Adenosine receptor Research Papers - Academia.edu (original) (raw)

Introduction: The 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) is a popular recreational drug and a major source of substance abuse, which ultimately leads to sensations of well-being, elation and euphoria, moderate... more

Introduction: The 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) is a popular recreational drug and a major source of substance abuse, which ultimately leads to sensations of well-being, elation and euphoria, moderate derealization/depersonalization, and cognitive disruptions, as well as intense sensory awareness. The mechanisms involved in memory impairment induced by MDMA are not completely understood.

This study describes the preparation and binding properties of [ 3 H]PSB-11, a novel, potent, and selective antagonist radioligand for human A 3 adenosine receptors (ARs). [ 3 H]PSB-11 binding to membranes of Chinese hamster ovary (CHO)... more

This study describes the preparation and binding properties of [ 3 H]PSB-11, a novel, potent, and selective antagonist radioligand for human A 3 adenosine receptors (ARs). [ 3 H]PSB-11 binding to membranes of Chinese hamster ovary (CHO) cells expressing the human A 3 AR was saturable and reversible. Saturation experiments showed that [ 3 H]PSB-11 labeled a single class of binding sites with high affinity (K D =4.9 nM) and limited capacity (B max =3500 fmol/mg of protein). PSB-11 is highly selective versus the other adenosine receptor subtypes. The new radioligand shows an extraordinarily low degree of non-specific binding rendering it a very useful tool for studying the (patho)physiological roles of A 3 ARs. #

Downstream A 3 receptor signalling plays an important role in the regulation of cell death and proliferation. Therefore, it is important to determine the molecular pathways involved through A 3 receptor stimulation. The... more

Downstream A 3 receptor signalling plays an important role in the regulation of cell death and proliferation. Therefore, it is important to determine the molecular pathways involved through A 3 receptor stimulation. The phosphatidylinositide-3-OH kinase (PI3K)/Akt and the Raf/ mitogen-activated protein kinase (MAPK/ERK) kinase (MEK)/mitogen-activated protein kinase (MAPK) pathways have central roles in the regulation of cell survival and proliferation. The crosstalk between these two pathways has also been investigated. The focus of this review centres on downstream mediators of A 3 adenosine receptor signalling.

The goal of this review is to highlight the wide range of biological activities displayed by purines, with particular emphasis on new purine-based agents which find potential application as chemical-biology tools and/or therapeutic... more

The goal of this review is to highlight the wide range of biological activities displayed by purines, with particular emphasis on new purine-based agents which find potential application as chemical-biology tools and/or therapeutic agents. The expanding interest in the biological properties of polyfunctionalized purine derivatives issues, in large part, from the development of rapid high-throughput screening essays for new protein targets, and the corresponding development of efficient synthetic methodology adapted to the construction of highly diverse purine libraries. Purine-based compounds have found new applications as inducers of interferon and lineage-committed cell dedifferentiation, agonists and antagonists of adenosine receptors, ligands of corticotropin-releasing hormone receptors, and as inhibitors of HSP90, Src kinase, p38a MAP kinase, sulfotransferases, phosphodiesterases, and Cdks. The scope of application of purines in biology is most certainly far from being exhausted. Testing purine derivatives against the multitude of biological targets for which small molecule probes have not yet been found should thus be a natural reflex.

Background Caffeine is the most commonly consumed psycho-stimulant in the world. The effects of caffeine on the body have been extensively studied; however, its effect on the structure of the brain has not been investigated to date.... more

Background Caffeine is the most commonly consumed psycho-stimulant in the world. The effects of caffeine on the body have been extensively studied; however, its effect on the structure of the brain has not been investigated to date. Results In the present study we found that the long-term consumption of caffeine can induce ventriculomegaly; this was observed in 40% of the study rats. In the caffeine-treated rats with ventriculomegaly, there was increased production of CSF, associated with the increased expression of Na+, K+-ATPase and increased cerebral blood flow (CBF). In contrast to the chronic effects, acute treatment with caffeine decreased the production of CSF, suggesting 'effect inversion' associated with caffeine, which was mediated by increased expression of the A1 adenosine receptor, in the choroid plexus of rats chronically treated with caffeine. The involvement of the A1 adenosine receptor in the effect inversion of caffeine was further supported by the inductio...

The binding affinities at rat AI, Aza, and & adenosine receptors of a wide range of derivatives of adenosine have been determined. Sites of modification include the purine moiety (1-, 3-, and 7-deaza; halo, alkyne, and amino substitutions... more

The binding affinities at rat AI, Aza, and & adenosine receptors of a wide range of derivatives of adenosine have been determined. Sites of modification include the purine moiety (1-, 3-, and 7-deaza; halo, alkyne, and amino substitutions a t the 2-and 8-positions; and NG-CHzring,-hydrazine, and-hydroxylamine) and the ribose moiety (2'-, 3'-, and 5'-deoxy; 2'-and 3'-0-methyl; 2'-deoxy 2'-fluoro; 6'4hio; 5'-uronamide; carbocyclic; 4'or 3'-methyl; and inversion of configuration). (-)-and (+)-5'-Noraristeromycin were 48-and 21-fold selective, respectively, for A2, vs A1 receptors. 2-Chloro-6'-thioadenosine displayed a K i value of 20 nM at Az, receptors (15-fold selective vs AI). 2-Chloroadenin-9-yl(~-~-2'-deoxy-6'-thiolyxofuranoside) displayed a Ki value of 8 pM at A1 receptors and appeared to be a n antagonist, on the basis of the absence of a GTP-induced shift in binding vs a radiolabeled antagonist (8-cyclopentyl-1,3-dipropylxanthine). 2-Chloro-2'-deoxyadenosine and 2-chloroadenin-9-yl(~-~-6'-thioarabinoside) were putative partial agonists at A1 receptors, with K i values of 7.4 and 5.4 pM, respectively. The Aza selective agonist 2-(1-hexynyl)-5'-(N-ethylcarbamoyl)adenosine displayed a K i value of 26 nM a t & receptors. The <-methyl substitution of adenosine was poorly tolerated, yet when combined with other favorable modifications, potency was restored. Thus, NG-benzyl-4'methyladenosine-5'-(N-methyluronamide) displayed a Ki value of 604 nM a t & receptors and was 103-and 88-fold selective vs A1 and Aga receptors, respectively. This compound was a full agonist in the &-mediated inhibition of adenylate cyclase in transfected CHO cells. The carbocyclic analogue of NG-(3-iodobenzyl)adenosine-5'-(N-methyluronamide) was 2-fold selective for & vs A1 receptors and was nearly inactive at A28 receptors.

