target cells. Purine nucleosides and nucleotides, especially guanosine, ATP and GTP stimulate incorporation of [3H]thymidine into DNA of astrocytes and microglia and concomitant mitosis in vitro. High concentrations of adenosine also induce apoptosis, through both activation of cell-surface A3 receptors and through a mechanism requiring uptake into the cells. Extracellular purines also stimulate the synthesis and release of protein trophic factors by astrocytes, including bFGF (basic fibroblast growth factor), nerve growth factor (NGF), neurotrophin-3, ciliary neurotrophic factor and S-100beta protein. In vivo infusion into brain of adenosine analogs stimulates reactive gliosis. Purine nucleosides and nucleotides also stimulate the differentiation and process outgrowth from various neurons including primary cultures of hippocampal neurons and pheochromocytoma cells. A tonic release of ATP from neurons, its hydrolysis by ecto-nucleotidases and subsequent re-uptake by axons appears crucial for normal axonal growth. Guanosine and GTP, through apparently different mechanisms, are also potent stimulators of axonal growth in vitro. In vivo the extracellular concentration of purines depends on a balance between the release of purines from cells and their re-uptake and extracellular metabolism. Purine nucleosides and nucleotides are released from neurons by exocytosis and from both neurons and glia by non-exocytotic mechanisms. Nucleosides are principally released through the equilibratory nucleoside transmembrane transporters whereas nucleotides may be transported through the ATP binding cassette family of proteins, including the multidrug resistance protein. The extracellular purine nucleotides are rapidly metabolized by ectonucleotidases. Adenosine is deaminated by adenosine deaminase (ADA) and guanosine is converted to guanine and deaminated by guanase. Nucleosides are also removed from the extracellular space into neurons and glia by transporter systems. Large quantities of purines, particularly guanosine and, to a lesser extent adenosine, are released extracellularly following ischemia or trauma.
Thus purines are likely to exert trophic effects in vivo following trauma.
The extracellular purine nucleotide GTP enhances the tonic release of adenine nucleotides, whereas the nucleoside guanosine stimulates tonic release of adenosine and its metabolic products. The trophic effects of guanosine and GTP may depend on this process.
Guanosine is likely to be an important trophic effector in vivo because high concentrations remain extracellularly for up to a week after focal brain injury.
Purine derivatives are now in clinical trials in humans as memory-enhancing agents in Alzheimer’s disease. Two of these, propentofylline and AIT-082, are trophic effectors in animals, increasing production of neurotrophic factors in brain and spinal cord. Likely more clinical uses for purine derivatives will be found; purines interact at the level of signal-transduction pathways with other transmitters, for example, glutamate. They can beneficially modify the actions of these other transmitters.
PMID:10845757[PubMed – indexed for MEDLINE]

Int J Dev Neurosci. 2001 Jul;19(4):395-414.
Involvement of astrocytes in purine-mediated reparative processes in the brain.
Ciccarelli R, Ballerini P, Sabatino G, Rathbone MP, D’Onofrio M, Caciagli F, Di Iorio P.
Source
Department of Biomedical Sciences, Section of Pharmacology, Via del Vestini Pal. B, 66013, Chieti, Italy. r.ciccarelli@dsb.unich.it
Abstract
Astrocytes are involved in multiple brain functions in physiological conditions, participating in neuronal development, synaptic activity and homeostatic control of the extracellular environment. They also actively participate in the processes triggered by brain injuries, aimed at limiting and repairing brain damages.
Purines may play a significant role in the pathophysiology of numerous acute and chronic disorders of the central nervous system (CNS). Astrocytes are the main source of cerebral purines.
 They release either adenine-based purines, e.g. adenosine and adenosine triphosphate, or guanine-based purines, e.g. guanosine and guanosine triphosphate, in physiological conditions and release even more of these purines in pathological conditions. Astrocytes express several receptor subtypes of P1 and P2 types for adenine-based purines. Receptors for guanine-based purines are being characterised. Specific ecto-enzymes such as nucleotidases, adenosine deaminase and, likely, purine nucleoside phosphorylase, metabolise both adenine- and guanine-based purines after release from astrocytes. This regulates the effects of nucleotides and nucleosides by reducing their interaction with specific membrane binding sites. Adenine-based nucleotides stimulate astrocyte proliferation by a P2-mediated increase in intracellular [Ca2+] and isoprenylated proteins. Adenosine also, via A2 receptors, may stimulate astrocyte proliferation, but mostly, via A1 and/or A3 receptors, inhibits astrocyte proliferation, thus controlling the excessive reactive astrogliosis triggered by P2 receptors. The activation of A1 receptors also stimulates astrocytes to produce trophic factors, such as nerve growth factor, S100beta protein and transforming growth factor beta, which contribute to protect neurons against injuries. Guanosine stimulates the output of adenine-based purines from astrocytes and in addition it directly triggers these cells to proliferate and to produce large amount of neuroprotective factors.
These data indicate that adenine- and guanine-based purines released in large amounts from injured or dying cells of CNS may act as signals to initiate brain repair mechanisms widely involving astrocytes
PMID:11378300[PubMed – indexed for MEDLINE]

Pol J Pharmacol. 2002 Jul-Aug;54(4):313-26.
Neuroprotective role of adenosine in the CNS.
Wardas J.
Department of Neuropsychopharmacology, Institute of Pharmacology, Polish Academy of Sciences, Smetna 12, PL 31-343 Kraków, Poland. wardas@if-pan.krakow.pl
Abstract
It is well established that in the CNS, endogenous adenosine plays a pivotal role in neurodegeneration. A low, nanomolar concentration of adenosine is normally present in the extracellular fluid, but it increases dramatically during enhanced nerve activity, hypoxia or ischemia. In these pathological conditions, adenosinergic transmission-potentiating agents, which elevate adenosine level by either inhibiting its degradation (adenosine deaminase and kinase inhibitors) or preventing its transport, offer protection against ischemic or excitotoxic neuronal damage.
The directly acting adenosine A1 receptor agonists are known to mediate neuroprotection, mostly by the blockade of Ca2+ influx, which results in the inhibition of glutamate release and reduction of its excitatory effects at a postsynaptic level. More recent data have shown that antagonists of adenosine A2A receptors markedly reduce cerebral ischemic damage in animal models of focal and global ischemia. Moreover, these compounds attenuate the neuronal loss induced by excitatory amino acids (EAA). A neuroprotective effect of adenosine A2A receptor antagonists was also shown in animal models of Parkinson’s disease (MPTP, 6-OHDA, methamphetamine). Hence, it might be suggested that adenosine A2A receptor antagonists may represent a novel strategy in the therapeutic approach to pathologies characterized by acute or chronic neurodegenerative events, since they not only reverse motor impairment but can act as neuroprotective compunds by promoting cell survival.
PMID: 12523485 [PubMed – indexed for MEDLINE]

