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1.  The Reno-Vascular A2B Adenosine Receptor Protects the Kidney from Ischemia 
PLoS Medicine  2008;5(6):e137.
Acute renal failure from ischemia significantly contributes to morbidity and mortality in clinical settings, and strategies to improve renal resistance to ischemia are urgently needed. Here, we identified a novel pathway of renal protection from ischemia using ischemic preconditioning (IP).
Methods and Findings
For this purpose, we utilized a recently developed model of renal ischemia and IP via a hanging weight system that allows repeated and atraumatic occlusion of the renal artery in mice, followed by measurements of specific parameters or renal functions. Studies in gene-targeted mice for each individual adenosine receptor (AR) confirmed renal protection by IP in A1−/−, A2A−/−, or A3AR−/− mice. In contrast, protection from ischemia was abolished in A2BAR−/− mice. This protection was associated with corresponding changes in tissue inflammation and nitric oxide production. In accordance, the A2BAR-antagonist PSB1115 blocked renal protection by IP, while treatment with the selective A2BAR-agonist BAY 60–6583 dramatically improved renal function and histology following ischemia alone. Using an A2BAR-reporter model, we found exclusive expression of A2BARs within the reno-vasculature. Studies using A2BAR bone-marrow chimera conferred kidney protection selectively to renal A2BARs.
These results identify the A2BAR as a novel therapeutic target for providing potent protection from renal ischemia.
Using gene-targeted mice, Holger Eltzschig and colleagues identify the A2B adenosine receptor as a novel therapeutic target for providing protection from renal ischemia.
Editors' Summary
Throughout life, the kidneys perform the essential task of filtering waste products and excess water from the blood to make urine. Each kidney contains about a million small structures called nephrons, each of which contains a filtration unit consisting of a glomerulus (a small blood vessel) intertwined with a urine-collecting tube called a tubule. If the nephrons stop working for any reason, the rate at which the blood is filtered (the glomerular filtration rate or GFR) decreases and dangerous amounts of waste products such as creatinine build up in the blood. Most kidney diseases destroy the nephrons slowly over years, producing an irreversible condition called chronic renal failure. But the kidneys can also stop working suddenly because of injury or poisoning. One common cause of “acute” renal failure in hospital patients is ischemia—an inadequate blood supply to an organ that results in the death of part of that organ. Heart surgery and other types of surgery in which the blood supply to the kidneys is temporarily disrupted are associated with high rates of acute renal failure.
Why Was This Study Done?
Although the kidneys usually recover from acute failure within a few weeks if the appropriate intensive treatment (for example, dialysis) is provided, acute renal failure after surgery can be fatal. Thus, new strategies to protect the kidneys from ischemia are badly needed. Like other organs, the kidneys can be protected from lethal ischemia by pre-exposure to several short, nonlethal episodes of ischemia. It is not clear how this “ischemic preconditioning” increases renal resistance to ischemia but some data suggest that the protection of tissues from ischemia might involve a signaling molecule called extracellular adenosine. This molecule binds to proteins called receptors on the surface of cells and sends signals into them that change their behavior. There are four different adenosine receptor—A1AR, A2AAR, A2BAR, and A3AR—and in this study, the researchers use ischemic preconditioning as an experimental strategy to investigate which of these receptors protects the kidneys from ischemia in mice, information that might provide clues about how to protect the kidneys from ischemia.
What Did the Researchers Do and Find?
The researchers first asked whether ischemic preconditioning protects the kidneys of mice strains that lack the genes for individual adenosine receptors (A1AR−/−, A2AAR−/−, A2BAR−/−, and A3AR−/− mice) from subsequent ischemia. Using a hanging-weight system, they intermittently blocked the renal artery of these mice before exposing them to a longer period of renal ischemia. Twenty-four hours later, they assessed the renal function of the mice by measuring their blood creatinine levels, GFRs, and urine production. Ischemic preconditioning protected all the mice from ischemia-induced loss of kidney function except the A2BAR−/− mice. It also prevented ischemia-induced structural damage and inflammation in the kidneys of wild-type but not A2BAR−/− mice. These results suggest that A2BAR may help to protect the kidneys from ischemia. Consistent with this idea, ischemic preconditioning did not prevent ischemia-induced renal damage in wild-type mice treated with a compound that specifically blocks the activity of A2BAR. However, wild-type mice (but not A2BAR−/− mice) treated with an A2BAR agonist (which activates the receptor) retained their kidney function after renal ischemia without ischemic preconditioning. Finally, the researchers report that A2BAR has to be present on the blood vessels in the kidney to prevent ischemia-induced acute renal failure.
What Do These Findings Mean?
These findings suggest that the protection of the kidneys from ischemia and the renal resistance to ischemia that is provided by ischemic preconditioning involve adenosine signaling through A2BAR. They also suggest that adenosine might provide protection against ischemia-induced damage by blocking inflammation in the kidney although other possible mechanisms of action need to be investigated. Importantly, these findings suggest that A2BAR might be a therapeutic target for the prevention of renal ischemia. However, results obtained in animals do not always reflect the situation in people, so before A2BAR agonists can be used to reduce the chances of patients developing acute renal failure after surgery, these results need confirming in people and the safety of A2BAR agonists need to be thoroughly investigated.
Additional Information.