Bipolar disorder afflicts approximately 1-3% of both men and women, and is coincident with major economic, societal, medical, and interpersonal consequences. Current mediations used for its treatment are associated with variable rates of... more

Bipolar disorder afflicts approximately 1-3% of both men and women, and is coincident with major economic, societal, medical, and interpersonal consequences. Current mediations used for its treatment are associated with variable rates of efficacy and often intolerable side effects. While preclinical and clinical knowledge in the neurosciences has expanded at a tremendous rate, recent years have seen no major breakthroughs in the development of novel types of treatment for bipolar disorder. We review here approaches to develop novel treatments specifically for bipolar disorder. Deliberate (ie not by serendipity) treatments may come from one of two general mechanisms: (1) Understanding the mechanism of action of current medications and thereafter designing novel drugs that mimics these mechanism(s); (2) Basing medication development upon the hypothetical or proven underlying pathophysiology of bipolar disorder. In this review, we focus upon the first approach. Molecular and cellular targets of current mood stabilizers include lithium inhibitable enzymes where lithium competes for a magnesium binding site (inositol monophosphatase, inositol polyphosphate 1-phosphatase, glycogen synthase kinase-3 (GSK-3), fructose 1,6-bisphosphatase, bisphosphate nucleotidase, phosphoglucomutase), valproate inhibitable enzymes (succinate semialdehyde dehydrogenase, succinate semialdehyde reductase, histone deacetylase), targets of carbamazepine (sodium channels, adenosine receptors, adenylate cyclase), and signaling pathways regulated by multiple drugs of different classes (phosphoinositol/protein kinase C, cyclic AMP, arachidonic acid, neurotrophic pathways). While the task of developing novel medications for bipolar disorder is truly daunting, we are hopeful that understanding the mechanism of action of current mood stabilizers will ultimately lead clinical trials with more specific medications and thus better treatments those who suffer from this devastating illness.

Stereotaxic injections of pertussis toxin (3-4 micrograms) over the right hippocampus resulted in blockade of long-term potentiation (LTP) induction in the ipsilateral stratum radiatum-CA1 and stratum oriens-CA1 synaptic systems. LTP of... more

Stereotaxic injections of pertussis toxin (3-4 micrograms) over the right hippocampus resulted in blockade of long-term potentiation (LTP) induction in the ipsilateral stratum radiatum-CA1 and stratum oriens-CA1 synaptic systems. LTP of intracellularly recorded excitatory postsynaptic potentials was prevented in slices obtained from the hippocampus at 3 and 4 but not 6 days post-toxin injection. Slices taken from the left (contralateral) hippocampus on the same days as above exhibited LTP which was similar to that obtained in control slices from uninjected rats. The post- but not presynaptic actions of adenosine were antagonized at 3, 4 and 6 days post-toxin injection. The observations suggest that the guanosine triphosphate binding proteins involved in LTP induction (GLTP) and those coupled to the postsynaptic adenosine receptors exhibit different turnover times.

ADP plays a key role in platelet aggregation which has led to the development of antiplatelet drugs that target the P2Y 12 receptor. The aim of this study was to characterize the effects of two novel P2Y 12 receptor antagonists, BX 667... more

ADP plays a key role in platelet aggregation which has led to the development of antiplatelet drugs that target the P2Y 12 receptor. The aim of this study was to characterize the effects of two novel P2Y 12 receptor antagonists, BX 667 and its active metabolite BX 048, on ...

The N-acylhydrazone (NAH) moiety is considered a privileged structure, being present in many compounds with diverse pharmacological activities. Among the activities attributed to NAH derivatives anti-inflammatory and analgesic ones are... more

The N-acylhydrazone (NAH) moiety is considered a privileged structure, being present in many compounds with diverse pharmacological activities. Among the activities attributed to NAH derivatives anti-inflammatory and analgesic ones are recurrent. As part of a research program aiming at the design of new analgesic and anti-inflammatory lead-candidates, a series of cyclohexyl-N-acylhydrazones 10–26 were structurally designed from molecular modification on the prototype LASSBio-294, representing a new class of cycloalkyl analogues. Compounds 10–26 and their conformationally restricted analogue 9 were synthetized and evaluated as analgesic and anti-inflammatory agents in classical pharmacologic protocols. The cyclohexyl-N-acylhydrazones 10–26 and the cyclohexenyl analogue 9 showed great anti-inflammatory and/or analgesic activities, but compound 13 stood out as a new prototype to treat acute and chronic painful states due to its important analgesic activity in a neuropathic pain model.

Acyclic nucleoside phosphonates are widely recognised antivirals. The oral prodrugs of prototype compounds, e.g., 9-[2-(phosphonomethoxy) ethyl]adenine (PMEA; adefovir), and 9-(R)-[2-(phosphonomethoxy)propyl]adenine [(R)-PMPA; tenofovir]... more

Acyclic nucleoside phosphonates are widely recognised antivirals. The oral prodrugs of prototype compounds, e.g., 9-[2-(phosphonomethoxy) ethyl]adenine (PMEA; adefovir), and 9-(R)-[2-(phosphonomethoxy)propyl]adenine [(R)-PMPA; tenofovir] were approved by FDA for treatment of hepatitis B (Hepsera), and acquired immunodeficiency syndrome (AIDS) (Viread), respectively. A number of acyclic nucleoside phosphonates possess immunostimulatory activity. The present experiments demonstrate that activation of cytokine and chemokine secretion is mediated by adenosine receptors. Included in the study were 9-(R)-[2-(phosphonomethoxy)propyl]adenine [tenofovir], N 6-cyclopentyl-(R)-9-[2-(phosphonomethoxy)propyl]-2,6-diaminopurine, N 6-cyclopropyl-(R)-9-[2-(phosphonomethoxy)propyl]-2,6-diaminopurine, and N 6-isobutyl-9-[2-(phosphonomethoxy)ethyl]-2,6-diaminopurine. All of them activate secretion of tumor necrosis factor-α (TNF-α), interleukin-10 (IL-10), "regulated on activation of normal T cell expressed and secreted" (RANTES/CCL5), and macrophage inflammatory protein-1α (MIP-1α/CCL3) in murine macrophages. With exception of MIP-1α, the effects were inhibited by antagonists of adenosine A 1 , A 2B , and A 3 receptors (not by adenosine A 2A receptor antagonist). The adenosine A 1 receptor antagonist inhibited TNF-α, IL-10, and RANTES, adenosine A 2B receptor antagonist inhibited TNF-α and RANTES, and adenosine A 3 receptor antagonist inhibited IL-10 and RANTES. The suppression is due to decreased transcription of cytokine mRNA. It may be suggested that acyclic nucleoside phosphonates are nonspecific ligands for purine P 1 receptors.

