Flowchart: Preparation: A2A Receptor
 


Text Box: Neca

Asthma

Autoimmune disease

Diabetes

Text Box: A2A receptor

 

Text Box: eNosText Box: iNoshttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=search&db=PubMed&term=inosText Box: Nf-kBText Box: NKP46Text Box: Il2

2007/4/19/6

 

 

 

 

 

 

 

J Neurosurg. 2007 Mar;106(3):436-41. Links

      

     Lin CL, Shih HC, Lieu AS, Lee KS, Dumont AS, Kassell NF, Howng SL, Kwan AL.

Department of Neurosurgery, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.

OBJECT: Impaired endothelium-dependent relaxation is present in vasospastic cerebral vessels after subarachnoid hemorrhage (SAH) and may result from deficient production of endothelial nitric oxide synthase (eNOS) or increased production and/or activity of inducible NOS (iNOS). Accumulating evidence demonstrates that adenosine A2A receptors increase the production of NO by human and porcine arterial endothelial cells, which in turn leads to vasodilation. This study was designed to examine the effects of an adenosine A2A receptor agonist, (2(4-[2-carboxyethyl]phenyl)ethylamino)-5'-N-ethylcarboxamidoadenosine (CGS 21680), in the prevention of SAH-induced vasospasm. METHODS:. Experimental SAH was induced in Sprague-Dawley rats by injecting 0.3 ml of autologous blood into the cisterna magna of each animal. Intraperitoneal injections of CGS 21680 or vehicle were administered 5 minutes and 24 hours after induction of SAH. The degree of vasospasm was determined by averaging measurements of cross-sectional areas of the basilar artery (BA) 48 hours after SAH. Expression of eNOS and iNOS in the BA was also evaluated. Prior to perfusion-fixation, there were no significant differences among animals in the control and treated groups in any physiological parameter that was recorded. The CGS 21680 treatment significantly attenuated SAH-induced vasospasm. Induction of iNOS mRNA and protein in the BA by the SAH was significantly diminished by administration of CGS 21680. The SAH-induced suppression of eNOS mRNA and protein was also relieved by the CGS 21680 treatment. CONCLUSIONS: This is the first evidence that adenosine A2A receptor agonism is effective in preventing SAH-induced vasospasm without significant complications. The beneficial effect of adenosine A2A receptor agonists may be, at least in part, related to the prevention of augmented expression of iNOS and the preservation of normal eNOS expression following SAH. Adenosine A2A receptor agonism holds promise in the treatment of cerebral vasospasm following SAH and merits further investigation.

PMID: 17367066 [PubMed - indexed for MEDLINE]

Immunol Res. 2006;36(1-3):91-9.Click here to read  Links

Adenosine-mediated inhibition of cytotoxic activity and cytokine production by IL-2/NKp46-activated NK cells: involvement of protein kinase A isozyme I (PKA I).

     Raskovalova T, Lokshin A, Huang X, Jackson EK, Gorelik E.

Department of Pathology, University of Pittsburgh, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213, USA.

Adenosine suppresses the production of various cytokines/ chemokines and inhibits the cytotoxic activity of murine and human NK cells activated with IL-2 or Ly49D, NKp46-receptor crosslinking, respectively. These effects are mediated by the type A2A adenosine receptor via stimulation of adenylyl cyclase, increased production of cAMP, and activation of PKA. PKA I, but not PKA II, participates in the inhibitory effects of adenosine. Blocking regulatory, but not catalytic, subunits of PKA I abrogates the inhibitory effects of adenosine. These findings suggest that tumor-produced adenosine inhibits the activity of NK and other effector cells and thereby protects tumors from immune-mediated destruction.

PMID: 17337770 [PubMed - in process]

1: Am J Physiol Lung Cell Mol Physiol. 2007 Feb 9; [Epub ahead of print]Click here to read  Links

Enhanced airway reactivity and inflammation in A2A adenosine receptor deficient allergic mice.

     Nadeem A, Fan M, Ansari HR, Ledent C, Mustafa SJ.

Physiology and Pharmacology, West Virginia University, Morgantown, West Virginia, United States.