Please access these Web sites via the online version of this summary at
The US National Institute of Diabetes and Digestive and Kidney Diseases provides information on how the kidneys work and what can go wrong with them, including a list of links to further information about kidney disease
The MedlinePlus encyclopedia has a page on acute kidney failure (in English and Spanish)
Wikipedia has pages on acute renal failure, ischemia, ischemic preconditioning, and adenosine (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
PMCID: PMC2504049  PMID: 18578565
2.  Partial Agonists for A3 Adenosine Receptors 
Selective agonists for A3 adenosine receptors (ARs) could potentially be therapeutic agents for a variety of disorders, including brain and heart ischemic conditions, while partial agonists may have advantages over full agonists as a result of an increased selectivity of action. A number of structural determinants for A3AR activation have recently been identified, including the N6-benzyl group, methanocarba substitution of ribose, 2-chloro and 2-fluoro substituents, various 2’- and 3’-substitutions and 4’-thio substitution of oxygen. The 2-chloro substitution of CPA and R-PIA led to A3 antagonism (CCPA) and partial agonism (Cl-R-PIA). 2-Chloroadenosine was a full agonist, while 2-fluoroadenosine was a partial agonist. Both 2’- and 3’- substitutions have a pronounced effect on its efficacy, although the effect of 2’-substitution was more dramatic. The 4-thio substitution of oxygen may also diminish efficacy, depending on other substitutions. Both N6-methyl and N6-benzyl groups may contribute to the A3 affinity and selectivity; however, an N6-benzyl group but not an N6-methyl group diminishes A3AR efficacy. N6-benzyl substituted adenosine derivatives have similar potency for human and rat A3ARS while N6-methyl substitution was preferable for the human A3AR. The combination of 2-chloro and N6-benzyl substitutions appeared to reduce efficacy further than either modification alone. The A2AAR agonist DPMA was shown to be an antagonist for the human A3AR. Thus, the efficacy of adenosine derivatives at the A3AR appears to be more sensitive to small structural changes than at other subtypes. Potent and selective partial agonists for the A3AR could be identified by screening known adenosine derivatives and by modifying adenosine and the adenosine derivatives.
PMCID: PMC3425644  PMID: 15078216
3.  Partial adenosine A1 receptor agonists for cardiovascular therapies 
Purinergic Signalling  2011;8(Suppl 1):91-99.
Adenosine, a purine nucleoside, is present in all cells in tightly regulated concentrations. It has many different physiological effects in the whole body and in the heart. Adenosine activates four G protein-coupled receptors A1, A2a, A2b, and A3. Activation of myocardial A1 receptors has been shown to inhibit a variety of myocardial pathologies associated with ischemia and reperfusion injury, including stunning, arrhythmogenesis, coronary and ventricular dysfunction, acute myocardial infarction, apoptosis, and chronic heart failure, implying several options for new cardiovascular therapies for diseases, like angina pectoris, control of cardiac rhythm, ischemic injury during an acute coronary syndrome, or heart failure. However, the main issue of using full A1 receptor agonists in such indications is the broad physiologic spectrum of cardiac and extracardiac effects. Desired A1 receptor-mediated protective and regenerative cardiovascular effects might be counter-regulated by unintended side effects when considering full A1 receptor agonists. These effects can be overcome by partial A1 agonists. Partial A1 agonists can be used to trigger only some of the physiological responses of receptor activation depending on endogenous adenosine levels and on receptor reserve in different tissues. CV-Therapeutics reported the identification of a partial A1 receptor agonist CVT-3619, and recently, another partial A1 receptor agonist VCP28 was published. Both compounds are adenosine derivatives. Adenosine-like A1 receptor agonists often have the drawback of a short half-life and low bioavailability, making them not suitable for chronic oral therapy. We identified the first non-adenosine-like partial A1 receptor agonist(s) with pharmacokinetics optimal for oral once daily treatment and characterized the qualities of the partial character of the A1 receptor agonist(s) in preclinical and clinical studies.
PMCID: PMC3265704  PMID: 22081230
Adenosine A1 receptor; Partial adenosine A1 receptor agonists; Cardiovascular diseases
4.  Protection against ischemic damage by adenosine amine congener, a potent and selective adenosine A1 receptor agonist 
European journal of pharmacology  1999;369(3):313-317.
Although the selectivity and potency of adenosine amine congener (ADAC) at adenosine A1receptors are similar to other highly selective agonists at this receptor type, the chemical structure of the N6 substituent is completely different. We now demonstrate that the characteristics of the therapeutic profile of ADAC are distinct from those observed during our previous studies of adenosine A1receptor agonist-mediated neuroprotection. Most significantly, chronic treatment with low microgram doses of ADAC (25–100 µg/kg) protects against both mortality and neuronal damage induced by 10 min bilateral carotid occlusion in gerbils. At higher chronic doses, the statistical significance of the protective effect is lost. Acute preischemic administration of the drug at 75–200 µg/kg also results in a statistically significant reduction of postischemic mortality and morbidity. These data indicate that, contrary to other adenosine A1 receptor agonists whose chronic administration enhances postocclusive brain damage, ADAC may be a promising agent in treatment of both acute (e.g., cerebral ischemia) and chronic (seizures) disorders of the central nervous system in which adenosine A1 receptors appear to be involved.
PMCID: PMC3438899  PMID: 10225368
Cerebral ischemia; Adenosine A1 receptor; Therapy; Gerbil
5.  Postischemic administration of adenosine amine congener (ADAC): analysis of recovery in gerbils 
European journal of pharmacology  1996;316(2-3):171-179.
Although adenosine receptor-based treatment of cerebral ischemia and other neurodegenerative disorders has been frequently advocated, cardiovascular side effects and an uncertain therapeutic time window of such treatment have constituted major obstacles to clinical implementation. Therefore, we have investigated the neuroprotective effects of the adenosine A1 receptor agonist adenosine amine congener (ADAC) injected after either 5 or 10 min ischemia at 100 μg/kg. When the drug was administered at either 6 or 12 h following 5 min forebrain ischemia, all animals were still alive on the 14th day after the occlusion. In both ADAC treated groups neuronal survival was approximately 85% vs. 50% in controls. Administration of a single dose of ADAC at times 15 min to 12 h after 10 min ischemia resulted in a significant improvement of survival in animals injected either at 15 or 30 min, or at 1, 2, or 3 h after the insult. In all 10 min ischemia groups, administration of ADAC resulted in a significant protection of neuronal morphology and preservation of microtubule associated protein 2 (MAP-2). However, postischemic Morris’ water maze tests revealed full preservation of spatial memory and learning ability in animals injected at 6 h. On the other hand, the performance of gerbils treated at 12 h postischemia was indistinguishable from that of the controls. Administration of ADAC at 100 μg/kg in non-ischemic animals did not result in bradycardia, hypotension, or hypothermia. The data indicate that when ADAC is used postischemically, the most optimal level of protection is obtained when drugs are given at 30 min to 6 h after the insult. Although the mechanisms involved in neuroprotective effects of adenosine A1 receptor agonists require further studies, the present results demonstrate the feasibility of their clinical applications.