Somatostatin, a peptide with antisecretory and antiproliferative effects, coexists with noradrenaline in sympathetic neurons. Octreotide, a stable somatostatin analogue, prevents hypertension and cardiovascular structural changes induced... more

Somatostatin, a peptide with antisecretory and antiproliferative effects, coexists with noradrenaline in sympathetic neurons. Octreotide, a stable somatostatin analogue, prevents hypertension and cardiovascular structural changes induced by prolonged infusion of Ž. DPSPX 1,3-dipropyl-8-sulfophenylxanthine, a non-selective adenosine receptor antagonist in rats. In the present work we investigated the effect of somatostatin and its analogue w 3 x octreotide on the release of H noradrenaline from sympathetic nerves in the rat mesenw 3 x Ž teric artery. Rat mesenteric arteries were incubated for 60 min with H noradrenaline 0.2. Ž M , mounted in perifusion chambers, washed out for 90 min and electrically stimulated 2. Hz, 5 min, 50 mA. Radioactivity was measured in the tissue and in the perifusion fluid before, during and after stimulation. Both somatostatin and octreotide inhibited tritium release evoked by electrical stimulation of in¨itro preparations of rat mesenteric arteries w 3 x preloaded with H noradrenaline. The maximal effects produced by octreotide and somatostatin were a 56 and 70% inhibition of noradrenaline release, respectively. For Ž. somatostatin an EC s 0.18 nM 0.01 nM᎐2.2 nM; n s 16 was calculated. When used alone, 50 Ž w x. the somatostatin receptor antagonist, cyclo 7-aminoheptanoyl-Phe-D-Trp-Lys-Thr BZL Ž. CYCAM; 1 M , had no effect on noradrenaline release induced by electrical stimulation. However, it was able to significantly antagonize the inhibitory effects of octreotide and somatostatin. These results are compatible with a negative modulatory role of somatostatin on sympathetic neurotransmission.

Hypoxia-inducible factor-1 (HIF-1) is a key regulator of genes crucial to many aspects of cancer biology. The purine nucleoside, adenosine, accumulates within many tissues under hypoxic conditions, including that of tumors. Because the... more

Hypoxia-inducible factor-1 (HIF-1) is a key regulator of genes crucial to many aspects of cancer biology. The purine nucleoside, adenosine, accumulates within many tissues under hypoxic conditions, including that of tumors. Because the levels of both HIF-1 and adenosine are elevated within the hypoxic environment of solid tumors, we investigated whether adenosine may regulate HIF-1. Here we show that, under hypoxic conditions (< 2% O 2 ), adenosine upregulates HIF-1A protein expression in a dose-dependent and timedependent manner, exclusively through the A 3 receptor subtype. The response to adenosine was generated at the cell surface because the inhibition of A 3 receptor expression, by using small interfering RNA, abolished nucleoside effects. A 3 receptor stimulation in hypoxia also increases angiopoietin-2 (Ang-2) protein accumulation through the induction of HIF-1A. In particular, we found that A 3 receptor stimulation activates p44/ p42 and p38 mitogen-activated protein kinases, which are required for A 3 -induced increase of HIF-1A and Ang-2. Collectively, these results suggest a cooperation between hypoxic and adenosine signals that ultimately may lead to the increase in HIF-1 -mediated effects in cancer cells. Neoplasia (2005) 7, 894 -903

Methylphenidate (MPH) is the preferred treatment used for attention-deficit/hyperactivity disorder (ADHD). Recently, misuse for MPH due to its apparent cognitive enhancer properties has been reported. Adenosine is a neuromodulator known... more

Methylphenidate (MPH) is the preferred treatment used for attention-deficit/hyperactivity disorder (ADHD). Recently, misuse for MPH due to its apparent cognitive enhancer properties has been reported. Adenosine is a neuromodulator known to exert influence on the dopaminergic neurotransmission, which is the main pharmacological target of MPH. We have reported that an overdosage of MPH up-regulates adenosine A 1 receptors in the frontal cortex, but this receptor was not involved in its anxiolytic effects. In this study, the role of adenosine A 1 receptor was investigated on MPH-induced effects on aversive and recognition memory in adult mice. Adult mice received acute and chronic (15 days) administration of methylphenidate (5 mg/kg, i.p.), or an acute overdosage (50 mg/kg, i.p) in order to model misuse. Memory was assessed in the inhibitory avoidance and object recognition task. Acute administration 5 mg/kg improved whereas 50 mg/kg disrupted recognition memory and decreased performance in the inhibitory avoidance task. Chronic administration did not cause any effect on memory, but decreased adenosine A 1 receptors immunocontent in the frontal cortex. The selective adenosine A 1 receptor antagonist, (DPCPX 1 mg/kg, i.p.), prevented methylphenidate-triggered recognition memory impairment. Our findings showed that recognition memory rather than aversive memory was differently affected by acute administration at both doses. Memory recognition was fully impaired by the overdosage, suggesting that misuse can be harmful for cognitive functions. The adenosinergic system via A 1 receptors may play a role in the methylphenidate actions probably by interfering with dopamine-enhancing properties of this drug.

Mucociliary clearance, vital to lung clearance, is dependent on cilia beat frequency (CBF), coordination of cilia, and the maintenance of periciliary fluid. Adenosine, the metabolic breakdown product of ATP, is an important modulator of... more

Mucociliary clearance, vital to lung clearance, is dependent on cilia beat frequency (CBF), coordination of cilia, and the maintenance of periciliary fluid. Adenosine, the metabolic breakdown product of ATP, is an important modulator of ciliary motility. However, the contributions of specific adenosine receptors to key airway ciliary motility processes are unclear. We hypothesized that adenosine modulates ciliary motility via activation of its cell surface receptors (A1, A2A, A2B, or A3). To test this hypothesis, mouse tracheal rings (MTRs) excised from wild-type and adenosine receptor knockout mice (A1, A2A, A2B, or A3, respectively), and bovine ciliated bronchial epithelial cells (BBECs) were stimulated with known cilia activators, isoproterenol (ISO; 10 μM) and/or procaterol (10 μM), in the presence or absence of 5′-(N-ethylcarboxamido) adenosine (NECA), a nonselective adenosine receptor agonist [100 nM (A1, A2A, A3); 10 μM (A2B)], and CBF was measured. Cells and MTRs were also s...

Adenosine is a purine nucleoside, which is produced inside the body under metabolic stress like hypoxic conditions, acute or chronic inflammatory tissue insults. The synthesis of adenosine involves the catabolism of adenine nucleotides... more

Adenosine is a purine nucleoside, which is produced inside the body under metabolic stress like hypoxic conditions, acute or chronic inflammatory tissue insults. The synthesis of adenosine involves the catabolism of adenine nucleotides (ATP, ADP and AMP) by the action of extracellular ectonucleotidases i.e. CD39 or nucleoside triphosphate dephosphorylase (NTPD) and CD73 or 5′-ectonucleotidase. Once adenosine is released in the extracellular environment, it binds to different types of adenosine (i.e. adenosine A 1 , A 2A , A 2B and A 3 receptors) receptors expressed on various innate immune cells [Neutrophils, macrophages, mast cells, dendritic cells and natural killer cells]. Thus, depending on the type of adenosine receptor to which it binds, adenosine modulates innate immune response during various inflammatory conditions [i.e. chronic (cancer, asthma) as well as acute (sepsis, acute lung injury) inflammatory diseases]. This review summarizes the effect of adenosine on innate immunity and the use of adenosine receptor specific agonists or antagonists in various immunologic disorders (asthma, cancer, HIV-1 infection) as future immunomodulatory therapeutics.