Ann N Y Acad Sci. 1999;890:79-92.
Brain adenosine receptors as targets for therapeutic intervention in neurodegenerative diseases.
Abbracchio MP, Cattabeni F.   Institute of Pharmacological Sciences, University of Milan, Italy. abbracch@mailserver.unimi.it
Abstract
Adenosine acts as a neurotransmitter in the brain through the activation of four specific G-protein-coupled receptors (the A1, A2A, A2B, and A3 receptors). The A1 receptor has long been known to mediate neuroprotection, mostly by blockade of Ca2+ influx, which results in inhibition of glutamate release and reduction of its excitatory effects at a postsynaptic level. However, the development of selective A1 receptor agonists as antiischemic agents has been hampered by their major cardiovascular side effects. More recently, apparently deleterious effects have been reported following the activation of other adenosine receptor subtypes, namely, the A2A and the A3 receptors. In particular, selective A2A receptor antagonists have been demonstrated to markedly reduce cell death associated with brain ischemia in the rat, suggesting that the cerebral A2A receptor may indeed contribute to the development of ischemic damage. The beneficial effects evoked by A2A antagonists may be due to blockade of presynaptic A2A receptors (which are stimulatory on glutamate release) and/or to inhibition of A2A receptor-mediated activation of microglial cells. Even more puzzling data have been reported for the A3 receptor subtype, which can indeed mediate both cell protection and cell death, simply depending upon the degree of receptor activation and/or specific pathophysiological conditions. In particular, a mild subthreshold activation of this receptor has been associated with a reinforcement of the cytoskeleton and reduction of spontaneous apoptosis, which may play a role in “ischemic preconditioning” of the brain, according to which a short ischemic period may protect the brain from a subsequent, sustained ischemic insult that would be lethal. In contrast, a robust and prolonged activation of the A3 receptor has been shown to trigger cell death by either necrosis or apoptosis. Such apparently opposing actions may be reconciled by hypothesizing that adenosine-mediated cell killing during ischemia may be aimed at isolating the most damaged areas to favor those parts of the brain that still retain a chance for functional recovery. In fact, both A3 receptor-mediated cell death and A2A receptor-mediated actions may be viewed as an attempt to selectively kill irreversibly damaged cells in the “core” ischemic area, in order to save space and energy for the surrounding live cells in the “pneumbra” area. Hence, the pharmacological modulation of the A2A and A3 receptors via selective ligands may represent a novel strategy in the therapeutic approach to pathologies characterized by acute or chronic neurodegenerative events.
PMID: 10668415 [PubMed – indexed for MEDLINE

Ann N Y Acad Sci. 1997 Oct 15;825:1-10.
Protective mechanisms of adenosine in neurons and glial cells.
Schubert P, Ogata T, Marchini C, Ferroni S, Rudolphi K.
Source
Department of Neuromorphology, Max Planck Institute for Psychiatry, Martinsried, Germany.
Abstract
As illustrated in Figure 1, a disturbance of the intracellular Ca2+ homeostasis is thought to be a common pathogenic factor for the generation of secondary nerve cell damage that develops after brain trauma or stroke or during the course of neurodegenerative diseases.
A neuronal Ca2+ overload which may result from an excessive glutamate-evoked membrane depolarization and consecutive Ca2+ influx as well as from an activation of metabotropic receptors and consecutive intracellular Ca2+ mobilization is known to have direct toxic effects on the cytoskeleton and the cell metabolism of neurons. In addition, a Ca(2+)-dependent activation of glial cells along with the loss of physiologically required mature astrocyte functions and with the acquisition of potentially neurotoxic microglial properties, has more recently been recognized as an additive pathogenic factor. This may provide an effective target for pharmacological interference. Specifically, the reinforcement of an endogenous homeostatic regulator, which obtained its sophisticated know-how during evolution, may provide a neuroprotective therapy which can handle the complexity of the pathological process with a minor risk of pharmacological side effects. Adenosine is such an ancient molecular signal that acts on both neurons and glial cells. In neurons, adenosine activates K+ and Cl- conductances, which limits synaptically evoked depolarization, thus counteracting the Ca2+ influx through voltage-dependent and NMDA receptor-operated ion channels.
This A1 receptor-mediated effect seems to be the major action by which adenosine adds directly to the protection of neurons against Ca(2+)-dependent damage
. In glial cells, the prevalent effect of adenosine is its regulatory influence on the Ca2+ and cAMP-dependent molecular signaling that determines the cellular proliferation rate, the differentiation state and related functions. When mimicking the activation of metabotropic glutamate receptors in cultures of immature rat astrocytes, which largely resemble pathologically activated astrocytes, a transient Ca2+ mobilization was initiated by adenosine. This A1 receptor-mediated Ca2+ signal caused a prolonged potentiation of the A2 receptor-mediated intracellular cAMP rise. An experimentally sustained enhancement of the cAMP signaling initiated the differentiation of cultured astrocytes and the new expression of K+ and Cl- channels which are required for the physiological astrocyte function to maintain the extracellular ion homeostasis. Evidence is accumulating that a strengthening of the cAMP signaling, which can be achieved by adenosine agonists and also by the pharmacon propentofylline (an adenosine uptake blocker and phosphodiesterase inhibitor), stimulates the mRNA production of neurotrophic factors in astrocytes. In cultured microglial cells, several days’ treatment with adenosine agonists or propentofylline markedly inhibited their proliferation rate, the in vitro spontaneously occurring transformation into macrophages and their particularly high formation of free oxygen radicals.
Adenosine agonists also depressed the release of the potentially toxic cytokine TNF alpha and induced programmed cell death in immunologically activated microglial cells.
We conclude that a pharmacological reinforcement of the endogenous cell modulator adenosine may provide neuroprotection by counteracting neuronal Ca2+ overload, by depressing potentially neurotoxic microglial functions and by regaining physiologically required properties of differentiated astrocytes.
Further information about the influence of adenosine on the molecular signaling and on ischemic brain damage is given in Refs. 37 and 38, and about the implicated possible relevance for the treatment of stroke in Ref. 39.
PMID:9369970[PubMed – indexed for MEDLINE]