A2A adenosine receptor (A2AAR) has potent anti-inflammatory properties, which may be important in the regulation of airway reactivity and inflammation. Inflammatory cells that possess A2AAR also produce nitrosative stress which is associated with pathophysiology of asthma, so we hypothesized that A2AAR deficiency may lead to increased airway reactivity and inflammation through nitrosative stress. Thus, the present study was carried out to investigate the role of A2AAR on airway reactivity, inflammation, nuclear factor kappa B (NF-kB) signaling and nitrosative stress in A2A AR knock-out (KO) and wild-type (WT) mice using our murine model of asthma. Animals were sensitized i.p. on days 1 and 6 with 200microg of ragweed, followed by aerosolized challenges with 0.5% ragweed on days 11, 12 and 13, twice a day. On day 14, airway reactivity to methacholine was assessed as enhanced pause (Penh) using whole body plethysmography followed by bronchoalveolar lavage (BAL) and lung collection for various analyses. Allergen challenge caused significant decrease in expression of A2AAR in A2AWT sensitized mice, with A2AAR expression being undetected in A2AKO sensitized group leading to decreased lung cAMP levels in both groups. A2AAR deletion/downregulation led to an increase in Penh to methacholine and influx of total cells, eosinophils, lymphocytes and neutrophils in BAL with highest values in A2AKO sensitized group. A2AKO sensitized group further had increased NF-kB expression and nitrosative stress as compared to WT sensitized group. These data suggest that A2AAR deficiency leads to airway inflammation and AHR, possibly via involvement of nitrosative stress in this model of asthma. Key words: A2A adenosine receptors, Inflammation, Nitrosative stress, Airway reactivity, Asthma.

PMID: 17293374 [PubMed - as supplied by publisher]

 

 

 

 

 

 

 

 

3D-Pharmacophore Models for Selective A(2A) and A(2B) Adenosine Receptor Antagonists.

     Wei J, Wang S, Gao S Dai X, Gao Q.

School of Pharmaceutical Science and Technology, Tianjin University, 92 Weijin Road, Nankai District, Tianjin 300072, P.R. China, NuBlocks LLC, 2420 Grand Avenue B1, Vista, California 92081, and Chemistry Department, XenoPort, Inc., 3410 Central Expressway, Santa Clara, California 95051.

Three-dimensional pharmacophore models were generated for A2A and A2B adenosine receptors (ARs) based on highly selective A2A and A2B antagonists using the Catalyst program. The best pharmacophore model for selective A2A antagonists (Hypo-A2A) was obtained through a careful validation process. Four features contained in Hypo-A2A (one ring aromatic feature (R), one positively ionizable feature (P), one hydrogen bond acceptor lipid feature (L), and one hydrophobic feature (H)) seem to be essential for antagonists in terms of binding activity and A2A AR selectivity. The best pharmacophore model for selective A2B antagonists (Hypo-A2B) was elaborated by modifying the Catalyst common features (HipHop) hypotheses generated from the selective A2B antagonists training set. Hypo-A2B also consists of four features: one ring aromatic feature (R), one hydrophobic aliphatic feature (Z), and two hydrogen bond acceptor lipid features (L). All features play an important role in A2B AR binding affinity and are essential for A2B selectivity. Both A2A and A2B pharmacophore models have been validated toward a wide set of test molecules containing structurally diverse selective antagonists of all AR subtypes. They are capable of identifying correspondingly high potent antagonists and differentiating antagonists between subtypes. The results of our study will act as a valuable tool for retrieving structurally diverse compounds with desired biological activities and designing novel selective adenosine receptor ligands.

PMID: 17330954 [PubMed - as supplied by publisher]

Shock. 2007 Mar;27(3):242-250.Click here to read  Links

HYPERTONIC STRESS REGULATES T-CELL FUNCTION BY THE OPPOSING ACTIONS OF EXTRACELLULAR ADENOSINE TRIPHOSPHATE AND ADENOSINE.

     Yip L, Cheung CW, Corriden R, Chen Y, Insel PA, Junger WG.

*Surgical Immunology Research Laboratory, Department of Surgery, Division of Trauma, University of California San Diego, San Diego; daggerDepartments of Pharmacology and Medicine, University of California San Diego, La Jolla, California.

Hypertonic saline (HS) treatment promotes interleukin (IL)-2 production and enhances T-cell activation by the release of cellular adenosine triphosphate (ATP) that activates P2 nucleotide receptors. Released ATP can be hydrolyzed to adenosine, which inhibits T-cell activation. We examined if adenosine affects the response of T cells to HS treatment, and found that the amount of ATP released from T cells is a function of the HS concentration and duration of HS exposure. Physiologically relevant HS concentrations (<40 mmol/L) induced rapid ATP release, with the highest ATP concentrations released within 1 min. The released ATP was converted to adenosine, which opposed the enhancing effects of HS on IL-2 production. We found that Jurkat and CD4 primary human T cells express most abundantly the A2A and A2B adenosine receptor subtypes, which mediate the suppressive effects of adenosine, as the A2 receptor agonist CGS 21680 suppressed IL-2 production, whereas the A2 receptor antagonist 3,7-dimethyl-1-(2-propynyl)xanthine augmented the enhancing effect of HS on T-cell function. Elimination of extracellular adenosine by adding exogenous adenosine deaminase also increased the enhancing effects of HS. These data suggest that the effect of HS treatment on T-cell function can be modulated with pharmacological agents that abolish the suppressive effects of adenosine formed from the ATP that is released in response to HS treatment.

PMID: 17304104 [PubMed - as supplied by publisher