Transcriptional factors and signalling molecules from intracellular metabolism modulate a complex set of events during brain development. Neurotransmitter and neuromodulator synthesis and their receptor expressions vary according to... more

Transcriptional factors and signalling molecules from intracellular metabolism modulate a complex set of events during brain development. Neurotransmitter and neuromodulator synthesis and their receptor expressions vary according to different stages of brain development. The dynamics of signalling systems is often accompanied by alterations in enzyme expression and activity. Adenosine is a neuromodulator that controls the release of several neurotransmitters, including acetylcholine, which is an important neurotransmitter during brain development. Caffeine is a non-specific antagonist of adenosine receptors and can reach the immature brain. We evaluated the effects of rat maternal caffeine intake (1g/L) on acetylcholine degradation and acetylcholinesterase expression from hippocampus of 7-, 14- and 21-day-old neonates in caffeine-treated and control groups. Caffeine was not able to change the age-dependent increase of acetylcholinesterase activity or the age-dependent decrease of acetylcholinesterase expression. However, caffeine promoted an increase of acetylcholinesterase activity (42%) without modifications on the level of acetylcholinesterase mRNA transcripts in 21-day-old rats. Considering the high score of phosphorylatable residues on acetylcholinesterase, this profile can be associated with a possible regulation by specific phosphorylation sites. These results highlight the ability of maternal caffeine intake to interfere on cholinergic neurotransmission during brain development.

The striatal dopamine D2 receptor (D2R) and adenosine A2A receptor (A2AAR) exhibit mutually antagonistic effects through physical interactions and by differential modulation of post-receptor signaling pathways. The expression of the A2AAR... more

The striatal dopamine D2 receptor (D2R) and adenosine A2A receptor (A2AAR) exhibit mutually antagonistic effects through physical interactions and by differential modulation of post-receptor signaling pathways. The expression of the A2AAR and the D2R are differentially regulated by nuclear factor-κB (NFkB). In this report, we determined the role of NFkB in regulation of these receptors by comparing mice deficient in the NFκB p50 subunit (p50 KO) with genetically intact B6129PF2/J (F2) mice. Quantification of adenosine receptor (AR) subtypes in mouse striatum by real time PCR, immunocytochemistry and radioligand binding assays showed more A2AAR but less A1AR in p50 KO mice as compared with F2 mice. Striata from p50 KO mice also had less D2R mRNA and [3H]-methylspiperone binding than did striata from F2 mice. Gαolf and Gαs proteins, which are transducers of A2AAR signals, were also present at a higher level in striata from the p50 KO versus F2 mice. In contrast, the Gαi1 protein, which transduces signals from the A1AR and D2R, was significantly reduced in striata from p50-/ mice. Behaviorally, p50 KO mice exhibited increased locomotor activity relative to that of F2 mice after caffeine ingestion. These data are consistent with a role for the NFkB in the regulation of A1AR, A2AAR, D2R and possibly their coupling G proteins in the striatum. Dysregulation of these receptors in the striata of p50 KO mice might sensitize these animals to locomotor stimulatory action of caffeine.

Fibroblast growth factors (FGFs) exert diverse effects resulting from their interaction with cognate receptors on target cells. Our current study was designed to examine the local production and action of two specific stromal-epithelial... more

Fibroblast growth factors (FGFs) exert diverse effects resulting from their interaction with cognate receptors on target cells. Our current study was designed to examine the local production and action of two specific stromal-epithelial cell mediatory factors, keratinocyte growth factor (KGF) and FGF-10, in human endometrial carcinoma cells. The RT-PCR method was used to determine gene expression of KGF, FGF-10, and KGF receptor in human endometrial carcinoma cells (HEC-1) and human endometrial stromal cells. KGF mRNAs were expressed in both of these cell types. On the other hand, FGF-10 mRNA was detected only in the endometrial stromal cells, and KGF receptor mRNA was observed in the HEC-1 cells. The novel finding of the present study is that KGF is expressed in carcinoma cells and FGF-10 is expressed in human endometrial stromal cells. The distinct phosphorylation of ERK-1 and-2 (ERK1/2), which are members of the MAPK family, was observed when HEC-1 cells were treated with KGF or FGF-10. KGF and FGF-10 could induce the prompt phosphorylation of ERK1/2 and consequently stimulate DNA synthesis. KGF and FGF-10 did not activate the phosphorylation of Akt, protein kinase C, or signal transducer and activator of transcription-3. Blocking the MAPK pathway with the specific methyl ethyl ketone 1/2 inhibitor (U0126) completely neutralized the enhancement of cell proliferation induced by KGF and FGF-10. In addition, KGF and FGF-10 activated expressions of downstream nuclear transcription factors, such as Elk-1 and c-myc, but not c-fos. These results demonstrate for the first time that KGF and FGF-10 are capable of stimulating the growth of endometrial carcinoma cells via activating MAPK pathway through autocrine/paracrine fashion.

The recent determination of X-ray structures of pharmacologically relevant GPCRs has made these targets accessible to structure-based ligand discovery. Here we explore whether novel chemotypes may be discovered for the A 2A adenosine... more

The recent determination of X-ray structures of pharmacologically relevant GPCRs has made these targets accessible to structure-based ligand discovery. Here we explore whether novel chemotypes may be discovered for the A 2A adenosine receptor, based on complementarity to its recently determined structure. The A 2A adenosine receptor signals in the periphery and the CNS, with agonists explored as anti-inflammatory drugs and antagonists explored for neurodegenerative diseases. We used molecular docking to screen a 1.4 million compound database against the X-ray structure computationally and tested 20 high-ranking, previously unknown molecules experimentally. Of these 35% showed substantial activity with affinities between 200 nM and 9 μM. For the most potent of these new inhibitors, over 50-fold specificity was observed for the A 2A versus the related A 1 and A 3 subtypes. These high hit rates and affinities at least partly reflect the bias of commercial libraries toward GPCR-like chemotypes, an issue that we attempt to investigate quantitatively. Despite this bias, many of the most potent new ligands were novel, dissimilar from known ligands, providing new lead structures for modulation of this medically important target.

