2-(4-(2-carboxyethyl)phenethylamino)-5--n-ethylcarboxamidoadenosine and Body-Weight

Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative method for blood cancers and other blood disorders, but is limited by the development of graft-versus-host disease (GVHD). GVHD results in inflammatory damage to the host liver, gastrointestinal tract and skin, resulting in high rates of morbidity and mortality in HSCT recipients. Activation of the A

Topics: Adenosine; Adenosine A2 Receptor Agonists; Animals; Body Weight; Cytokines; Disease Models, Animal; Female; Graft vs Host Disease; Humans; Mice; Phenethylamines; T-Lymphocytes, Regulatory

Multiple sclerosis (MS) is a common autoimmune disease that inevitably causes inflammatory nerve demyelination. However, an effective approach to prevent its course is still lacking and urgently needed. Recently, the adenosine A2A receptor (A2AR) has emerged as a novel inflammation regulator. Manipulation of A2AR activity may suppress the MS process and protect against nerve damage. To test this hypothesis, we treated murine experimental autoimmune encephalomyelitis (EAE), a model for MS, with the selective A2AR agonist, CGS21680 (CGS). We evaluated the effects of CGS on the pathological features of EAE progression, including CNS cellular infiltration, inflammatory cytokine expression, lymphocyte proliferation, and cell surface markers. Treatment with CGS significantly suppressed specific lymphocyte proliferation, reduced infiltration of CD4(+) T lymphocytes, and attenuated the expression of inflammatory cytokines, which in turn inhibited the EAE progression. For the first time, we demonstrate that CGS can increase the intracellular calcium concentration ([Ca(2+)]i) in murine lymphocytes, which may be the mechanism underlying the suppressive effects of CGS-induced A2AR activation on EAE progression. Our findings strongly suggest that A2AR is a potential therapeutic target for MS and provide insight into the mechanism of action of A2AR agonists, which may offer a therapeutic option for this disease.

Topics: Adenosine; Adenosine A2 Receptor Agonists; Animals; Body Weight; Calcium; Disease Progression; Encephalomyelitis, Autoimmune, Experimental; Female; Immunologic Factors; Intracellular Space; Lymphocytes; Mice, Inbred C57BL; Myelin Sheath; Phenethylamines; Receptor, Adenosine A2A; Severity of Illness Index; Spinal Cord

Evidence indicate that adenosine A2A receptor subtype is of critical importance in stroke. An overexpression of A2A adenosine receptors occurs at central level on neurons and microglia of ischemic striatum and cortex after focal ischemia. Adenosine A2A receptor subtype is localized not only at central level but also peripherally on blood cells, where it is known to exert antiinflammatory effect. Purpose of the present work was to investigate the putative neuroprotective effect of the adenosine A2A receptor agonist CGS21680 in a rat model of transient medial cerebral artery occlusion (MCAo). Transient cerebral ischemia was induced by 1h occlusion of MCA. CGS21680 (0.01 and 0.1mg/kg, i.p.) was administered starting 4h after ischemia according to a chronic protocol (twice/day for 7 days). CGS21680, at the dose of 0.1mg/kg transiently increased heart frequency but did not modify blood pressure. At the dose of 0.01mg/kg the drug did not modify either heart frequency or blood pressure. Following transient MCAo, CGS21680 at both doses protected from neurological deficit from the first day up to 7 days thereafter. At this time, it has reduced microgliosis, astrogliosis and improved myelin organization in the striatum and cytoarchitecture of the ischemic cortex and striatum. Two days after transient MCAo, CGS21680 has reduced the number of infiltrated granulocytes into the ischemic tissue. Data indicate that CGS21680 systemically administered is protective by immunosuppressive effects.

