DOCSLIB.ORG

A2AAR) Expression

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
A2AAR) Expression Safhi, Mohammed Mohsen A. (2008) Priming of STAT1 and STAT3 for cytokine-triggered degradation by the proteasome upon A2Aadenosine receptor (A2AAR) expression. PhD thesis http://theses.gla.ac.uk/310/ Copyright and moral rights for this thesis are retained by the author A copy can be downloaded for personal non-commercial research or study, without prior permission or charge This thesis cannot be reproduced or quoted extensively from without first obtaining permission in writing from the Author The content must not be changed in any way or sold commercially in any format or medium without the formal permission of the Author When referring to this work, full bibliographic details including the author, title, awarding institution and date of the thesis must be given. Glasgow Theses Service http://theses.gla.ac.uk/ [email protected] Priming of STAT1 and STAT3 for Cytokine-triggered Degradation by the Proteasome upon A2AAdenosine Receptor (A 2AAR) Expression Mohammed Mohsen A. Safhi M.Sc. (Hons) A thesis submitted in fulfilment of requirements for the degree of Doctor of Philosophy Faculty of Biomedical and life Sciences University of Glasgow © Mohammed Mohsen A. Safhi, March 2008 i Acknowledgements ii Abbreviations iii Table of Contents viii List of Figures xi List of Table xv Abstract xvi ii ACKNOWLEDGMENTS This thesis could not have been completed without the assistance and guidance from numerous people. I would like to express my appreciation and gratitude to my supervisor, Dr. Tim Palmer for his valuable supervision and useful suggestions given to me throughout my PhD. I would also like to thank Dr. Billy Sands for all the helpful discussion of my work and all the members of the Palmer Lab, past and present, for all their assistance and friendship. I would like to extend my thanks to Ministry of Health in Saudi Arabia for scholarship. I would like also to thank numerous people from the department for their help and encouragement throughout the years. A special thanks to my assessor panel, Professor Graeme Milligan, Dr Rob Strang, Dr Andrew Pitt for their helpful discussions and suggestions. I would also like to thank my Dad, Mum, brothers and sister for the love and support they have given me throughout it all. Finally many thanks to my wife and my children for their support and patience throughout my research. iii Abbreviations A2AAR A2A adenosine receptor ADP Adenosine 5-diphosphateَ AMP Adenosine 5-monophosphateَ APR Acute phase response AR Adenosine receptors ARHI A Ras homologue member I ATP Adenosine triphosphate AVs Adenoviruses BCA Bicinchonic acid salt BMI Body mass index BSA Bovine serum albumin BSF-3 B-cell-stimulating factor-3 CaM Calmodulin cAMP Cyclic AMP CBM Cytokine-binding module C-ERMAD C-terminal ERM-associated domain cGMP Cyclic GMP CIS Cytokine-inducible SH2 protein CNTF Ciliary neurotrophic factor CRP C-reactive protein CT-1 Cardiotrophin-1 CUE Coupling of Ub conjugation to ER degradation Cul4A Cullin 4A DMAM Dulbeco’s modified Eagle’s medium DMSO Dimethyl sulphoxide dNTPs Deoxynucleotide 5-triphosphatesَ DTT Dithiothreitol DUB Deubiquitylating enzyme EBM-2 Endothelial Basal Media-2TM ECL Enhanced chemiluminescence ECM Extracellular matrix ECs Endothelial cells EDTA Ethylenediaminotetra-acetic acid EGF Epidermal growth factor EGTA Ethylene glycol-bis (2-aminoethylether)-N,N,N’,N’-tetracetic acid EPAC Exchange protein activated by cAMP EPO Erythropoietin ERK Extracellular-signal regulated kinase ERM Ezrin-radixin-moesin FERM Four-point-one ezrin radixin moesin iv FBS Foetal bovine serum FBS Phosphate-buffered saline GAGs Glycosaminoglycans G-CSFR Granulocyte colony-stimulating factor receptor GH Growth hormone GM Granulocyte-macrophages Gp 130 Glycoprotein 130 HAEC Human aortic endothelial cells HEPES N-(2-Hydroxyethyl)-piperazine-N’-(2-ethanesulfonic acid) hFGF-B Human fibroblast growth factor-B HRP Horseradish peroxidase IFN Interferon IGF-l Insulin-like growth factor-l Ig Immunoglobulin IgSF Immunoglobulin superfamily IKK IκB kinase IL Interleukin IL-6Rα IL-6 receptor α IPTG Isopropyl-β-D-thiogalactopyranoside IRAK IL-1 receptor-associated kinase JAK Janus kinase JH JAK homology KIR kinase inhibitory region LIF leukaemia inhibitory factor LIF-R leukemia inhibitory factor receptor LPS lipopolysaccharide MAPK Mitogen-activated protein kinase MD-2 Myeloid differentiation protein-2 MEF Mouse embryonic fibroblast MHC Major histocompatibility complex MI Myocardial infarction MTT 3-(4,5-dimethylthiazol-2yl)-2,5-diphenyl 2H-tetrazolium bromide MTX Methotrexate