Pituicyte stellation in vitro represents a useful model with which to study morphological changes that occur in vivo in these cells during times of high neurohypophysial hormone output. This model has helped us establish the hypothesis of... more

Pituicyte stellation in vitro represents a useful model with which to study morphological changes that occur in vivo in these cells during times of high neurohypophysial hormone output. This model has helped us establish the hypothesis of a purinergic regulation of pituicyte morphological plasticity. We first show that ATP induces stellation in 37% of pituicytes, an effect that is secondary to the metabolism of ATP to adenosine. Adenosine-induced stellation of pituicytes appears to be mediated by A 1-type receptors. The effect is independent of intracellular calcium and does not involve the mitogen-activated protein kinase pathway. The basal (nonstellate) state of pituicytes depends on tonic activation of a Rho GTPase because both C3 transferase (a Rho inhibitor) and Y-27632 (an inhibitor of p160Rho kinase) can induce stellation. Lysophosphatidic acid, a Rho activator, blocks the morphogenic effect of adenosine dose-dependently. Using a specific RhoA pull-down assay, we also show that downregulation of activated RhoA is the key event coupling A 1 receptor activation to pituicyte stellation, via F-actin depolymerization and microtubule reorganization. Finally, both vasopressin and oxytocin can prevent or reverse adenosine-induced stellation. The effects of vasopressin, and those of high concentrations of oxytocin, are mediated through V 1a receptors. Placed within the context of the relevant literature, our data suggest the possibility of a purinergic regulation of pituicyte morphological plasticity and subsequent modulation of hormone release, with these hormones providing a negative feedback mechanism.

In the present study, we sought to determine whether administration of caffeine, a non-selective adenosine receptor antagonist, would affect the thermal antihyperalgesic efficacy of acute amitriptyline in a rat model of neuropathic pain.... more

In the present study, we sought to determine whether administration of caffeine, a non-selective adenosine receptor antagonist, would affect the thermal antihyperalgesic efficacy of acute amitriptyline in a rat model of neuropathic pain. Rats were rendered neuropathic by unilateral tight ligation of the fifth and sixth lumbar spinal nerves, and tested for thermal hyperalgesia using a focused beam of light. Ž. Systemic administration of caffeine 1.5-7.5 mgrkg , at the same time as amitriptyline, blocked the thermal antihyperalgesic effect of 10 Ž. mgrkg amitriptyline. The greatest degree of block exerted by caffeine was observed with 3.75 mgrkg 100% block , a dose that had no Ž. observable intrinsic effect. Spinal administration of amitriptyline 60 mg exhibited a mild antihyperalgesic effect that was unaffected by Ž. Ž pretreatment with intrathecal caffeine 100 mg. Peripheral administration of amitriptyline into the neuropathic paw under brief. anesthesia produced an antihyperalgesic effect at both 30 and 100 nmol, with a greater effect being observed at 100 nmol. Ž. Coadministration of caffeine 1500 nmol partially antagonized the effects of both doses of amitriptyline. The results of this study suggest that the thermal antihyperalgesic effect of acute amitriptyline in this model may involve enhancement of an endogenous adenosine tone. This involvement is important in light of the widespread consumption of caffeine, which may potentially act to reduce the benefits of amitriptyline in the treatment of neuropathic pain.

Intraperitoneal guanosine has been shown to prevent quinolinic acid-induced seizures in mice. In this study, we investigated the effect of orally administered guanosine on seizures induced by the glutamate agonists quinolinic acid and... more

Intraperitoneal guanosine has been shown to prevent quinolinic acid-induced seizures in mice. In this study, we investigated the effect of orally administered guanosine on seizures induced by the glutamate agonists quinolinic acid and kainate, and the endogenous glutamate releaser a-dendrotoxin. Guanosine (7.5 mg / kg, per os), administered 75 min in advance, prevented 70% of seizures induced by i.c.v. quinolinic acid, being as efficient as the NMDA channel blocker MK-801 administered intraperitoneally. Guanosine was ineffective against kainate-induced seizures, but significantly reversed the potentiation of seizures and death caused by the concomitant injection of MK-801. Guanosine also significantly prevented seizures and death induced by i.c.v. a-dendrotoxin, whereas MK-801 and phenobarbital only prevented death. Altogether, our findings underscore the therapeutic potential of oral administration of guanosine for treating diseases involving glutamatergic excitotoxicity, including epilepsy.

We examined the effects of the antioxidant propolis on seizures induced by kainic acid (KA). Sprague-Dawley rats received propolis (75 and 150 mg/kg, p.o.) five times at 12 h intervals. KA (10 mg/kg, i.p.) was injected 1 h after the last... more

We examined the effects of the antioxidant propolis on seizures induced by kainic acid (KA). Sprague-Dawley rats received propolis (75 and 150 mg/kg, p.o.) five times at 12 h intervals. KA (10 mg/kg, i.p.) was injected 1 h after the last propolis treatment. Pretreatment with propolis significantly attenuated KA-induced seizures and KA-induced increases in hippocampal AP-1 DNA binding activity in a dosedependent manner. KA induced increases in the levels of malondialdehyde and protein carbonyl, and a decrease in the ratio of GSH/GSSG. These oxidative stresses and neuronal degenerations were significantly attenuated by pretreatment with propolis. The neuroprotective effects of propolis appeared to be counteracted by adenosine receptor antagonists [A 1 antagonist, 8-cyclopentyl-1,3-dimethylxanthine (25 or 50 mg/kg); A 2A antagonist, 1,3,7-trimethyl-8-(3-chlorostyryl)xanthine (0.5 or 1 mg/kg); and A 2B antagonist, alloxazine (1.5 or 3.0 mg/kg)]. However, this counteraction was most pronounced in the presence of the A 1 antagonist. Our results suggest that the protective effect of propolis against KA-induced neurotoxic oxidative damage is, at least in part, via adenosine A 1 receptor modulation.

The influence of chronic dietary lithium administration and electroconvulsive therapy on adenosine A 1 and A 2 receptors in rat brain were determined. A 2 receptor activity was measured by accumulation of cyclic AMP in a cerebral cortical... more

The influence of chronic dietary lithium administration and electroconvulsive therapy on adenosine A 1 and A 2 receptors in rat brain were determined. A 2 receptor activity was measured by accumulation of cyclic AMP in a cerebral cortical slice preparation after in vitro addition of 2-chloro-adenosine, and was unchanged in animals which received chronic Li but reduced following chronic ECT. A similar reduction was found in the response to noradrenaline and a combination of the two agents. A 1 receptors were measured by binding of [3H]cyclohexyladenosine. Both K a and Bma X values were unchanged after chronic Li or a single ECS, but chronic ECT led to a 70% increase in Bma x. It is proposed that this effect may mediate the reduced locomotor activity seen after chronic ECT in rats, and that it may also be related to the increase in seizure thresholds seen during a course of ECS treatment in humans.