J Neurosci Res. 1999 Jul 15;57(2):207-18.
Extracellular adenosine triphosphate affects neural cell adhesion molecule (NCAM)-mediated cell adhesion and neurite outgrowth.
Skladchikova G, Ronn LC, Berezin V, Bock E.
Source
Protein Laboratory, Institute of Molecular Pathology, University of Copenhagen, Copenhagen, Denmark. galina@plab.ku.dk
Abstract
The neural cell adhesion molecule (NCAM) plays an important role in synaptic plasticity in embryonic and adult brain. Recently, it has been demonstrated that NCAM is capable of binding and hydrolyzing extracellular ATP. The purpose of the present study was to evaluate the role of extracellular ATP in NCAM-mediated cellular adhesion and neurite outgrowth. We here show that extracellularly added adenosine triphosphate (ATP) and its structural analogues, adenosine-5′-O-(3-thiothiophosphate), beta, gamma-methylenadenosine-5′-triphosphate, beta, gamma-imidoadenosine-5-triphosphate, and UTP, in varying degrees inhibited aggregation of hippocampal neurons. Rat glial BT4Cn cells are unable to aggregate when grown on agar but acquire this capacity when transfected with NCAM. However, addition of extracellular ATP to NCAM-transfected BT4Cn cells inhibited aggregation. Furthermore, neurite outgrowth from hippocampal neurons in cultures allowing NCAM-homophilic interactions was inhibited by addition of extracellular nucleotides. These findings indicate that NCAM-mediated adhesion may be modulated by extracellular ATP. Moreover, extracellularly added ATP stimulated neurite outgrowth from hippocampal neurons under conditions non-permissive for NCAM-homophilic interactions, and neurite outgrowth stimulated by extracellular ATP could be inhibited by a synthetic peptide corresponding to the so-called cell adhesion molecule homology domain (CHD) of the fibroblast growth factor receptor (FGFR) and by FGFR antibodies binding to this domain. Antibodies against the fibronectin type-III homology modules of NCAM, in which a putative site for ATP binding and hydrolysis is located, also abolished the neurite outgrowth-promoting effect of ATP. The non-hydrolyzable analogues of ATP all strongly inhibited neurite outgrowth.
Our results indicate that extracellular ATP may be involved in synaptic plasticity through a modulation of NCAM-mediated adhesion and neurite outgrowth.
Copyright 1999 Wiley-Liss, Inc.PMID:10398298[PubMed – indexed for MEDLINE]

J Neurosci Res. 2007 Mar;85(4):703-11.
Cyclic guanosine monophosphate signalling pathway plays a role in neural cell adhesion molecule-mediated neurite outgrowth and survival.
Ditlevsen DK, Køhler LB, Berezin V, Bock E.
Source
Protein Laboratory, Institute of Molecular Pathology, University of Copenhagen, Panum Institute 6.2, Copenhagen, Denmark.
Abstract
The neural cell adhesion molecule (NCAM) plays a crucial role in neuronal development, regeneration, and synaptic plasticity associated with learning and memory consolidation. Homophilic binding of NCAM leads to neurite extension and neuroprotection in various types of primary neurons through activation of a complex network of signalling cascades, including fibroblast growth factor receptor, Src-family kinases, the mitogen-activated protein kinase pathway, protein kinase C, phosphatidylinositol-3 kinase, and an increase in intracellular Ca(2+). Here we present data indicating an involvement of cyclic GMP in NCAM-mediated neurite outgrowth in both hippocampal and dopaminergic neurons and in NCAM-mediated neuroprotection of dopaminergic neurons. In addition, evidence is presented suggesting that NCAM mediates activation of cGMP via synthesis of nitric oxide (NO) by NO synthase (NOS) and activation of soluble guanylyl cyclase by NO, leading to an increased synthesis of cGMP and activation by cGMP of protein kinase G.
PMID:17279552[PubMed – indexed for MEDLINE]

Handb Exp Pharmacol. 2009;(193):471-534.
Adenosine receptors and the central nervous system.
Sebastião AM, Ribeiro JA.
Institute of Pharmacology and Neurosciences, Institute of Molecular Medicine, University of Lisbon, 1649-028 Lisbon, Portugal. anaseb@fm.ul.pt
Abstract
The adenosine receptors (ARs) in the nervous system act as a kind of “go-between” to regulate the release of neurotransmitters (this includes all known neurotransmitters) and the action of neuromodulators (e.g., neuropeptides, neurotrophic factors). Receptor-receptor interactions and AR-transporter interplay occur as part of the adenosine’s attempt to control synaptic transmission. A(2A)ARs are more abundant in the striatum and A(1)ARs in the hippocampus, but both receptors interfere with the efficiency and plasticity-regulated synaptic transmission in most brain areas.
The omnipresence of adenosine and A(2A) and A(1) ARs in all nervous system cells (neurons and glia), together with the intensive release of adenosine following insults, makes adenosine a kind of “maestro” of the tripartite synapse in the homeostatic coordination of the brain function.
Under physiological conditions, both A(2A) and A(1) ARs play an important role in sleep and arousal, cognition, memory and learning, whereas under pathological conditions (e.g., Parkinson’s disease, Alzheimer’s disease, amyotrophic lateral sclerosis, stroke, epilepsy, drug addiction, pain, schizophrenia, depression), ARs operate a time/circumstance window where in some circumstances A(1)AR agonists may predominate as early neuroprotectors, and in other circumstances A(2A)AR antagonists may alter the outcomes of some of the pathological deficiencies. In some circumstances, and depending on the therapeutic window, the use of A(2A)AR agonists may be initially beneficial; however, at later time points, the use of A(2A)AR antagonists proved beneficial in several pathologies. Since selective ligands for A(1) and A(2A) ARs are now entering clinical trials, the time has come to determine the role of these receptors in neurological and psychiatric diseases and identify therapies that will alter the outcomes of these diseases, therefore providing a hopeful future for the patients who suffer from these diseases.
PMID: 19639292 [PubMed – indexed for MEDLINE