NCA Neutrophil cytoplasmic antibody NCAM Neural cell adhesion molecule NEDD8 Neural precursor cell expressed developmentally down-regulated 8 NF-кB Nuclear factor-кB NK Natural killer NLS Nuclear localisation sequence NNT-1 Neurotrophin-1 NPC Nuclear pore complex NRTK Non-receptor tyrosine kinase OSM Oncostatin M PH Pleckstrin homology v PIAS Protein inhibitor of activated STAT PKA Protein kinase A PlGF Placental growth factor PLR Prolactin PMN Polymorphonuclear PMSF Phenylmethylsulphonyl fluoride PTK Protein tyrosine kinase PTPase Protein tyrosine phosphatase RANTES Regulated upon activation normal T cell expressed presumed secreted ROS Reactive oxygen species RTK Receptor tyrosine kinase SAA Serum amyloid SCID Severe combined immunodeficiency disease SDS Sodium dodecyl sulphate SH2 Src homology2 SHP2 SH2-domain-containing protein tyrosine phosphatase SOCS Suppressor of cytokine signalling STAT Signal transducer and activator of transcription StIP1 STAT3 interacting protein SUMO Small ubiquitin-like modifier TAP Two-step tandem affinity purification TBS Tris-buffered saline TEMED N,N,N’,N’-tetramethylethylenediamine TGF-β Transforming growth factor-β Th1 Type-1 T-helper cells TMB 3,3’5,5’ –tetramethylbenzidine TNF-α Tumour necrosis factor-α TPO Thrombopoietin TRIS Tris(hydromethyl-amino)ethane TSLP Thymic stromal lymphopoietin Ub Ubiquitin UBA Ub-associated domain UBD Ub-binding domain UBL Ub-like domain UBP Ub-specific processing protease UIM Ub-interacting motif VEGF Vascular endothelial growth factor VEGFR2 Vascular endothelial growth factor receptor 2 VIPs V-interaction proteins WT Wild-type vi Pharmacological Names CGS21680 2-p-(2-Carboxyethyl)phenethylamino-5-N-ethylcarboxamidoadenosineَ hydrochloride ZM241385 4-(2-[7-amino-2-{2-furyl}{1,2,4}triazolo{2,3-α}{1,3,5}triazin-5-yl- amino]ethyl)phenol vii Table of Contents Chapter 1 Introduction ............................................................................1 1.1 JAKs in cytokine signalling.........................................................................2 1.2 The Signal transducer and activator of transcription (STAT) family of transcription factors ................................................................................................4 1.3 Regulation of cytokine signalling by suppressor of cytokine signalling (SOCS) family molecules.........................................................................................8 1.3.1 SOCS1....................................................................................................9 1.3.2 SOCS3..................................................................................................10 1.4 Cytokines ....................................................................................................12 1.4.1 IL-6 ......................................................................................................13 1.4.1.1 IL-6 structure .......................................................................................14 1.4.1.2 IL-6 Receptors .....................................................................................14 1.4.1.3 Signalling of IL-6-type cytokines ........................................................17 1.4.2 IFN alpha .............................................................................................18 1.4.2.1 IFN-inducible STAT complexes..........................................................20 1.4.3 Leptin Biology.....................................................................................23 1.4.3.1 Leptin receptor.....................................................................................24 1.5 Adenosine receptors...................................................................................25 1.5.1 A2AAR..................................................................................................26 1.5.1.1 The A 2AAR as anti-inflammatory GPCR.............................................29 1.6 Ubiquitination ............................................................................................33 1.6.1 Ub as an inducible and reversible signal..............................................34 1.6.2 Proteasomal degradation......................................................................35 1.7 E3 ligase and STAT degradation..............................................................36 1.8 Aims and objectives of research ...............................................................38 Chapter 2 Materials and Methods ........................................................41 2.1 Chemicals and Suppliers ...........................................................................42 2.2 Cell Culture & Transfection Methods .....................................................46 2.2.1 Cell maintenance..................................................................................46 2.2.2 Transfection with Fugene ....................................................................47 2.2.3 Infection of HUVECs with AVs..........................................................47