Two adenosine receptors A, and A, are associated with either stimulation (AZ) or inhibition (A,) of adenylate cyclase. Using the clonal cell line Obl771, we have studied the expression of the two receptors during the process of adipose... more

Two adenosine receptors A, and A, are associated with either stimulation (AZ) or inhibition (A,) of adenylate cyclase. Using the clonal cell line Obl771, we have studied the expression of the two receptors during the process of adipose conversion accelerated by exposure to dexamethasone and 3-isobutyl-1-methylxanthine (IBMX) during the first 3 days post-confluence. The effects mediated by the two receptors on preadipocyte differentiation and adipocyte metabolism were also investigated. The two adenosine agonists NECA and PIA were used as preferential agonists of the A,-and A,-receptor, respectively. In preadipose cells (just confluent). both of the mouse clonal line and human primary culture, NECA dose-dependently stimulated CAMP production with a significant higher potency (P < 0.01) than did PIA. In adipose cells (16-day post-confluent) NECA was found to exert a biphasic effect on forskolin-stimulated CAMP production; i.e., NECA was clearly inhibitory in the femto-to picomolar concentration range whereas this effect gradually diminished at higher concentrations. The effect of PIA in 16-day post-confluent adipose cells however, was purely inhibitory on both CAMP production (IC,,: 33.52 f 0.44 fM) and lipolysis (64% k 7%; P < 0.01). These findings were corroborated by Northern blot analysis which revealed A,-receptor mRNA to be exclusively expressed in the mature adipocytes. whereas AZ-receptor mRNA gradually declined during the differentiation process except in 16-day post-confluent cells. In addition, NECA significantly enhanced the effect of corticosterone-induced differentiation by 46.8% (P < 0.05) but failed to have any adipogenic potency acting either alone or in concert with carbaprostacyclin (cPG1,). Thus, endogenous adenosine may have a bimodal action on adipose tissue metabolism mediated through stimulatory A,-and inhibitory A,-receptors, respectively, as a function of adipose conversion.

The methyl xanthines (MX), theophylline, caffeine, and theobromine, are potent antagonists of adenosine receptors. Adaptation of the human tongue to methyl xanthines at concentrations ranging from 10-s M to 10-2 M was found to potentiate... more

The methyl xanthines (MX), theophylline, caffeine, and theobromine, are potent antagonists of adenosine receptors. Adaptation of the human tongue to methyl xanthines at concentrations ranging from 10-s M to 10-2 M was found to potentiate taste. The artificial sweetener acesulfam-K, which has a bitter component, was potentiated the most by MX, i.e., approximately 100%. This increase in perceived intensity for acesulfam-K occurred at 10-5 M MX, a concentration known to inhibit adenosine receptors but below that required to inhibit phosphodiesterase. Increasing the concentration of MX as high as 10-z M did not increase the degree of enhancement appreciably. Taste enhancement was found for NaCI and quinine hydrochiodde as well. When 10-'~ M adenosine was added to the MX, the potentiation was reversed. The human results were confirmed by animal studies in which single unit extracellular recordings were made from the nucleus of the solitary tract. These results suggest that the inhibitory A~ adenosine receptor plays an important local role in taste perception.

Whereas structurally dissimilar D 1 antagonists competing for [ 3 H]-SCH23390 binding recognize primarily one site in striatum, two distinct affinity states are observed in both amygdala and hippocampus. The binding profile of SCH23390 is... more

Whereas structurally dissimilar D 1 antagonists competing for [ 3 H]-SCH23390 binding recognize primarily one site in striatum, two distinct affinity states are observed in both amygdala and hippocampus. The binding profile of SCH23390 is similar in both of these regions, with the high affinity site (K D ~0.4 nM) consistent with D 1 /D 5 receptors. The appearance of the low affinity site (K D ~ 300 nM) is dependent upon the absence of MgCl 2 , but independent of D 1 expression (i.e., still present in D 1 knockout mice). Although the density of high affinity state receptor is lower in hippocampus or amygdala of D 1 knockout mice, some residual binding remains, consistent with the known expression of D 5 receptors in these regions. Remarkably, in hippocampus, the affinity of the low affinity site is shifted rightward in the presence of the D 2 antagonist domperidone and is largely absent in the hippocampus of D 2 knockout animals. Additionally, this site is also shifted rightward in the presence of the A 2A ligands SCH58261, CSC, or NECA, or in the absence of A 2A receptors. The affinity of SCH23390 for this low affinity site is greater than seen for SCH23390 binding to D 2 receptors in heterologous expression systems, consistent with the hypothesis that both D 2 and A 2A receptors are involved in the low affinity binding site. Therefore, we suggest that the heteromerization of D 2 and A 2A receptors reported previously in vitro also may occur in the brain of both rats and mice.

Adenosine can regulate synaptic transmission through modulation of the action of other neurotransmitters. The influence of adenosine on VIP enhancement of synaptic transmission in hippocampal slices was investigated. Facilitation of fEPSP... more

Adenosine can regulate synaptic transmission through modulation of the action of other neurotransmitters. The influence of adenosine on VIP enhancement of synaptic transmission in hippocampal slices was investigated. Facilitation of fEPSP slope by 1 nM VIP (23.3 AE 1.3%) was turned into an inhibition (À12.1 AE 3.4%) when extracellular endogenous adenosine was removed using adenosine deaminase (ADA, 1 U/ ml). Blockade of adenosine A 1 receptors with 1,3-dipropyl-8-cyclopentylxanthine (DPCPX, 10 nM) or of A 2A receptors with ZM241385 (20 nM) attenuated the effect of VIP. When both DPCPX and ZM241385 were present the effect of VIP was abolished. In the presence of ADA, selective A 1 receptor activation with N 6 -cyclopentyladenosine (CPA, 15 nM) or A 2A receptor-activation with CGS21680 (10 nM) partially readmitted the excitatory effect of VIP on fEPSPs. In contrast, facilitation of PS amplitude by 1 nM VIP (19.1 AE 1.2%) was attenuated in the presence of ADA or DPCPX but was not changed by ZM241385. CPA, in the presence of ADA, fully restored the effect of VIP on PS amplitude. In conclusion, VIP facilitation of synaptic transmission to hippocampal pyramidal cell dendrites is dependent on both A 1 and A 2A receptor activation by endogenous adenosine. VIP effects on PS amplitude are only dependent on A 1 adenosine receptor activation. This differential sensitivity to adenosine modulation might be due to the different VIP circuits contributing to VIP effects on pyramidal cell dendrites and pyramidal cell bodies.

The A3 adenosine receptor, A3AR, belongs to the family of Gi proteins, which upon induction, suppresses the formation of cAMP and its downstream eectors. Recent studies have indicated that activation of A3AR by its agonist, IB-MECA,... more

The A3 adenosine receptor, A3AR, belongs to the family of Gi proteins, which upon induction, suppresses the formation of cAMP and its downstream eectors. Recent studies have indicated that activation of A3AR by its agonist, IB-MECA, results in growth inhibition of malignant cells. Here we demonstrate the ability of IB-MECA to decrease the levels of protein kinase A, a downstream eector of cAMP, and protein kinase B/Akt in melanoma cells. Examination of glycogen synthase kinase 3b, GSK-3b, whose phosphorylation is controlled by protein kinase A and B, showed a substantial decrease in the levels of its phosphorylated form and an increase in total GSK-3b levels in IB-MECA treated melanoma cells. This observation suggests that the treatment of cells with IB-MECA augments the activity of GSK-3b in the cells. Evaluation of b-catenin, a key component of Wnt signaling pathway which, upon phosphorylation by GSK-3b rapidly ubiquitinates, showed a substantial decrease in its level after IB-MECA treatment. Accordingly, the level of b-catenin responsive cell growth regulatory genes including c-myc and cyclin D1 was severely declined upon treatment of the cells with IB-MECA. These observations which link cAMP to the Wnt signaling pathway provide mechanistic evidence for the involvement of Wnt pathway via its key elements GSK-3b and b-catenin in the anti-tumor activity of A3AR agonists.