Prog Neurobiol. 2007 Dec;83(5):310-31. Epub 2007 Sep 29.
Adenosine A2A receptors and brain injury: broad spectrum of neuroprotection, multifaceted actions and “fine tuning” modulation.
Chen JF, Sonsalla PK, Pedata F, Melani A, Domenici MR, Popoli P, Geiger J, Lopes LV, de Mendonça A.
Source
Department of Neurology, Boston University School of Medicine, 715 Albany Street, C329, Boston, MA 02118, USA. chenjf@bu.edu
Abstract
This review summarizes recent developments that have contributed to understand how adenosine receptors, particularly A2A receptors, modulate brain injury in various animal models of neurological disorders, including Parkinson’s disease (PD), stroke, Huntington’s disease (HD), multiple sclerosis, Alzheimer’s disease (AD) and HIV-associated dementia. It is clear that extracellular adenosine acting at adenosine receptors influences the functional outcome in a broad spectrum of brain injuries, indicating that A2A Rs may modulate some general cellular processes to affect neuronal cells death. Pharmacological, neurochemical and molecular/genetic approaches to the complex actions of A2A receptors in different cellular elements suggest that A2A receptor activation can be detrimental or protective after brain insults, depending on the nature of brain injury and associated pathological conditions. An interesting concept that emerges from these studies is A2A R’s ability to fine tune neuronal and glial functions to produce neuroprotective effects. While the data presented here clearly highlight the complexity of using adenosinergic agents therapeutically in PD and other neurodegenerative disorders and point out many areas for further inquiry, they also confirm that adenosine receptor ligands, particularly A2A receptor ligands, have many promising characteristics that encourage the pursuit of their therapeutic potential.
PMID:18023959[PubMed – indexed for MEDLINE]

Front Biosci (Landmark Ed). 2011 Jun 1;16:2326-41.
Role of purinergic signalling in neuro-immune cells and adult neural progenitors.
Fumagalli M, Lecca D, Abbracchio MP.
Source
Laboratory of Molecular and Cellular Pharmacology of Purinergic Transmission, Department of Pharmacological Sciences, via Balzaretti 9, 20133 Milan, Italy.
Abstract
Inflammation has a key role in a vast range of central nervous system diseases. Under acute and chronic neurodegenerative conditions, resident microglia and astrocytes and blood-borne immune cells concur to neuroinflammation and remodeling/repair at the inflammed site. Distinct inflammatory cell states characterized by either a beneficial or a detrimental phenotype have been identified, depending upon the timing after the initial insult and activation by specific pro- or anti-inflammatory molecules. Of note, quiescent adult neuroprogenitor cells located in both brain’s neurogenic areas and parenchyma have been recently shown to interact with immune cells and actively participate to restore function. Among other systems, extracellular nucleotides and their receptors have emerged as early alerting signals in inflammation and as key players in orchestrating the release of inflammatory molecules and the interaction between different cell types. Here, we revise the state of the art in this expanding field with the final aim of unveiling whether new purinergic-based therapies may be useful to halt excessive inflammation and foster endogenous repair in neuroinflammatory disorders.
PMID:21622179[PubMed – indexed for MEDLINE]

J Immunol. 2012 Jun 1;188(11):5713-22.
A2A adenosine receptor signaling in lymphocytes and the central nervous system regulates inflammation during experimental autoimmune encephalomyelitis.
Mills JH, Kim DG, Krenz A, Chen JF, Bynoe MS.
Source
Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853, USA.
Abstract
Extracellular adenosine has an important role in regulating the severity of inflammation during an immune response. Although there are four adenosine receptor (AR) subtypes, the A2AAR is both highly expressed on lymphocytes and known as a prime mediator of adenosine’s anti-inflammatory effects. To define the importance of A2AAR signaling during neuroinflammatory disease progression, we used the experimental autoimmune encephalomyelitis (EAE) animal model for multiple sclerosis. In EAE induction experiments, A2AAR antagonist treatment protected mice from disease development and its associated CNS lymphocyte infiltration. However, A2AAR(-/-) mice developed a more severe acute EAE phenotype characterized by more proinflammatory lymphocytes and activated microglia/macrophages. Interestingly, very high levels of A2AAR were expressed on the choroid plexus, a well-established CNS lymphocyte entry point. To determine the contribution of A2AAR signaling in lymphocytes and the CNS during EAE, we used bone marrow chimeric mice. Remarkably, A2AAR(-/-) donor hematopoietic cells potentiated severe EAE, whereas lack of A2AAR expression on nonhematopoietic cells protected against disease development. Although no defect in the suppressive ability of A2AAR(-/-) regulatory T cells was observed, A2AAR(-/-) lymphocytes were shown to proliferate more and produced more IFN-γ following stimulation. Despite this more proinflammatory phenotype, A2AAR antagonist treatment still protected against EAE when A2AAR(-/-) lymphocytes were adoptively transferred to T cell-deficient A2AAR(+/+) mice. These results indicate that A2AAR expression on nonimmune cells (likely in the CNS) is required for efficient EAE development, while A2AAR lymphocyte expression is essential for limiting the severity of the inflammatory response.
PMID:22529293[PubMed – indexed for MEDLINE] PMCID:PMC3358473