Load more

Recommended publications
  • Advances in Non-Dopaminergic Treatments for Parkinson's Disease
    REVIEW ARTICLE published: 22 May 2014 doi: 10.3389/fnins.2014.00113 Advances in non-dopaminergic treatments for Parkinson’s disease Sandy Stayte 1,2 and Bryce Vissel 1,2* 1 Neuroscience Department, Neurodegenerative Disorders Laboratory, Garvan Institute of Medical Research, Sydney, NSW, Australia 2 Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia Edited by: Since the 1960’s treatments for Parkinson’s disease (PD) have traditionally been directed Eero Vasar, University of Tartu, to restore or replace dopamine, with L-Dopa being the gold standard. However, chronic Estonia L-Dopa use is associated with debilitating dyskinesias, limiting its effectiveness. This has Reviewed by: resulted in extensive efforts to develop new therapies that work in ways other than Andrew Harkin, Trinity College Dublin, Ireland restoring or replacing dopamine. Here we describe newly emerging non-dopaminergic Sulev Kõks, University of Tartu, therapeutic strategies for PD, including drugs targeting adenosine, glutamate, adrenergic, Estonia and serotonin receptors, as well as GLP-1 agonists, calcium channel blockers, iron Pille Taba, Universoty of Tartu, chelators, anti-inflammatories, neurotrophic factors, and gene therapies. We provide a Estonia Pekka T. Männistö, University of detailed account of their success in animal models and their translation to human clinical Helsinki, Finland trials. We then consider how advances in understanding the mechanisms of PD, genetics, *Correspondence: the possibility that PD may consist of multiple disease states, understanding of the Bryce Vissel, Neuroscience etiology of PD in non-dopaminergic regions as well as advances in clinical trial design Department, Neurodegenerative will be essential for ongoing advances. We conclude that despite the challenges ahead, Disorders Laboratory, Garvan Institute of Medical Research, patients have much cause for optimism that novel therapeutics that offer better disease 384 Victoria Street, Darlinghurst, management and/or which slow disease progression are inevitable.
    [Show full text]
  • The Interaction of Selective A1 and A2A Adenosine Receptor Antagonists with Magnesium and Zinc Ions in Mice: Behavioural, Biochemical and Molecular Studies
    International Journal of Molecular Sciences Article The Interaction of Selective A1 and A2A Adenosine Receptor Antagonists with Magnesium and Zinc Ions in Mice: Behavioural, Biochemical and Molecular Studies Aleksandra Szopa 1,* , Karolina Bogatko 1, Mariola Herbet 2 , Anna Serefko 1 , Marta Ostrowska 2 , Sylwia Wo´sko 1, Katarzyna Swi´ ˛ader 3, Bernadeta Szewczyk 4, Aleksandra Wla´z 5, Piotr Skałecki 6, Andrzej Wróbel 7 , Sławomir Mandziuk 8, Aleksandra Pochodyła 3, Anna Kudela 2, Jarosław Dudka 2, Maria Radziwo ´n-Zaleska 9, Piotr Wla´z 10 and Ewa Poleszak 1,* 1 Chair and Department of Applied and Social Pharmacy, Laboratory of Preclinical Testing, Medical University of Lublin, 1 Chod´zkiStreet, PL 20–093 Lublin, Poland; [email protected] (K.B.); [email protected] (A.S.); [email protected] (S.W.) 2 Chair and Department of Toxicology, Medical University of Lublin, 8 Chod´zkiStreet, PL 20–093 Lublin, Poland; [email protected] (M.H.); [email protected] (M.O.); [email protected] (A.K.) [email protected] (J.D.) 3 Chair and Department of Applied and Social Pharmacy, Medical University of Lublin, 1 Chod´zkiStreet, PL 20–093 Lublin, Poland; [email protected] (K.S.);´ [email protected] (A.P.) 4 Department of Neurobiology, Polish Academy of Sciences, Maj Institute of Pharmacology, 12 Sm˛etnaStreet, PL 31–343 Kraków, Poland; [email protected] 5 Department of Pathophysiology, Medical University of Lublin, 8 Jaczewskiego Street, PL 20–090 Lublin, Poland; [email protected] Citation: Szopa, A.; Bogatko, K.; 6 Department of Commodity Science and Processing of Raw Animal Materials, University of Life Sciences, Herbet, M.; Serefko, A.; Ostrowska, 13 Akademicka Street, PL 20–950 Lublin, Poland; [email protected] M.; Wo´sko,S.; Swi´ ˛ader, K.; Szewczyk, 7 Second Department of Gynecology, 8 Jaczewskiego Street, PL 20–090 Lublin, Poland; B.; Wla´z,A.; Skałecki, P.; et al.