Objective. The aim of this study was to evaluate the effect of CF101, a synthetic agonist to the A3 adenosine receptor (A3AR), on the production of granulocyte colony-stimulating factor (G-CSF). The ability of CF101 to act as a... more

Objective. The aim of this study was to evaluate the effect of CF101, a synthetic agonist to the A3 adenosine receptor (A3AR), on the production of granulocyte colony-stimulating factor (G-CSF). The ability of CF101 to act as a myeloprotective agent in chemotherapy-treated mice was tested. Methods. CF101 was administered orally to naïve mice and its effect was studied on blood cell counts (coulter counter), serum G-CSF level (ELISA), bone marrow colony-forming cells (soft agar culture), and splenocytes' ability to produce ex vivo G-CSF. Protein extract was prepared from splenocytes and Western blot analysis was carried out to evaluate expression level of key proteins. In an additional set of experiments, CF101 was administered to mice 48 hours after cyclophosphamide treatment and blood cell counts as well as serum G-CSF levels were monitored.

The A 3 adenosine receptor (A 3 AR) agonists IB-MECA and Cl-IB-MECA act as anticancer agents by inhibiting the growth of melanoma and colon carcinoma cells both in vitro and in vivo. The A 3 AR is highly expressed in these tumor cells and... more

The A 3 adenosine receptor (A 3 AR) agonists IB-MECA and Cl-IB-MECA act as anticancer agents by inhibiting the growth of melanoma and colon carcinoma cells both in vitro and in vivo. The A 3 AR is highly expressed in these tumor cells and upon agonist binding receptor internalization and recycling occurs. The downstream signaling pathways that follow these events include a decrease in the expression level of protein kinase A (PKA) and protein kinase B/Akt (PKB/Akt) leading to the deregulation of the Wnt and the NF-kB signaling pathways. Interestingly, IB-MECA and Cl-IB-MECA generate the opposite, beneficial effect on myeloid cells. These agonists induce the production of granulocyte colonystimulating factor (G-CSF) by murine splenocytes. The molecular mechanisms underlying the events prior to G-CSF production include the upregulation of NF-kB and the upstream kinases phosphoinositide 3kinase (PI3K), PKB/Akt, and IKK. In addition, a myeloprotective effect is noted upon administration of IB-MECA and Cl-IB-MECA to chemotherapy-treated mice. This was expressed by accelerated recovery of white blood cells and neutrophil counts in cyclophosphamide-treated mice following agonist administration. Taken together, activation of the A 3 AR on tumor and normal cells generates opposing responses: in tumor cells, NF-kB expression level decreases, resulting in tumor growth inhibition, while in normal cells it is upregulated, leading to G-CSF production and the induction of myelostimulation. It thus appears that A 3 AR agonists act as tumor growth inhibitors, simultaneously maintaining the myeloid system, capable of preventing the damage of chemotherapeutic agents. Drug Dev. Res. 58:386-389, 2003.

dioxol-5-yl-2-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-1-methyl-1Hpyrazol-3-yloxy]-acetamide] is a selective antagonist ligand of A 2B adenosine receptors. For use as a radioligand, 1,3-diallyl-xanthine, the precursor... more

dioxol-5-yl-2-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-1-methyl-1Hpyrazol-3-yloxy]-acetamide] is a selective antagonist ligand of A 2B adenosine receptors. For use as a radioligand, 1,3-diallyl-xanthine, the precursor of [ 3 H]-MRE 2029-F20, was synthesized, and tritiated on the allyl groups. [ 3 H]-MRE 2029-F20 bound to human A 2B receptors expressed in CHO cells showed a K D value of 1.65 AE 0.10 nM and B max value of 36 AE 4 fmol/mg protein. [ 3 H]-MRE2029-F20 represents a useful tool for the pharmacological characterization of human A 2B adenosine receptor subtype.

Mucociliary clearance, vital to lung clearance, is dependent on cilia beat frequency (CBF), coordination of cilia, and the maintenance of periciliary fluid. Adenosine, the metabolic breakdown product of ATP, is an important modulator of... more

Mucociliary clearance, vital to lung clearance, is dependent on cilia beat frequency (CBF), coordination of cilia, and the maintenance of periciliary fluid. Adenosine, the metabolic breakdown product of ATP, is an important modulator of ciliary motility. However, the contributions of specific adenosine receptors to key airway ciliary motility processes are unclear. We hypothesized that adenosine modulates ciliary motility via activation of its cell surface receptors (A1, A2A, A2B, or A3). To test this hypothesis, mouse tracheal rings (MTRs) excised from wild-type and adenosine receptor knockout mice (A1, A2A, A2B, or A3, respectively), and bovine ciliated bronchial epithelial cells (BBECs) were stimulated with known cilia activators, isoproterenol (ISO; 10 μM) and/or procaterol (10 μM), in the presence or absence of 5′-(N-ethylcarboxamido) adenosine (NECA), a nonselective adenosine receptor agonist [100 nM (A1, A2A, A3); 10 μM (A2B)], and CBF was measured. Cells and MTRs were also s...

OBJECTIVE To determine the mechanisms by which blockade of adenosine A2B receptors (A2BRs) reduces insulin resistance. RESEARCH DESIGN AND METHODS We investigated the effects of deleting or blocking the A2BR on insulin sensitivity using... more

OBJECTIVE To determine the mechanisms by which blockade of adenosine A2B receptors (A2BRs) reduces insulin resistance. RESEARCH DESIGN AND METHODS We investigated the effects of deleting or blocking the A2BR on insulin sensitivity using glucose tolerance tests (GTTs) and hyperinsulinemic-euglycemic clamps in mouse models of type 2 diabetes. The effects of diabetes on A2BR transcription and signaling were measured in human and mouse macrophages and mouse endothelial cells. In addition, tag single nucleotide polymorphisms (SNPs) in ∼42 kb encompassing the A2BR gene, ADORA2B, were evaluated for associations with markers of diabetes and inflammation. RESULTS Treatment of mice with the nonselective adenosine receptor agonist 5′-N-ethylcarboxamidoadensoine (NECA) increased fasting blood glucose and slowed glucose disposal during GTTs. These responses were inhibited by A2BR deletion or blockade and minimally affected by deletion of A1Rs or A2ARs. During hyperinsulinemic-euglycemic clamp of...