PMCID: PMC3449162  PMID: 8982684
Ischemia; treatment; Adenosine; Memory; MAP2 (microtubule-associated protein 2); (Gerbil)
6.  Adenosine A2A receptors in ventral striatum, hypothalamus and nociceptive circuitry. Implications for drug addiction, sleep and pain 
Progress in neurobiology  2007;83(5):332-347.
Adenosine A2A receptors localized in the dorsal striatum are considered as a new target for the development of antiparkinsonian drugs. Co-administration of A2A receptor antagonists has shown a significant improvement of the effects of L-DOPA. The present review emphasizes the possible application of A2A receptor antagonists in pathological conditions other than parkinsonism, including drug addiction, sleep disorders and pain. In addition to the dorsal striatum, the ventral striatum (nucleus accumbens) contains a high density of A2A receptors, which presynaptically and postsynaptically regulate glutamatergic transmission in the cortical glutamatergic projections to the nucleus accumbens. It is currently believed that molecular adaptations of the cortico-accumbens glutamatergic synapses are involved in compulsive drug seeking and relapse. Here we review recent experimental evidence suggesting that A2A antagonists could become new therapeutic agents for drug addiction. Morphological and functional studies have identified lower levels of A2A receptors in brain areas other than the striatum, such as the ventrolateral preoptic area of the hypothalamus, where adenosine plays an important role in sleep regulation. Although initially believed to be mostly dependent on A1 receptors, here we review recent studies that demonstrate that the somnogenic effects of adenosine are largely mediated by hypothalamic A2A receptors. A2A receptor antagonists could therefore be considered as a possible treatment for narcolepsy and other sleep-related disorders. Finally, nociception is another adenosine-regulated neural function previously thought to mostly involve A1 receptors. Although there is some conflicting literature on the effects of agonists and antagonists, which may partly be due to the lack of selectivity of available drugs, the studies in A2A receptor knockout mice suggest that A2A receptor antagonists might have some therapeutic potential in pain states, in particular where high intensity stimuli are prevalent.
PMCID: PMC2141681  PMID: 17532111
Adenosine A2A receptor; striatum; hypothalamus; peripheral nervous system; drug addiction; sleep; pain
7.  Oral antiplatelet therapy for atherothrombotic disease: overview of current and emerging treatment options 
Clinical presentations of atherothrombotic vascular disease, such as acute coronary syndromes, ischemic stroke or transient ischemic attack, and symptomatic peripheral arterial disease, are major causes of morbidity and mortality worldwide. Platelet activation and aggregation play a seminal role in the arterial thrombus formation that precipitates acute manifestations of atherothrombotic disease. As a result, antiplatelet therapy has become the cornerstone of therapy for the prevention and treatment of atherothrombotic disease. Dual antiplatelet therapy with aspirin and a P2Y12 adenosine diphosphate (ADP) receptor inhibitor, such as clopidogrel or prasugrel, is the current standard-of-care antiplatelet therapy in patients with acute coronary syndromes managed with an early invasive strategy. However, these agents are associated with several important clinical limitations, including significant residual risk for ischemic events, bleeding risk, and variability in the degree of platelet inhibition. The residual risk can be attributed to the fact that aspirin and P2Y12 inhibitors block only the thromboxane A2 and ADP platelet activation pathways but do not affect the other pathways that lead to thrombosis, such as the protease-activated receptor-1 pathway stimulated by thrombin, the most potent platelet agonist. Bleeding risk associated with aspirin and P2Y12 inhibitors can be explained by their inhibitory effects on the thromboxane A2 and ADP pathways, which are critical for protective hemostasis. Interpatient variability in the degree of platelet inhibition in response to antiplatelet therapy may have a genetic component and contribute to poor clinical outcomes. These considerations underscore the clinical need for therapies with a novel mechanism of action that may reduce ischemic events without increasing the bleeding risk.
PMCID: PMC3292409  PMID: 22393298
acute coronary syndromes; antiplatelet therapy; ADP; thromboxane A2; PAR-1; bleeding
8.  Novel allosteric agonists of M1 muscarinic acetylcholine receptors induce brain region-specific responses that correspond with behavioral effects in animal models 
The Journal of Neuroscience  2012;32(25):8532-8544.
M1 muscarinic acetylcholine receptors (mAChRs) represent a viable target for treatment of multiple disorders of the central nervous system (CNS) including Alzheimer’s disease and schizophrenia. The recent discovery of highly selective allosteric agonists of M1 receptors has provided a major breakthrough in developing a viable approach for discovery of novel therapeutic agents that target these receptors. Here, we describe the characterization of two novel M1 allosteric agonists VU0357017 and VU0364572 that display profound differences in their efficacy in activating M1 coupling to different signaling pathways including Ca++ and β-arrestin responses. Interestingly, the ability of these agents to differentially activate coupling of M1 to specific signaling pathways leads to selective actions on some but not all M1-mediated responses in brain circuits. These novel M1 allosteric agonists induced robust electrophysiological effects in rat hippocampal slices but showed lower efficacy in striatum and no measureable effects on M1-mediated responses in medial prefrontal cortical pyramidal cells in mice. Consistent with these actions, both M1 agonists enhanced acquisition of hippocampal-dependent cognitive function but did not reverse amphetamine-induced hyperlocomotion in rats. Together, these data reveal that M1 allosteric agonists can differentially regulate coupling of M1 to different signaling pathways and this can dramatically alter the actions of these compounds on specific brain circuits important for learning and memory and psychosis.