Curr Top Med Chem. 2003;3(4):463-9.
Pharmacology and therapeutic applications of A3 receptor subtype.
Fishman P, Bar-Yehuda S.
Laboratory of Clinical and Tumor Immunology, The Felsenstein Medical Research Center, Sackler School of Medicine, Tel-Aviv University, Rabin Medical Center, Petach-Tikva, Israel. pnina@canfite.co.il
The present study summarizes the biological effects elicit upon A(3) adenosine receptor (A(3)AR) activation in normal and tumor cells. Anti-inflamatory response is mediated upon A(3)AR activation in neutrophils, eosinophils and macrophages via direct effect on cell degranulation or the production of anti-inflamatory cytokines. In basophils, which highly express A(3)AR, degranulation and mediator release upon receptor activation lead to pro-inflammatory effects resulting in bronchospasm and asthma. In other normal cells such as cardiomyocytes, neuronal cells and bone marrow cells A(1)AR activation induces cytoprotective effects in vitro.
In vivo, A(3)AR agonists act as cardio- and neuroprotective agents and attenuate ischemic damage. Furthermore, agonists to A(3)AR induce granulocyte colony stimulating factor (G-CSF) production and myeloprotective effect in chemotherapy treated mice.
Interestingly, A(3)AR agonists inhibit tumor cell growth both in vitro and in vivo through a cytostatic effect mediated via the de-regulation of the Wnt signaling pathway. The variety of activities elicit by A(3)AR agonists suggest their potential use as therapeutic agents in inflammation, brain/cardiac ischemia and cancer.   Antagonists to A(3)AR may be implemented to the therapy of asthma and additional allergic conditions.
PMID: 12570762 [PubMed – indexed for MEDLINE]

Neurosci Lett. 2006 Mar 20;396(1):1-6. Epub 2005 Dec 1.
Activation of adenosine A3 receptor suppresses lipopolysaccharide-induced TNF-alpha production through inhibition of PI 3-kinase/Akt and NF-kappaB activation in murine BV2 microglial cells.
Lee JY, Jhun BS, Oh YT, Lee JH, Choe W, Baik HH, Ha J, Yoon KS, Kim SS, Kang I.
Department of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University, 1 Hoegi-dong, Seoul 130-701, Korea.
Adenosine is an endogenous nucleoside that regulates many processes, including inflammatory responses, through activation of its receptors. Adenosine receptors have been reported to be expressed in microglia, which are major immune cells of brain, yet little is known about the role of adenosine receptors in microglial cytokine production. Thus, we investigated the effect of adenosine and adenosine A3 receptor ligands on LPS-induced tumor necrosis factor (TNF-alpha) production and its molecular mechanism in mouse BV2 microglial cells. Adenosine and Cl-IB-MECA, a specific adenosine A3 receptor agonist, suppressed LPS-induced TNF-alpha protein and mRNA levels. Moreover, MRS1523, a selective A3 receptor antagonist, blocked suppressive effects of both adenosine and Cl-IB-MECA on TNF-alpha. We further examined the effect of adenosine on signaling molecules, such as PI 3-kinase, Akt, p38, ERK1/2, and NF-kappaB, which are involved in the regulation of inflammatory responses. Adenosine inhibited LPS-induced phosphatidylinositol (PI) 3-kinase activation and Akt phosphorylation, whereas it had no effect on the phosphorylation of p38 and ERK1/2. We also found that adenosine as well as Cl-IB-MECA inhibited LPS-induced NF-kappaB DNA binding and luciferase reporter activity.
Taken together, these results suggest that adenosine A3 receptor activation suppresses TNF-alpha production by inhibiting PI 3-kinase/Akt and NF-kappaB activation in LPS-treated BV2 microglial cells.
PMID: 16324785 [PubMed – indexed for MEDLINE]

Handb Exp Pharmacol. 2009;(193):535-87.
Adenosine receptors and neurological disease: neuroprotection and neurodegeneration.
Stone TW, Ceruti S, Abbracchio MP.  Institute of Biomedical and Life Sciences, University of Glasgow, Glasgow G12 8QQ, UK. T.W.Stone@bio.gla.ac.uk
Abstract
Adenosine receptors modulate neuronal and synaptic function in a range of ways that may make them relevant to the occurrence, development and treatment of brain ischemic damage and degenerative disorders. A(1) adenosine receptors tend to suppress neural activity by a predominantly presynaptic action, while A(2A) adenosine receptors are more likely to promote transmitter release and postsynaptic depolarization. A variety of interactions have also been described in which adenosine A(1) or A(2) adenosine receptors can modify cellular responses to conventional neurotransmitters or receptor agonists such as glutamate, NMDA, nitric oxide and P2 purine receptors. Part of the role of adenosine receptors seems to be in the regulation of inflammatory processes that often occur in the aftermath of a major insult or disease process. All of the adenosine receptors can modulate the release of cytokines such as interleukins and tumor necrosis factor-alpha from immune-competent leukocytes and glia. When examined directly as modifiers of brain damage, A(1) adenosine receptor (AR) agonists, A(2A)AR agonists and antagonists, as well as A(3)AR antagonists, can protect against a range of insults, both in vitro and in vivo. Intriguingly, acute and chronic treatments with these ligands can often produce diametrically opposite effects on damage outcome, probably resulting from adaptational changes in receptor number or properties. In some cases molecular approaches have identified the involvement of ERK and GSK-3beta pathways in the protection from damage. Much evidence argues for a role of adenosine receptors in neurological disease. Receptor densities are altered in patients with Alzheimer’s disease, while many studies have demonstrated effects of adenosine and its antagonists on synaptic plasticity in vitro, or on learning adequacy in vivo.
The combined effects of adenosine on neuronal viability and inflammatory processes have also led to considerations of their roles in Lesch-Nyhan syndrome, Creutzfeldt-Jakob disease, Huntington’s disease and multiple sclerosis, as well as the brain damage associated with stroke.
In addition to the potential pathological relevance of adenosine receptors, there are earnest attempts in progress to generate ligands that will target adenosine receptors as therapeutic agents to treat some of these disorders.
PMID: 19639293 [PubMed – indexed for MEDLINE