Topics: Adenosine; Adenosine A2 Receptor Agonists; Animals; Blood Pressure; Body Weight; Brain Ischemia; Cerebral Cortex; Corpus Striatum; Disease Models, Animal; Gliosis; Heart Rate; Male; Motor Activity; Neuroprotective Agents; Phenethylamines; Rats; Rats, Wistar; Weight Loss

Caffeine is frequently administered in human preterm newborns. Although some data suggest a potential risk for the developing brain, its impact has not been fully evaluated. We used a murine model of postnatal caffeine treatment in which mouse pups received intraperitoneal injections of caffeine from postnatal days 3 to 10. Caffeine exposure resulted in a transient reduction of glial fibrillary acidic protein and S100beta protein expression in various brain areas during the first 2 postnatal weeks (19.8% and 23.2% reduction in the hippocampus at P15, respectively). This effect was dose-dependent and at least partly involved a reduction of glial proliferation, as a caffeine-induced decrease of 5-bromodeoxyuridine incorporation was observed in the dentate gyrus and subventricular zone (25.8% and 26.6%, respectively) and no increase of programmed cell death (cleaved caspase-3 immunostaining) was observed at postnatal day 7. This effect could be reproduced with an antagonist of A(2a) adenosine receptor (A(2a)R) and was blocked by co-injection of an agonist. These results suggest that postnatal caffeine treatment might induce an alteration of astrocytogenesis via A(2a)R blockade during brain development. Although no obvious neuritic abnormalities (microtubule-associated protein 2 and synaptophysin immunostaining) were observed, postnatal caffeine treatment could have long-term consequences on brain function.

Topics: Adenosine; Animals; Animals, Newborn; Apoptosis; Astrocytes; Behavior, Animal; Body Weight; Brain; Caffeine; Cell Differentiation; Cell Proliferation; Dose-Response Relationship, Drug; Glial Fibrillary Acidic Protein; Immunohistochemistry; Injections, Intraperitoneal; Mice; Microtubule-Associated Proteins; Models, Animal; Nerve Growth Factors; Organ Size; Phenethylamines; Pyrimidines; Receptor, Adenosine A2A; S100 Calcium Binding Protein beta Subunit; S100 Proteins; Synaptophysin; Time Factors; Triazoles

It has been observed that a cytokine synthesis inhibitor, pentoxifylline, prevents the apoptotic processes taking place in the amygdala following myocardial infarction. However, it is unknown if the cardioprotective effect of A(2A) adenosine receptor agonist, CGS21680, which reduces cytokine synthesis, would lead to such amygdala apoptosis regression. Thus, this study was designed to investigate whether cardioprotective A(2A) adenosine receptor activation reduces apoptosis in the amygdala following myocardial infarction. Anesthetized rats were subjected to left anterior descending coronary artery occlusion for 40 min, followed by 72 h of reperfusion. The A(2A) agonist CGS21680 (0.2 mug/kg/min i.v.) was administered continuously for 120 min, starting (1) five minutes prior to instituting reperfusion (Early) or (2) five minutes after the beginning of reperfusion (Late). After reperfusion, myocardial infarct size was determined and the amygdala was dissected from the brain. Infarct size was reduced significantly in the Early compared to the Control group (34.6 +/- 1.8% and 52.3 +/- 2.8% respectively; p < 0.05), with no difference compared to the Late group (40.1 +/- 6.1%). Apoptosis regression was documented in the amygdala of the Early group by an enhanced phosphatidylinositol 3-kinase-Akt pathway activation and Bcl-2 expression concurrently to a caspase-3 activation limitation and reduction in TUNEL-positive cells staining. On the other hand, amygdala TUNEL-positive cell numbers were not reduced in the Late group. Moreover, TNFalpha was significantly reduced in the amygdala of the Early group compared to the Control and Late groups. These results indicate that A(2A) adenosine receptor stimulation is associated with apoptosis regression in the amygdala following myocardial infarction.