PMCID: PMC3398407  PMID: 22723693
9.  Adenosine and Stroke: Maximizing the Therapeutic Potential of Adenosine as a Prophylactic and Acute Neuroprotectant 
Current Neuropharmacology  2009;7(3):217-227.
Stroke is a leading cause of morbidity and mortality in the United States. Despite intensive research into the development of treatments that lessen the severity of cerebrovascular injury, no major therapies exist. Though the potential use of adenosine as a neuroprotective agent in the context of stroke has long been realized, there are currently no adenosine-based therapies for the treatment of cerebral ischemia and reperfusion. One of the major obstacles to developing adenosine-based therapies for the treatment of stroke is the prevalence of functional adenosine receptors outside the central nervous system. The activities of peripheral immune and vascular endothelial cells are particularly vulnerable to modulation via adenosine receptors. Many of the pathophysiological processes in stroke are a direct result of peripheral immune infiltration into the brain. Ischemic preconditioning, which can be induced by a number of stimuli, has emerged as a promising area of focus in the development of stroke therapeutics. Reprogramming of the brain and immune responses to adenosine signaling may be an underlying principle of tolerance to cerebral ischemia. Insight into the role of adenosine in various preconditioning paradigms may lead to new uses for adenosine as both an acute and prophylactic neuroprotectant.
PMCID: PMC2769005  PMID: 20190963
Adenosine; adenosine receptors; cerebral ischemia; neuroprotection; preconditioning; stroke; treatment.
10.  A Novel Pharmacological Approach to Treating Cardiac Ischemia 
The Journal of biological chemistry  2000;275(39):30272-30279.
Adenosine released during cardiac ischemia exerts a potent, protective effect in the heart via activation of A1 or A3 receptors. However, the interaction between the two cardioprotective adenosine receptors and the question of which receptor is the more important anti-ischemic receptor remain largely unexplored. The objective of this study was to test the hypothesis that activation of both receptors exerted a cardioprotective effect that was significantly greater than activation of either receptor individually. This was accomplished by using a novel design in which new binary conjugates of adenosine A1 and A3 receptor agonists were synthesized and tested in a novel cardiac myocyte model of adenosine-elicited cardioprotection. Binary drugs having mixed selectivity for both A1 and A3 receptors were created through the covalent linking of functionalized congeners of adenosine agonists, each being selective for either the A1 or A3 receptor subtype. MRS 1740 and MRS 1741, thiourea-linked, regioisomers of a binary conjugate, were highly potent and selective in radioligand binding assays for A1 and A3 receptors (Ki values of 0.7–3.5 nm) versus A2A receptors. The myocyte models utilized cultured chick embryo cells, either ventricular cells expressing native adenosine A1 and A3 receptors, or engineered atrial cells, in which either human A3 receptors alone or both human A1 and A3 receptors were expressed. The binary agonist MRS 1741 coactivated A1 and A3 receptors simultaneously, with full cardioprotection (EC50 ~0.1 nm) dependent on expression of both receptors. Thus, co-activation of both adenosine A1 and A3 receptors by the binary A1/A3 agonists represents a novel general cardioprotective approach for the treatment of myocardial ischemia.
PMCID: PMC3561767  PMID: 10887176
11.  Activation of adenosine1 (A1) receptors suppresses head shakes induced by a serotonergic hallucinogen in rats 
Neuropharmacology  2009;56(8):1082-1087.
Modulation of glutamatergic neurotransmission by metabotropic glutamate2/3 (mGlu2/3) receptor agonists effectively treats seemingly diverse neuropsychiatric illness such as generalized anxiety disorder and schizophrenia. Activation of adenosine A1 heteroceptors, like mGlu2 autoreceptors, decreases glutamate release in the medial prefrontal cortex (mPFC) and other limbic brain regions. Previously, we have reported electrophysiological, neurochemical and behavioral evidence for interactions between the 5-hydroxytryptamine2A (5-HT2A) and mGlu2/3 receptors in the mPFC. The present studies were designed to investigate the effects in rats of adenosine A1 receptor activation/blockade on a behavior modulated by 5-HT2A receptor activation/blockade in the mPFC: head shakes induced in the rat by phenethylamine hallucinogens. An adenosine A1 receptor agonist, N6-cyclohexyladenosine (CHA) suppressed head shakes induced by activation of 5-HT2A receptors with the phenethylamine hallucinogen (±)-2,5-dimethoxy-4-iodoamphetamine hydrochloride (DOI). An adenosine A1 receptor antagonist, 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), enhanced DOI-induced head shakes and blocked the suppressant action of an adenosine A1 receptor agonist on DOI-induced head shakes. Thus, the pattern of activity for an agonist and antagonist at the adenosine A1 receptor with respect to modulating DOI-induced head shakes is similar to the pattern observed with mGlu2/3 receptor agonists and antagonists. These novel observations with an adenosine A1 receptor agonist suggests that this pharmacological action could contribute to antipsychotic effects in addition to thymoleptic effects.
PMCID: PMC2706691  PMID: 19324062
head shakes; phenethylamine hallucinogens; DOI; adenosine; glutamate; medial prefrontal cortex
12.  Periodic 17β-Estradiol Pretreatment Protects Rat Brain from Cerebral Ischemic Damage via Estrogen Receptor-β 
PLoS ONE  2013;8(4):e60716.