Purinergic Signal. 2013 Jul 12. [Epub ahead of print]
Gliopreventive effects of guanosine against glucose deprivation in vitro.
Quincozes-Santos A, Bobermin LD, de Souza DG, Bellaver B, Gonçalves CA, Souza DO.
Source
Departamento de Bioquímica, Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos, 2600, Anexo Bairro Santa Cecília, 90035 003, Porto Alegre, Rio Grande do Sul, Brazil, andrequincozes@yahoo.com.br.
Abstract
Guanosine, a guanine-based purine, is recognized as an extracellular signaling molecule that is released from astrocytes and confers neuroprotective effects in several in vivo and in vitro studies.
Astrocytes regulate glucose metabolism, glutamate transport, and defense mechanism against oxidative stress. C6 astroglial cells are widely used as an astrocyte-like cell line to study the astrocytic function and signaling pathways. Our previous studies showed that guanosine modulates the glutamate uptake activity, thus avoiding glutamatergic excitotoxicity and protecting neural cells. The goal of this study was to determine the gliopreventive effects of guanosine against glucose deprivation in vitro in cultured C6 cells. Glucose deprivation induced cytotoxicity, an increase in reactive oxygen and nitrogen species (ROS/RNS) levels and lipid peroxidation as well as affected the metabolism of glutamate, which may impair important astrocytic functions. Guanosine prevented glucose deprivation-induced toxicity in C6 cells by modulating oxidative and nitrosative stress and glial responses, such as the glutamate uptake, the glutamine synthetase activity, and the glutathione levels. Glucose deprivation decreased the level of EAAC1, the main glutamate transporter present in C6 cells. Guanosine also prevented this effect, most likely through PKC, PI3K, p38 MAPK, and ERK signaling pathways.
Taken together, these results show that guanosine may represent an important mechanism for protection of glial cells against glucose deprivation. Additionally, this study contributes to a more thorough understanding of the glial- and redox-related protective properties of guanosine in astroglial cells.
PMID:23846842[PubMed – as supplied by publisher]

J Neurochem. 2013 May 29.
Guanosine controls inflammatory pathways to afford neuroprotection of hippocampal slices under oxygen and glucose deprivation conditions.
Dal-Cim T, Ludka FK, Martins WC, Reginato C, Parada E, Egea J, López MG, Tasca CI.
Source
Departamento de Bioquímica, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil.
Abstract
Guanosine (GUO) is an endogenous modulator of glutamatergic excitotoxicity and has been shown to promote neuroprotection in in vivo and in vitro models of neurotoxicity. This study was designed to understand the neuroprotective mechanism of GUO against oxidative damage promoted by oxygen/glucose deprivation and reoxygenation (OGD). GUO (100 μM) reduced reactive oxygen species production and prevented mitochondrial membrane depolarization induced by OGD. GUO also exhibited anti-inflammatory actions as inhibition of nuclear factor kappa B activation and reduction of inducible nitric oxide synthase induction induced by OGD. These GUO neuroprotective effects were mediated by adenosine A1 receptor, phosphatidylinositol-3 kinase and MAPK/ERK. Furthermore, GUO recovered the impairment of glutamate uptake caused by OGD, an effect that occurred via a Pertussis toxin-sensitive G-protein-coupled signaling, blockade of adenosine A2A receptors (A2A R), but not via A1 receptor. The modulation of glutamate uptake by GUO also involved MAPK/ERK activation. In conclusion, GUO, by modulating adenosine receptor function and activating MAPK/ERK, affords neuroprotection of hippocampal slices subjected to OGD by a mechanism that implicates the following: (i) prevention of mitochondrial membrane depolarization, (ii) reduction of oxidative stress, (iii) regulation of inflammation by inhibition of nuclear factor kappa B and inducible nitric oxide synthase, and (iv) promoting glutamate uptake.
© 2013 International Society for Neurochemistry.
PMID:23713463[PubMed – as supplied by publisher]

Neurochem Int. 2013 Apr;62(5):610-9.
Extracellular cyclic GMP and its derivatives GMP and guanosine protect from oxidative glutamate toxicity.
Albrecht P, Henke N, Tien ML, Issberner A, Bouchachia I, Maher P, Lewerenz J, Methner A.
Source
Department of Neurology, Heinrich-Heine Universität Düsseldorf, Düsseldorf, Germany.
Abstract
Cell death in response to oxidative stress plays a role in a variety of neurodegenerative diseases and can be studied in detail in the neuronal cell line HT22, where extracellular glutamate causes glutathione depletion by inhibition of the glutamate/cystine antiporter system xc(-), elevation of reactive oxygen species and eventually programmed cell death caused by cytotoxic calcium influx. Using this paradigm, we screened 54 putative extracellular peptide or small molecule ligands for effects on cell death and identified extracellular cyclic guanosine monophosphate (cGMP) as a protective substance. Extracellular cGMP was protective, whereas the cell-permeable cGMP analog 8-pCPT-cGMP or the inhibition of cGMP degradation by phosphodiesterases was toxic. Interestingly, metabolites GMP and guanosine were even more protective than cGMP and the inhibition of the conversion of GMP to guanosine attenuated its effect, suggesting that GMP offers protection through its conversion to guanosine. Guanosine increased system xc(-) activity and cellular glutathione levels in the presence of glutamate, which can be explained by transcriptional upregulation of xCT, the functional subunit of system xc(-). However, guanosine also provided protection when added late in the cell death cascade and significantly reduced the number of calcium peaking cells, which was most likely not mediated by transcriptional mechanisms. We observed no changes in the classical protective pathways such as phosphorylation of Akt, ERK1/2 or induction of Nrf2 or ATF4.
We conclude that extracellular guanosine protects against endogenous oxidative stress by two probably independent mechanisms involving system xc(-) induction and inhibition of cytotoxic calcium influx.
Copyright © 2013 Elsevier Ltd. All rights reserved.PMID:23357478[PubMed – in process]