Topics: Adenosine; Adenosine A2 Receptor Agonists; Amygdala; Animals; Antihypertensive Agents; Apoptosis; bcl-2-Associated X Protein; Body Weight; Caspase 3; Caspases; In Situ Nick-End Labeling; Myocardial Infarction; Myocardium; Organ Size; Phenethylamines; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-bcl-2; Rats; Rats, Sprague-Dawley; Receptor, Adenosine A2A; Reperfusion Injury; Tumor Necrosis Factor-alpha

This study examined the effects of chronic administration of adenosine and CGS 21680 hydrochloride (adenosine A(2A) receptor agonist) on motor nerve conduction velocity (MNCV), nerve blood flow (NBF) and histology of sciatic nerve in animal model of diabetic neuropathy. Adenosinergic agents were administered for 2 weeks after 6 weeks of streptozotocin-induced (50 mg/kg i.p.) diabetes in male Sprague-Dawley rats. Significant reduction in sciatic MNCV and NBF were observed after 8 weeks in diabetic animals in comparison with control (non diabetic) rats. Adenosine (10 mg/kg, i.p.) significantly improved sciatic MNCV and NBF in diabetic rats. The protective effect of adenosine on MNCV and NBF was completely reversed by theophylline (50 mg/kg, i.p.), a non-selective adenosine receptor antagonist, suggesting that the adenosine effect was mediated via adenosinergic receptors. CGS 21680 (0.1 mg/kg, i.p.) significantly improved NBF; however, MNCV was not significantly improved in diabetic rats. At a dose of 1 mg/kg, neither MNCV nor NBF was improved by CGS 21680 in diabetic rats. ZM 241385 (adenosine A(2A) receptor antagonist) prevented the effect of CGS 21680 (0.1 mg/kg, i.p.). Histological changes observed in sciatic nerve were partially improved by the adenosinergic agents in diabetic rats. Results of the present study, suggest the potential of adenosinergic agents in the therapy of diabetic neuropathy.

Topics: Adenosine; Animals; Blood Glucose; Body Weight; Diabetes Mellitus, Experimental; Dose-Response Relationship, Drug; Drug Interactions; Neural Conduction; Phenethylamines; Purinergic P2 Receptor Agonists; Rats; Regional Blood Flow; Sciatic Nerve; Staining and Labeling; Streptozocin; Theophylline; Time Factors; Triazines; Triazoles

Reduction of A2A receptor expression is one of the earliest events occurring in both Huntington's disease (HD) patients and mice overexpressing the N-terminal part of mutated huntingtin. Interestingly, increased activity of A2A receptors has been found in striatal cells prone to degenerate in experimental models of this neurodegenerative disease. However, the role of A2A receptors in the pathogenesis of HD remains obscure. In the present study, using A2A-/- mice and pharmacological compounds in rat, we demonstrate that striatal neurodegeneration induced by the mitochondrial toxin 3-nitropropionic acid (3NP) is regulated by A2A receptors. Our results show that the striatal outcome induced by 3NP depends on a balance between the deleterious activity of presynaptic A2A receptors and the protective activity of postsynaptic A2A receptors. Moreover, microdialysis data demonstrate that this balance is anatomically determined, because the A2A presynaptic control on striatal glutamate release is absent within the posterior striatum. Therefore, because blockade of A2A receptors has differential effects on striatal cell death in vivo depending on its ability to modulate presynaptic over postsynaptic receptor activity, therapeutic use of A2A antagonists in Huntington's as well as in other neurodegenerative diseases could exhibit undesirable biphasic neuroprotective-neurotoxic effects.

Topics: Adenosine; Animals; Body Weight; Cell Death; Corpus Striatum; Disease Models, Animal; Drug Administration Schedule; Encephalitis; Genetic Predisposition to Disease; Glutamic Acid; Huntington Disease; Male; Mice; Mice, Knockout; Neuroprotective Agents; Nitro Compounds; Phenethylamines; Propionates; Rats; Rats, Inbred Lew; Rats, Wistar; Receptor, Adenosine A2A; Receptors, Purinergic P1; RNA, Messenger; Signal Transduction; Survival Rate; Synapses; Xanthines