Although chronic 17β-estradiol (E2) has been shown to be a cognition-preserving and neuroprotective agent in animal brain injury models, concern regarding its safety was raised by the failed translation of this phenomenon to the clinic. Previously, we demonstrated that a single bolus of E2 48 hr prior to ischemia protected the hippocampus from damage in ovariectomized rats via phosphorylation of cyclic-AMP response element binding protein, which requires activation of estrogen receptor subtype beta (ER-β). The current study tests the hypothesis that long-term periodic E2-treatment improves cognition and reduces post-ischemic hippocampal injury by means of ER-β activation. Ovariectomized rats were given ten injections of E2 at 48 hr intervals for 21 days. Hippocampal-dependent learning, memory and ischemic neuronal loss were monitored. Results demonstrated that periodic E2 treatments improved spatial learning, memory and ischemic neuronal survival in ovariectomized rats. Additionally, periodic ER-β agonist treatments every 48 hr improved post-ischemic cognition. Silencing of hippocampal ER-β attenuated E2-mediated ischemic protection suggesting that ER-β plays a key role in mediating the beneficial effects of periodic E2 treatments. This study emphasizes the need to investigate a periodic estrogen replacement regimen to reduce cognitive decline and cerebral ischemia incidents/impact in post-menopausal women.
PMCID: PMC3625208  PMID: 23593292
13.  Reduction of postischemic brain damage and memory deficits following treatment with the selective adenosine A1 receptor agonist 
European journal of pharmacology  1996;302(1-3):43-48.
Agonists of adenosine A1 receptors have been frequently proposed as candidates for clinical development in treatment of cerebral ischemia and stroke. Numerous experimental studies have shown that pre- and postischemic administration of these drugs results in a very significant reduction of postischemic brain damage. However, only a few studies determined the impact of cerebral ischemia and drug treatment on postischemic recovery of spatial memory. The present paper demonstrates that preischemic i.p. administration of adenosine amine congener (ADAC) at 100 μg/kg in gerbils results in a significant (P < 0.05) reduction of postischemic mortality and hippocampal, cortical and striatal morbidity. Postischemic Morris’ water maze tests show that preischemic treatment with ADAC also leads to a very significant (P < 0.001) reduction of postischemic spatial memory loss. Our results indicate feasibility of further consideration of adenosine A1 receptor agonists as a clinically applicable acute treatment of brain ischemia. Recent development of neuroprotective adenosine A1 receptor agonists that are free of cardiovascular side effects supports such development.
PMCID: PMC3449166  PMID: 8790990
Cerebral ischemia; Adenosine receptor; Spatial memory; Water maze; (Gerbil)
14.  Adenosine A2A receptors in Parkinson’s disease treatment 
Purinergic Signalling  2008;4(4):305-312.
Latest results on the action of adenosine A2A receptor antagonists indicate their potential therapeutic usefulness in the treatment of Parkinson’s disease. Basal ganglia possess high levels of adenosine A2A receptors, mainly on the external surfaces of neurons located at the indirect tracts between the striatum, globus pallidus, and substantia nigra. Experiments with animal models of Parkinson’s disease indicate that adenosine A2A receptors are strongly involved in the regulation of the central nervous system. Co-localization of adenosine A2A and dopaminergic D2 receptors in striatum creates a milieu for antagonistic interaction between adenosine and dopamine. The experimental data prove that the best improvement of mobility in patients with Parkinson’s disease could be achieved with simultaneous activation of dopaminergic D2 receptors and inhibition of adenosine A2A receptors. In animal models of Parkinson’s disease, the use of selective antagonists of adenosine A2A receptors, such as istradefylline, led to the reversibility of movement dysfunction. These compounds might improve mobility during both monotherapy and co-administration with L-DOPA and dopamine receptor agonists. The use of adenosine A2A receptor antagonists in combination therapy enables the reduction of the L-DOPA doses, as well as a reduction of side effects. In combination therapy, the adenosine A2A receptor antagonists might be used in both moderate and advanced stages of Parkinson’s disease. The long-lasting administration of adenosine A2A receptor antagonists does not decrease the patient response and does not cause side effects typical of L-DOPA therapy. It was demonstrated in various animal models that inhibition of adenosine A2A receptors not only decreases the movement disturbance, but also reveals a neuroprotective activity, which might impede or stop the progression of the disease. Recently, clinical trials were completed on the use of istradefylline (KW-6002), an inhibitor of adenosine A2A receptors, as an anti-Parkinson drug.
PMCID: PMC2583202  PMID: 18438720
Parkinson’s disease; Adenosine; Adenosine receptors; Dopamine receptors; Neuroprotection
15.  The ischemic preconditioning effect of adenosine in patients with ischemic heart disease 
In vivo and in vitro evidence suggests that adenosine and its agonists play key roles in the process of ischemic preconditioning. The effects of low-dose adenosine infusion on ischemic preconditioning have not been thoroughly studied in humans.
We hypothesised that a low-dose adenosine infusion could reduce the ischemic burden evoked by physical exercise and improve the regional left ventricular (LV) systolic function.
Materials and methods
We studied nine severely symptomatic male patients with severe coronary artery disease. Myocardial ischemia was induced by exercise on two separate occasions and quantified by Tissue Doppler Echocardiography. Prior to the exercise test, intravenous low-dose adenosine or placebo was infused over ten minutes according to a randomized, double blind, cross-over protocol. The LV walls were defined as ischemic if a reduction, no increment, or an increment of < 15% in peak systolic velocity (PSV) was observed during maximal exercise compared to the baseline values observed prior to placebo-infusion. Otherwise, the LV walls were defined as non-ischemic.
PSV increased from baseline to maximal exercise in non-ischemic walls both during placebo (P = 0.0001) and low-dose adenosine infusion (P = 0.0009). However, in the ischemic walls, PSV increased only during low-dose adenosine infusion (P = 0.001), while no changes in PSV occurred during placebo infusion (P = NS).
Low-dose adenosine infusion reduced the ischemic burden and improved LV regional systolic function in the ischemic walls of patients with exercise-induced myocardial ischemia, confirming that adenosine is a potential preconditioning agent in humans.