Behav Brain Res. 2012 Oct 1;234(2):137-48.
Guanosine produces an antidepressant-like effect through the modulation of NMDA receptors, nitric oxide-cGMP and PI3K/mTOR pathways.
Bettio LE, Cunha MP, Budni J, Pazini FL, Oliveira Á, Colla AR, Rodrigues AL.
Source
Departamento de Bioquímica, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Campus Universitário, Trindade, 88040-900, Florianópolis, SC, Brazil.
Abstract
Guanosine is an extracellular signaling molecule implicated in the modulation of glutamatergic transmission and neuroprotection. The present study evaluated the antidepressant-like effect of guanosine in the forced swimming test (FST) and in the tail suspension test (TST) in mice. The contribution of NMDA receptors as well as l-arginine-NO-cGMP and PI3K-mTOR pathways to this effect was also investigated. Guanosine administered orally produced an antidepressant-like effect in the FST (0.5-5 mg/kg) and TST (0.05-0.5 mg/kg). The anti-immobility effect of guanosine in the TST was prevented by the treatment of mice with NMDA (0.1 pmol/site, i.c.v.), d-serine (30 μg/site, i.c.v., a co-agonist of NMDA receptors), l-arginine (750 mg/kg, i.p., a substrate for nitric oxide synthase), sildenafil (5 mg/kg, i.p., a phosphodiesterase 5 inhibitor), LY294002 (10 μg/site, i.c.v., a reversible PI3K inhibitor), wortmannin (0.1 μg/site, i.c.v., an irreversible PI3K inhibitor) or rapamycin (0.2 nmol/site, i.c.v., a selective mTOR inhibitor). In addition, the administration of ketamine (0.1 mg/kg, i.p., a NMDA receptor antagonist), MK-801 (0.001 mg/kg, i.p., another NMDA receptor antagonist), 7-nitroindazole (50 mg/kg, i.p., a neuronal nitric oxide synthase inhibitor) or ODQ (30 pmol/site i.c.v., a soluble guanylate cyclase inhibitor) in combination with a sub-effective dose of guanosine (0.01 mg/kg, p.o.) reduced the immobility time in the TST when compared with either drug alone. None of the treatments affected locomotor activity. Altogether, results firstly indicate that guanosine exerts an antidepressant-like effect that seems to be mediated through an interaction with NMDA receptors, l-arginine-NO-cGMP and PI3K-mTOR pathways.
Copyright © 2012 Elsevier B.V. All rights reserved. PMID:22743004[PubMed – indexed for MEDLINE]

Brain Res. 2011 Aug 17;1407:79-89.
Systemic administration of guanosine promotes functional and histological improvement following an ischemic stroke in rats.
Rathbone MP, Saleh TM, Connell BJ, Chang R, Su C, Worley B, Kim M, Jiang S.
Source
Department of Medicine (Neurology, Neurobiochemistry), Health Sciences Centre, Room 4E15, 1200 Main Street West, Hamilton, ON, Canada L8N 3Z5.
Abstract
Previously we have found that extracellular guanosine (Guo) has neuroprotective properties in in vitro and in vivo. Moreover, extracellular Guo significantly increased in the ipsilateral hemisphere within 2h following focal stroke in rats, and remained elevated for one week. Therefore, we hypothesized that Guo could be a potential candidate for a non-toxic neuroprotective agent. In the present study, we examined the effects of Guo on rats following permanent middle cerebral artery occlusion (MCAO). We also determined whether Guo can precondition neurons by modulating endoplasmic reticulum (ER) stress proteins. As most therapies employ a combination treatment regimen, we optimized the neuroprotection by combining pre- and post-MCAO treatments with Guo, attempting to reduce both ischemic cell death and improve functional recovery. A combination of 4mg/kg Guo given 30min pre-stroke and 8mg/kg Guo given 3, 24 and 48h post-stroke exerted the most significant decrease in infarct volume and sustainable improvement in neurological function. Moreover, these effects are not attributable to Guo metabolites. Measurements taken 6h post-MCAO from animals pre-treated with Guo did not reveal any significant changes in ER stress proteins (GRP 78 and 94) or HSP 70, but did reveal significantly increased levels of m-calpain. Thus, our data indicate that there is a treatment regimen for Guo as a neuroprotectant following ischemic stroke. The mechanism by which Guo confers neuroprotection may involve an increase in m-calpain, possibly resulting from a mild increase in intracellular calcium. M-calpain may be involved in the preconditioning response to ischemia by upregulating endogenous pro-survival mechanisms in neurons.
Copyright © 2011 Elsevier B.V. All rights reserved.PMID: 21774919 [PubMed – indexed for MEDLINE]

ChemMedChem. 2011 Jun 6;6(6):1074-80.
Evidence for the existence of a specific g protein-coupled receptor activated by guanosine.
Volpini R, Marucci G, Buccioni M, Dal Ben D, Lambertucci C, Lammi C, Mishra RC, Thomas A, Cristalli G.
Source
School of Pharmacy, Medicinal Chemistry Unit, University of Camerino via S. Agostino 1, 62032 Camerino, Italy.
Abstract
Guanosine, released extracellularly from neurons and glial cells, plays important roles in the central nervous system, including neuroprotection. The innovative DELFIA Eu-GTP binding assay was optimized for characterization of the putative guanosine receptor binding site at rat brain membranes by using a series of novel and known guanosine derivatives. These nucleosides were prepared by modifying the purine and sugar moieties of guanosine at the 6- and 5′-positions, respectively. Results of these experiments prove that guanosine, 6-thioguanosine, and their derivatives activate a G protein-coupled receptor that is different from the well-characterized adenosine receptors.
Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
PMID:21500353[PubMed – indexed for MEDLINE]

Neuroscience. 2011 Jun 2;183:212-20.
Guanosine is neuroprotective against oxygen/glucose deprivation in hippocampal slices via large conductance Ca²+-activated K+ channels, phosphatidilinositol-3 kinase/protein kinase B pathway activation and glutamate uptake.
Dal-Cim T, Martins WC, Santos AR, Tasca CI.
Source
Departamento de Bioquímica, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Trindade, 88040-900 Florianópolis, SC, Brazil.
Abstract
Guanine derivatives (GD) have been implicated in many relevant brain extracellular roles, such as modulation of glutamate transmission and neuronal protection against excitotoxic damage. GD are spontaneously released to the extracellular space from cultured astrocytes and during oxygen/glucose deprivation (OGD). The aim of this study has been to evaluate the potassium channels and phosphatidilinositol-3 kinase (PI3K) pathway involvement in the mechanisms related to the neuroprotective role of guanosine in rat hippocampal slices subjected to OGD. The addition of guanosine (100 μM) to hippocampal slices subjected to 15 min of OGD and followed by 2 h of re-oxygenation is neuroprotective. The presence of K+ channel blockers, glibenclamide (20 μM) or apamin (300 nM), revealed that neuroprotective effect of guanosine was not dependent on ATP-sensitive K+ channels or small conductance Ca²+-activated K+ channels. The presence of charybdotoxin (100 nM), a large conductance Ca²+-activated K+ channel (BK) blocker, inhibited the neuroprotective effect of guanosine. Hippocampal slices subjected to OGD and re-oxygenation showed a significant reduction of glutamate uptake. Addition of guanosine in the re-oxygenation period has blocked the reduction of glutamate uptake. This guanosine effect was inhibited when hippocampal slices were pre-incubated with charybdotoxin or wortmanin (a PI3K inhibitor, 1 μM) in the re-oxygenation period. Guanosine promoted an increase in Akt protein phosphorylation. However, the presence of charybdotoxin blocked such effect. In conclusion, the neuroprotective effect of guanosine involves augmentation of glutamate uptake, which is modulated by BK channels and the activation of PI3K pathway. Moreover, neuroprotection caused by guanosine depends on the increased expression of phospho-Akt protein.
Copyright © 2011 IBRO. Published by Elsevier Ltd. All rights reserved.
PMID:21435378[PubMed – indexed for MEDLINE]