1. Recently we demonstrated that the administration of an A2A adenosine receptor agonist, CGS 21680, to anaesthetized rats with acute heart failure (1 h post-coronary artery ligation) resulted in an increase in cardiac output. In the present investigation, the effects of CGS 21680 on cardiac output, vascular resistance, heart rate, blood pressure and mean circulatory filling pressure (Pmcf) were investigated in anaesthetized rats with chronic heart failure (8 weeks post-coronary artery ligation). 2. Experiments were conducted in five groups (n = 6) of animals: sham-operated vehicle-treated (0.9% NaCl; 0.037 mL kg(-1) min(-1)) animals in which the occluder was placed but not pulled to ligate the coronary artery; coronary artery-ligated vehicle-treated animals; and coronary artery-ligated CGS 21680-treated (0.1. 0.3 or 1.0 microg kg(-1) min(-1)) animals. 3. Baseline blood pressure, cardiac output and rate of rise in left ventricular pressure (+dP/dt) were significantly reduced in animals with coronary artery ligation when compared to sham-operated animals. Coronary artery ligation resulted in a significant increase in left ventricular end-diastolic pressure, Pmcf and venous resistance when compared to sham-operated animals. 4. Administration of CGS 21680 at 0.3 and 1.0 microg kg(-1) min(-1) significantly (n = 6; P<0.05) increased cardiac output by 19+/-4% and 39+/-5%, and heart rate by 14+/-2% and 15+/-1%, respectively, when compared to vehicle treatment in coronary artery-ligated animals. Administration of CGS 21680 also significantly reduced blood pressure and arterial resistance when compared to coronary artery-ligated vehicle-treated animals. Infusion of CGS 21680 also significantly reduced venous resistance when compared to vehicle-treated coronary artery-ligated animals. 5. The results show that heart failure is characterized by reduced cardiac output, and increased left ventricular end-diastolic pressure, venous resistance and Pmcf. Acute treatment with CGS 21680 in animals with chronic heart failure decreased left ventricular end-diastolic pressure and increased cardiac output. This increase in cardiac output was the result of reduced arterial and venous resistances and increased heart rate.

Topics: Adenosine; Anesthesia; Animals; Antihypertensive Agents; Blood Pressure; Body Weight; Cardiac Output; Coronary Disease; Heart Failure; Heart Rate; Hemodynamics; Ligation; Male; Organ Size; Phenethylamines; Purinergic P1 Receptor Agonists; Rats; Rats, Sprague-Dawley; Receptor, Adenosine A2A; Time Factors; Vascular Resistance

1. In this study, the authors examined the effects of chronic (14 days) changes in thyroid function on a major neuromodulatory receptor system in the brain- the adenosinergic system. While previous investigators have examined the effects of alteration in thyroid function on adenosine receptors in peripheral tissues (adipocytes), this is the first study to examine such effects in brain. 2. Three groups of male Sprague-Dawley rats were treated for 14 days with either a) oral PTU (0.00625%), iodine-free diet, and i.p. saline injections, b) i.p. saline injections, or c) i.p. triiodothyronine (25 micrograms/100 g) injections. 3. These manipulations reliably resulted in the production of hypothyroidism (TSH 30.2 +/- 8.6 ng/ml), euthyroidism (TSH 2.1 +/- 0.9), and hyperthyroidism (TSH < 0.4). 4. Treatment had no significant effect on the Bmax or Kd of [3H]DPCPX (A1-antagonist) binding to homogenates from cerebral cortex, cerebellum or hippocampus; similarly, no effect on [3H]CGS-21680 (A2-agonist) binding to striatal homogenates was noted. 5. Similarly, quantitative autoradiographic studies failed to reveal consistent regional alterations unique to either hypo- or hyperthyroidism. 6. Incubation of sections with GppNHp resulted in the expected reduction (approximately 40%) in agonist binding, but there was no differential effect seen for either the hypo- or hyperthyroid tissues. 7. These preliminary findings suggest that alterations in brain adenosine receptors or G-protein-receptor coupling are unlikely to be requisite correlates of abnormal thyroid hormone levels.

Topics: Adenosine; Animals; Antihypertensive Agents; Autoradiography; Body Weight; Brain Chemistry; Hyperthyroidism; Hypothyroidism; Iodine; Male; Phenethylamines; Rats; Rats, Sprague-Dawley; Receptors, Purinergic P1; Thyroid Hormones; Xanthines