PMCID: PMC2779183  PMID: 19891770
16.  Regadenoson in the detection of coronary artery disease 
Myocardial perfusion studies use either physical exercise or pharmacologic vasodilator stress to induce maximum myocardial hyperemia. Adenosine and dipyridamole are the most commonly used agents to induce coronary arterial vasodilation for myocardial perfusion imaging. Both cause frequent undesirable side-effects. Because of its ultrashort half-life, adenosine must be administered by constant intravenous infusion during the examination. A key feature of an ideal A2A agonist for myocardial perfusion imaging studies would be an optimal level and duration of hyperemic response. Drugs with a longer half-time and more selective A2A adenosine receptor agonism, such as regadenoson, should theoretically result in a similar degree of coronary vasodilation with fewer or less severe side-effects than non-selective, ultrashort-lasting adenosine receptor stimulation. The available preclinical and clinical data suggest that regadenoson is a highly subtype-selective, potent, low-affinity A2A adenosine receptor agonist that holds promise for future use as a coronary vasodilator in myocardial perfusion imaging studies. Infusion of regadenoson achieves maximum coronary hyperemia that is equivalent to adenosine. After a single bolus infusion over 10 s, hyperemia is maintained significantly longer (approximately 2–5 min) than with adenosine, which should facilitate radionuclide distribution for myocardial perfusion imaging studies. In comparison with the clinically competitive A2A adenosine receptor agonist binodenoson, regadenoson has a several-fold shorter duration of action, although the magnitude of hyperemic response is comparable between the two. The more rapid termination of action of regadenoson points to an advantage of enhanced control for the clinical application. Regadenoson selectively causes vasodilation of the coronary circulation, whereas effects on systemic blood pressure are only mild. The clinical adverse effect profile of regadenoson appears to be favorable, particularly with respect to dreaded atrioventricular conduction disturbances and bronchospasm.
PMCID: PMC2496979  PMID: 18561509
regadenoson; adenosine; coronary vasodilation; physical exercise; ultrashort-lasting adenosine receptor stimulation; selective A2A adenosine receptor agonism
17.  Adenosine and Ischemic Preconditioning 
Current pharmaceutical design  1999;5(12):1029-1041.
Adenosine is released in large amounts during myocardial ischemia and is capable of exerting potent cardioprotective effects in the heart. Although these observations on adenosine have been known for a long time, how adenosine acts to achieve its anti-ischemic effect remains incompletely understood. However, recent advances on the chemistry and pharmacology of adenosine receptor ligands have provided important and novel information on the function of adenosine receptor subtypes in the cardiovascular system. The development of model systems for the cardiac actions of adenosine has yielded important insights into its mechanism of action and have begun to elucidate the sequence of signalling events from receptor activation to the actual exertion of its cardioprotective effect. The present review will focus on the adenosine receptors that mediate the potent anti-ischemic effect of adenosine, new ligands at the receptors, potential molecular signalling mechanisms downstream of the receptor, mediators for cardioprotection, and possible clinical applications in cardiovascular disorders.
PMCID: PMC3561763  PMID: 10607860
18.  Adenosine signaling in normal and sickle erythrocytes and beyond 
Microbes and infection / Institut Pasteur  2012;14(10):10.1016/j.micinf.2012.05.005.
Sickle cell disease (SCD) is a debilitating hemolytic genetic disorder with high morbidity and mortality affecting millions of individuals worldwide. Although SCD was discovered more than a century ago, no effective mechanism-based prevention and treatment are available due to poorly understood molecular basis of sickling, the fundamental pathogenic process of the disease. SCD patients constantly face hypoxia. One of the best-known signaling molecules to be induced under hypoxic conditions is adenosine. Recent studies demonstrate that hypoxia-mediated elevated adenosine signaling plays an important role in normal erythrocyte physiology. In contrast, elevated adenosine signaling contributes to sickling and multiple life threatening complications including tissue damage, pulmonary dysfunction and priapism. Here, we summarize recent research on the role of adenosine signaling in normal and sickle erythrocytes, progression of the disease and therapeutic implications.
In normal erythrocytes, both genetic and pharmacological studies demonstrate that adenosine can enhance 2,3-bisphosphoglycerate (2,3-BPG) production via A2B receptor (ADORA2B) activation, suggesting that elevated adenosine has an unrecognized role in normal erythrocytes to promote O2 release and prevent acute ischemic tissue injury. However, in sickle erythrocytes, the beneficial role of excessive adenosine-mediated 2,3-BPG induction becomes detrimental by promoting deoxygenation, polymerization of sickle hemoglobin and subsequent sickling. Additionally, adenosine signaling via the A2A receptor (ADORA2A) on invariant natural killer T (iNKT) cells inhibits iNKT cell activation and attenuates pulmonary dysfunction in SCD mice. Finally, elevated adenosine coupled with ADORA2BR activation is responsible for priapism, a dangerous complication seen in SCD.
Overall, the research reviewed here reveals a differential role of elevated adenosine in normal erythrocytes, sickle erythrocytes, iNK cells and progression of disease. Thus, adenosine signaling represents a potentially important therapeutic target for the treatment and prevention of disease.
PMCID: PMC3842013  PMID: 22634345
sickle cell disease; malaria; adenosine; adenosine A2B receptor; 2,3-diphosphoglycerate; adenosine deaminase
19.  Adverse and Protective Influences of Adenosine on the Newborn and Embryo: Implications for Preterm White Matter Injury and Embryo Protection 
Pediatric research  2011;69(4):271-278.
Few signaling molecules have the potential to influence the developing mammal as the nucleoside adenosine. Adenosine levels increase rapidly with tissue hypoxia and inflammation. Adenosine antagonists include the methlyxanthines caffeine and theophylline. The receptors that transduce adenosine action are the A1, A2a, A2b, and A3 adenosine receptors (ARs). In the postnatal period, A1AR activation may contribute to white matter injury in the preterm infant by altering oligodendrocyte (OL) development. In models of perinatal brain injury, caffeine is neuroprotective against periventricular white matter injury (PWMI) and hypoxic-ischemic encephalopathy (HIE). Supporting the notion that blockade of adenosine action is of benefit in the premature infant, caffeine reduces the incidence of broncho-pulmonary dysplasia and cerebral palsy in clinical studies. In comparison with the adverse effects on the postnatal brain, adenosine acts via A1ARs to play an essential role in protecting the embryo from hypoxia. Embryo protective effects are blocked by caffeine, and caffeine intake during early pregnancy increases the risk of miscarriage and fetal growth retardation. Adenosine and adenosine antagonists play important modulatory roles during mammalian development. The protective and deleterious effects of adenosine depend on the time of exposure and target sites of action.