We previously found that the endogenous anticonvulsant adenosine, acting through A2A and A3 adenosine receptors (ARs), alters the stability of currents (IGABA) generated by GABAA receptors expressed in the epileptic human mesial temporal... more

We previously found that the endogenous anticonvulsant adenosine, acting through A2A and A3 adenosine receptors (ARs), alters the stability of currents (IGABA) generated by GABAA receptors expressed in the epileptic human mesial temporal lobe (MTLE). Here we examined whether ARs alter the stability (desensitization) of IGABA expressed in focal cortical dysplasia (FCD) and in periglioma epileptic tissues. The experiments were performed with tissues from 23 patients, using voltage-clamp recordings in Xenopus oocytes microinjected with membranes isolated from human MTLE and FCD tissues or using patch-clamp recordings of pyramidal neurons in epileptic tissue slices. On repetitive activation, the epileptic GABAA receptors revealed instability, manifested by a large IGABA rundown, which in most of the oocytes (≈70%) was obviously impaired by the new A2A antagonists ANR82, ANR94, and ANR152. In most MTLE tissue-microtransplanted oocytes, a new A3 receptor antagonist (ANR235) significantly ...

To examine ischemic tolerance in the absence of A1 adenosine receptors (A1ARs), isolated wild-type (WT) and A1AR knockout (A1KO) murine hearts underwent global ischemia-reperfusion, and injury was measured in terms of functional recovery... more

To examine ischemic tolerance in the absence of A1 adenosine receptors (A1ARs), isolated wild-type (WT) and A1AR knockout (A1KO) murine hearts underwent global ischemia-reperfusion, and injury was measured in terms of functional recovery and efflux of lactate dehydrogenase (LDH). Hearts were analyzed by real-time RT-PCR both at baseline and at intervals during ischemia-reperfusion to determine whether compensatory expression of other adenosine receptor subtypes occurs with either A1AR deletion and/or ischemia-reperfusion. A1KO hearts had higher baseline coronary flow (CF) and left ventricular developed pressure (LVDP) than WT hearts, whereas heart rate was unchanged by A1AR deletion. After 20 min of ischemia, CF was attenuated in A1KO compared with WT hearts, and this reduction persisted throughout reperfusion. Final recovery of LVDP was decreased in A1KO hearts (54.4 ± 5.1 vs. WT 81.1 ± 3.4% preischemic baseline) and correlated with higher diastolic pressure during reperfusion. Pos...

In situations of impending tissue danger, such as during ischaemia, the concentration of the endogenous purine nucleoside adenosine rapidly increases. Subsequent stimulation of G-protein coupled adenosine receptors induces several... more

In situations of impending tissue danger, such as during ischaemia, the concentration of the endogenous purine nucleoside adenosine rapidly increases. Subsequent stimulation of G-protein coupled adenosine receptors induces several cardiovascular effects, such as vasodilation, inhibition of inflammation, modulation of sympathetic nervous system activity, and increasing myocardial tolerance against ischaemia-reperfusion, which are all aimed at protecting the affected tissue. Although animal models have consistently shown profound cardiovascular protection by adenosine, up to now translation of this knowledge into clinical practice is limited. This current review is focused on human in vivo studies on the cardiovascular effects of adenosine. Several techniques, such as microdialysis, venous occlusion plethysmography, and 99m Tc-annexin A5 scintigraphy can be used to study these effects of adenosine in healthy volunteers in vivo. By use of these techniques, recent studies have shown that the cardiovascular effects of adenosine can be modulated by genetic factors (e.g. a single nucleotide polymorphism in the gene encoding for adenosine monophosphate deaminase), by metabolic factors (e.g. by the plasma homocysteine concentration), and by drugs, such as caffeine, dipyridamole, and methotrexate. Given the cardiovascular protective properties of adenosine, these factors could well modulate the risk or extent of cardiovascular disease in patients and knowledge of these factors could be of benefit in daily clinical practice to optimize treatment in patients with cardiovascular disease.

Adenosine is an endogenous purine nucleoside that plays a neuromodulatory role in the central nervous system. A2a adenosine receptors have been involved in reward-related processes, inflammatory phenomena and neurotoxicity reactions. In... more

Adenosine is an endogenous purine nucleoside that plays a neuromodulatory role in the central nervous system. A2a adenosine receptors have been involved in reward-related processes, inflammatory phenomena and neurotoxicity reactions. In the present study, we investigated the role of A2a adenosine receptors on the acute pharmacological effects, reinforcement and neuroinflammation induced by MDMA administration. First, the acute effects of MDMA on body temperature, locomotor activity and anxiety-like responses were measured in A2a knockout mice and wild-type littermates. Second, MDMA reinforcing properties were evaluated using the intravenous self-administration paradigm. Finally, we assessed striatal astrogliosis and microgliosis as markers of MDMA neurotoxicity. Our results showed that acute MDMA produced a biphasic effect on body temperature and increased locomotor activity and anxiogenic-like responses in both genotypes. However, MDMA reinforcing properties were dramatically affec...

There is considerable evidence that purines are vasoactive molecules involved in the regulation of blood flow. Adenosine is a well known vasodilator that also acts as a modulator of the response to other vasoactive substances. Adenosine... more

There is considerable evidence that purines are vasoactive molecules involved in the regulation of blood flow. Adenosine is a well known vasodilator that also acts as a modulator of the response to other vasoactive substances. Adenosine exerts its effects by interacting ...

Brain iron insufficiency has been implicated in several neurological disorders. The dopamine system is consistently altered in studies of iron deficiency in rodent models. Changes in striatal dopamine D 2 receptors are directly... more

Brain iron insufficiency has been implicated in several neurological disorders. The dopamine system is consistently altered in studies of iron deficiency in rodent models. Changes in striatal dopamine D 2 receptors are directly proportional to the degree of iron deficiency. In light of the unknown mechanism for the iron deficiency-dopamine connection and because of the known interplay between adenosinergic and dopaminergic systems in the striatum we examined the effects of iron deficiency on the adenosine system. We first attempted to assess whether there is a functional change in the levels of adenosine receptors in response to this low iron. Mice made iron-deficient by diet had an increase in the density of striatal adenosine A 2A (A 2A R) but not A 1 receptor (A 1 R) compared to mice on a normal diet. Between two inbred murine strains, which had 2-fold differences in their striatal iron concentrations under normal dietary conditions, the strain with the lower striatal iron had the highest striatal A 2A R density. Treatment of SH-SY5Y (human neuroblastoma) cells with an iron chelator resulted in increased density of A 2A R. In these cells, A 2A R agonist-induced cyclic AMP production was enhanced in response to iron chelation, also demonstrating a functional upregulation of A 2A R. A significant correlation (r 2 =0.79) was found between a primary marker of cellular iron status (transferrin receptor (TfR)) and A 2A R protein density. In conclusion, the A 2A R is increased across different iron-insufficient conditions. The relation between A 2A R and cellular iron status may be an important pathway by which adenosine may alter the function of the dopaminergic system.