J Neurochem. 2012 May;121(3):329-42.
Purine nucleosides: endogenous neuroprotectants in hypoxic brain.
Thauerer B, Zur Nedden S, Baier-Bitterlich G.
Source
Division of Neurobiochemistry, Biocenter Department, Medical University of Innsbruck, Innsbruck, Austria.
Abstract
Even a short blockade of oxygen flow in brain may lead to the inhibition of oxidative phosphorylation and depletion of cellular ATP, which results in profound deficiencies in cellular function. Following ischemia, dying, injured, and hypoxic cells release soluble purine-nucleotide and -nucleoside pools.
Growing evidence suggests that purine nucleosides might act as trophic factors in the CNS and PNS.
 In addition to equilibrative nucleoside transporters (ENTs) regulating purine nucleoside concentrations intra- and extracellularly, specific extracellular receptor subtypes for these compounds are expressed on neurons, glia, and endothelial cells, mediating stunningly diverse effects. Such effects range from induction of cell differentiation, apoptosis, mitogenesis, and morphogenetic changes, to stimulation of synthesis and/or release of cytokines and neurotrophic factors under both physiological and pathological conditions. Multiple signaling pathways regulate the critical balance between cell death and survival in hypoxia-ischemia. A convergent pathway for the regulation of multiple modalities involved in O₂ sensing is the mitogen activated protein kinase (p42/44 MAPK) or (ERK1/2 extracellular signal-regulated kinases) pathway terminating in a variety of transcription factors, for example, hypoxia-inducible factor 1α. In this review, the coherence of purine nucleoside-related pathways and MAPK activation in the endogenous neuroprotective regulation of the nervous system’s development and neuroplasticity under hypoxic stress will be discussed.
© 2012 The Authors. Journal of Neurochemistry © 2012 International Society for Neurochemistry.
PMID: 22335456 [PubMed – indexed for MEDLINE]  PMCID: PMC3499684

Neurol Neurochir Pol. 2011 Sep-Oct;45(5):489-99.
The role of ecto-purines in inflammation leading to demyelination – new means for therapies against multiple sclerosis.[Article in Polish]
Cieślak M, Komoszyński M.
Source
Wojewódzki Szpital Zespolony, Oddział Neurologiczny,Toruñ. marcies@autograf.pl
Abstract
Nucleotides released from activated and/or injured cells activate P2 receptors. Extracellular nucleotides serve as danger signals or damage-associated molecular patterns (DAMPs) that trigger various immune responses. Indeed, P2 receptors are highly expressed in the astrocytes, microglia and other immune cells such as T and B lymphocytes that migrate to the central nervous system. The activation of P2 receptors triggers the secretion of proinflammatory cytokines and chemokines as well as immune cell migration and proliferation that contribute to demyelination and axonal damage. The activation of P2 receptors is controlled by the ectonucleotidases which hydrolyze extracellular nucleotides. Ecto-NTPDases and ecto-5′-nucleotidase are expressed in the astrocytes, oligodendrocytes, microglia, endothelial cells and activated T cells.
The hydrolysis of extracellular ATP and ADP by enzymes results in the generation of extracellular adenosine. This nucleoside interacts with P1 receptors and activates anti-inflammatory and immunosuppressive responses in the cells involved in MS.
PMID:22127945[PubMed – indexed for MEDLINE]

Purinergic Signal. 2011 Dec;7(4):393-402.
Emerging role of extracellular nucleotides and adenosine in multiple sclerosis.
Cieślak M, Kukulski F, Komoszyński M.
Source
Department of Neurology, WSZ Hospital, 53/59 St. Joseph Street, Toruń, 87-100, Poland, marcies@autograf.pl.
Abstract
Extracellular nucleotides and adenosine play important roles in inflammation. These signaling molecules interact with the cell-surface-located P2 and P1 receptors, respectively, that are widely distributed in the central nervous system and generally exert opposite effects on immune responses. Indeed, extracellular ATP, ADP, UTP, and UDP serve as alarmins or damage-associated molecular patterns that activate mainly proinflammatory mechanisms, whereas adenosine has potent anti-inflammatory and immunosuppressive effects. This review discusses the actual and potential role of extracellular nucleotides and adenosine in multiple sclerosis (MS).
PMID:21792574[PubMed] PMCID:PMC3224637

Curr Opin Neurobiol. 2013 Feb 26.
Sleep and immune function: glial contributions and consequences of aging.        
Ingiosi AM, Opp MR, Krueger JM.
Source
Neuroscience Graduate Program, University of Michigan, Ann Arbor, MI, United States; Department of Anesthesiology and Pain Medicine, University of Washington, Seattle, WA, United States.
Abstract
The reciprocal interactions between sleep and immune function are well-studied. Insufficient sleep induces innate immune responses as evidenced by increased expression of pro-inflammatory mediators in the brain and periphery. Conversely, immune challenges upregulate immunomodulator expression, which alters central nervous system-mediated processes and behaviors, including sleep. Recent studies indicate that glial cells, namely microglia and astrocytes, are active contributors to sleep and immune system interactions. Evidence suggests glial regulation of these interactions is mediated, in part, by adenosine and adenosine 5′-triphosphate actions at purinergic type 1 and type 2 receptors. Furthermore, microglia and astrocytes may modulate declines in sleep-wake behavior and immunity observed in aging.
Copyright © 2013. Published by Elsevier Ltd.
PMID:23452941[PubMed – as supplied by publisher] PMCID:PMC3695049[Available on 2014/8/26]