PMCID: PMC3100210  PMID: 21228731
20.  Cytotoxic purine nucleoside analogues bind to A1, A2A and A3 adenosine receptors 
Naunyn-Schmiedeberg's archives of pharmacology  2012;385(5):10.1007/s00210-011-0719-6.
Fludarabine, clofarabine and cladribine are anti-cancer agents which are analogues of the purine nucleoside adenosine. These agents have been associated with cardiac and neurological toxicities. Because these agents are analogues of adenosine, they may act through adenosine receptors to elicit their toxic effects. The objective of this study was to evaluate the ability of cytotoxic nucleoside analogues to bind and activate adenosine receptor subtypes (A1, A2A, A2B, and A3). Radioligand binding studies utilizing chinese hamster ovary cells, stably transfected with adenosine A1, A2A, or A3 receptor subtype, were used to assess the binding affinities of these compounds, whereas adenylyl cyclase activity was used to assess the binding to A2B receptors. Clofarabine and cladribine both bound to the A2A receptor with a Ki of 17 and 15 μM, respectively. Clofarabine was the only adenosine analogue to bind to the A3 receptor with a Ki of 10 μM, and none of these compounds bound to the A2B receptor. Results show that clofarabine, cladribine and fludarabine bind to the A1 receptor. In addition, clofarabine, cladribine, and fludarabine were A1 agonists (IC50 3.1, 30 and 30 μM, respectively). Neither pyrimidine nucleoside analogues, gemcitabine nor cytarabine, associated with any of the adenosine receptor subtypes (Ki > 100μM). This is the first report of an interaction between all adenosine receptor subtypes and chemotherapeutic nucleoside analogues commonly used in the treatment of cancer. Therefore, activation of these receptors may be at least one mechanism through which fludarabine-associated toxicity occurs.
PMCID: PMC3831620  PMID: 22249336
Adenosine receptors; purine analogues; A1; A2A; A2B; A3 ligands; fludarabine; clofarabine; cladribine
21.  Adenosine receptors as drug targets — what are the challenges? 
Nature reviews. Drug discovery  2013;12(4):265-286.
Adenosine signalling has long been a target for drug development, with adenosine itself or its derivatives being used clinically since the 1940s. In addition, methylxanthines such as caffeine have profound biological effects as antagonists at adenosine receptors. Moreover, drugs such as dipyridamole and methotrexate act by enhancing the activation of adenosine receptors. There is strong evidence that adenosine has a functional role in many diseases, and several pharmacological compounds specifically targeting individual adenosine receptors — either directly or indirectly — have now entered the clinic. However, only one adenosine receptor-specific agent — the adenosine A2A receptor agonist regadenoson (Lexiscan; Astellas Pharma) — has so far gained approval from the US Food and Drug Administration (FDA). Here, we focus on the biology of adenosine signalling to identify hurdles in the development of additional pharmacological compounds targeting adenosine receptors and discuss strategies to overcome these challenges.
PMCID: PMC3930074  PMID: 23535933
22.  Neuroprotection by adenosine in the brain: From A1 receptor activation to A2A receptor blockade 
Purinergic Signalling  2005;1(2):111-134.
Adenosine is a neuromodulator that operates via the most abundant inhibitory adenosine A1 receptors (A1Rs) and the less abundant, but widespread, facilitatory A2ARs. It is commonly assumed that A1Rs play a key role in neuroprotection since they decrease glutamate release and hyperpolarize neurons. In fact, A1R activation at the onset of neuronal injury attenuates brain damage, whereas its blockade exacerbates damage in adult animals. However, there is a down-regulation of central A1Rs in chronic noxious situations. In contrast, A2ARs are up-regulated in noxious brain conditions and their blockade confers robust brain neuroprotection in adult animals. The brain neuroprotective effect of A2AR antagonists is maintained in chronic noxious brain conditions without observable peripheral effects, thus justifying the interest of A2AR antagonists as novel protective agents in neurodegenerative diseases such as Parkinson’s and Alzheimer’s disease, ischemic brain damage and epilepsy. The greater interest of A2AR blockade compared to A1R activation does not mean that A1R activation is irrelevant for a neuroprotective strategy. In fact, it is proposed that coupling A2AR antagonists with strategies aimed at bursting the levels of extracellular adenosine (by inhibiting adenosine kinase) to activate A1Rs might constitute the more robust brain neuroprotective strategy based on the adenosine neuromodulatory system. This strategy should be useful in adult animals and especially in the elderly (where brain pathologies are prevalent) but is not valid for fetus or newborns where the impact of adenosine receptors on brain damage is different.
PMCID: PMC2096528  PMID: 18404497
A1 receptors; A2A receptors; adenosine; adenosine kinase; brain; neuroprotection
23.  Autophagy is required for preconditioning by the adenosine A1 receptor-selective agonist CCPA 
Basic research in cardiology  2009;104(2):157-167.
We have shown that the cellular process of macroautophagy plays a protective role in HL-1 cardiomyocytes subjected to simulated ischemia/reperfusion (sI/R) (Hamacher-Brady et al. in J Biol Chem 281(40):29776–29787). Since the nucleoside adenosine has been shown to mimic both early and late phase ischemic preconditioning, a potent cardioprotective phenomenon, the purpose of this study was to determine the effect of adenosine on autophagosome formation. Autophagy is a highly regulated intracellular degradation process by which cells remove cytosolic long-lived proteins and damaged organelles, and can be monitored by imaging the incorporation of microtubule-associated light chain 3 (LC3) fused to a fluorescent protein (GFP or mCherry) into nascent autophagosomes. We investigated the effect of adenosine receptor agonists on autophagy and cell survival following sI/R in GFP-LC3 infected HL-1 cells and neonatal rat cardiomyocytes. The A1 adenosine receptor agonist 2-chloro-N(6)-cyclopentyl-adenosine (CCPA) (100 nM) caused an increase in the number of autophagosomes within 10 min of treatment; the effect persisted for at least 300 min. A significant inhibition of autophagy and loss of protection against sI/R measured by release of lactate dehydrogenase (LDH), was demonstrated in CCPA-pretreated cells treated with an A1 receptor antagonist, a phospholipase C inhibitor, or an intracellular Ca(+2) chelator. To determine whether autophagy was required for the protective effect of CCPA, autophagy was blocked with a dominant negative inhibitor (Atg5K130R) delivered by transient transfection (in HL-1 cells) or protein transduction (in adult rat cardiomyocytes). CCPA attenuated LDH release after sI/R, but protection was lost when autophagy was blocked. To assess autophagy in vivo, transgenic mice expressing the red fluorescent autophagy marker mCherry-LC3 under the control of the alpha myosin heavy chain promoter were treated with CCPA 1 mg/kg i.p. Fluorescence microscopy of cryosections taken from the left ventricle 30 min after CCPA injection revealed a large increase in the number of mCherry-LC3-labeled structures, indicating the induction of autophagy by CCPA in vivo. Taken together, these results indicate that autophagy plays an important role in mediating the cardioprotective effects conferred by adenosine pretreatment.
PMCID: PMC3682823  PMID: 19242639
Preconditioning; Ischemia/reperfusion; Autophagy; Cardiomyocytes; Adenosine; Cardioprotection
24.  Regulation of Adenosine Receptor Subtypes during Cultivation of Human Monocytes: Role of Receptors in Preventing Lipopolysaccharide-Triggered Respiratory Burst  
Infection and Immunity  2004;72(3):1349-1357.
Adenosine is a potent anti-inflammatory agent that modulates the function of cells involved in the inflammatory response. Here we show that it inhibits lipopolysaccharide (LPS)-induced formation of reactive oxygen intermediates (ROI) in both freshly isolated and cultured human monocytes. Blocking of adenosine uptake and inactivation of the adenosine-degrading enzyme adenosine deaminase enhanced the inhibitory action of adenosine, indicating that both pathways regulate the extracellular adenosine concentration. Adenosine-mediated inhibition could be reversed by XAC (xanthine amine congener), an antagonist of the adenosine receptor A2A, and MRS 1220 {N-9-chloro-2-(2-furanyl)[1, 2, 4]-triazolo[1,5-c]quinazolin-5-benzeneacetamide}, an A3 receptor antagonist, in both cell populations, while DPCPX (1,3-dipropyl-8-cyclopentylxanthine), an A1 receptor antagonist, had no effect. Similar to what was seen with adenosine, CGS 21680, an A2A and A3 receptor agonist, and IB-MECA, a nonselective A1 and A3 receptor agonist, dose dependently prevented ROI formation, indicating the involvement of A3 and probably also A2A in the suppressive effect of adenosine. Pretreatment of monocytes with adenosine did not lead to changes in the LPS-induced increase in intracellular calcium levels ([Ca2+]i). Thus, participation of [Ca2+]i in the action of adenosine seems unlikely. The adenosine-mediated suppression of ROI production was found to be more pronounced when monocytes were cultured for 18 h, a time point at which changes in the mRNA expression of adenosine receptors were observed. Most prominent was the increase in the A2A receptor mRNA. These data demonstrate that cultivation of monocytes is accompanied by changes in the inhibitory action of adenosine mediated by A3 and probably also the A2A receptor and that regulation of adenosine receptors is an integral part of the monocyte differentiation program.
PMCID: PMC355997  PMID: 14977938
25.  Adenosine A1 receptor activation attenuates lung ischemia-reperfusion injury 
Ischemia-reperfusion injury significantly contributes to morbidity and mortality in lung transplant patients. Currently no therapeutic agents are clinically available to prevent ischemia-reperfusion injury, and treatment strategies are limited to maintaining oxygenation and lung function. Adenosine can modulate inflammatory activity and injury via binding to various adenosine receptors, but the role of adenosine A1 receptor in ischemia-reperfusion injury and inflammation is not well understood. This study tests the hypothesis that selective, exogenous activation of A1 receptor is anti-inflammatory and attenuates lung ischemia-reperfusion injury.
Wild-type and A1 receptor knockout mice underwent 1 hour left lung ischemia and 2 hours reperfusion using an in vivo hilar-clamp model. An A1 receptor agonist, CCPA, was administered 5 minutes before ischemia. After reperfusion, lung function was evaluated by measuring airway resistance, pulmonary compliance and pulmonary artery pressure. Wet/dry weight ratio was used to assess edema. Myeloperoxidase and cytokine levels in bronchoalveolar lavage fluid were measured to determine neutrophil infiltration and inflammation.
In wild-type animals, CCPA significantly improved lung function and attenuated edema, cytokine expression and myeloperoxidase levels compared to vehicle-treated mice after ischemia-reperfusion. Lung ischemia-reperfusion injury was similar between A1 receptor knockout and wild-type mice, but CCPA had no effects in A1 receptor knockout mice. In vitro treatment of neutrophils with CCPA significantly reduced chemotaxis.
Exogenous A1 receptor activation improves lung function and decreases inflammation, edema and neutrophil chemotaxis after ischemia-reperfusion. These results suggest a potential therapeutic application for A1 receptor agonists for the prevention of lung ischemia-reperfusion injury after transplantation.
PMCID: PMC3657333  PMID: 23398646

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