    [Show full text]
  • A Differential Role for the Adenosine A2A Receptor in Opiate Reinforcement Vs Opiate-Seeking Behavior
    Neuropsychopharmacology (2009) 34, 844–856 & 2009 Nature Publishing Group All rights reserved 0893-133X/09 $32.00 www.neuropsychopharmacology.org A Differential Role for the Adenosine A2A Receptor in Opiate Reinforcement vs Opiate-Seeking Behavior 1,2 2 1,3 4 Robyn Mary Brown , Jennifer Lynn Short , Michael Scott Cowen , Catherine Ledent and ,1,3 Andrew John Lawrence* 1Brain Injury and Repair Group, Howard Florey Institute, University of Melbourne, Parkville, VIC, Australia; 2Monash Institute of Pharmaceutical 3 4 Sciences, Parkville, VIC, Australia; Centre for Neuroscience, University of Melbourne, Parkville, VIC, Australia; Faculte de Medecine, Institut de Recherche Interdisciplinaire, Universite de Bruxelles, Brussels, Belgium The adenosine A2A receptor is specifically enriched in the medium spiny neurons that make up the ‘indirect’ output pathway from the ventral striatum, a structure known to have a crucial, integrative role in processes such as reward, motivation, and drug-seeking behavior. In the present study we investigated the impact of adenosine A receptor deletion on behavioral responses to morphine in a number of 2A reward-related paradigms. The acute, rewarding effects of morphine were evaluated using the conditioned place preference paradigm. Operant self-administration of morphine on both fixed and progressive ratio schedules as well as cue-induced drug-seeking was assessed. In addition, the acute locomotor response to morphine as well as sensitization to morphine was evaluated. Decreased morphine self- administration and breakpoint in A2A knockout mice was observed. These data support a decrease in motivation to consume the drug, perhaps reflecting diminished rewarding effects of morphine in A2A knockout mice. In support of this finding, a place preference to morphine was not observed in A knockout mice but was present in wild-type mice.
    [Show full text]
  • Neuroprotection by Caffeine and A2A Adenosine Receptor Inactivation in a Model of Parkinson’S Disease
    The Journal of Neuroscience, 2001, Vol. 21 RC143 1of6 Neuroprotection by Caffeine and A2A Adenosine Receptor Inactivation in a Model of Parkinson’s Disease Jiang-Fan Chen,1 Kui Xu,1 Jacobus P. Petzer,2 Roland Staal,3 Yue-Hang Xu,1 Mark Beilstein,1 Patricia K. Sonsalla,3 Kay Castagnoli,2 Neal Castagnoli Jr,2 and Michael A. Schwarzschild1 1Molecular Neurobiology Laboratory, Department of Neurology, Massachusetts General Hospital, Charlestown, Massachusetts 02129, 2Harvey W. Peters Center, Department of Chemistry, Virginia Tech, Blacksburg, Virginia 24061-0212, and 3Department of Neurology, University of Medicine and Dentistry of New Jersey, Piscataway, New Jersey 08854-5635 Recent epidemiological studies have established an associa- 58261), 3,7-dimethyl-1-propargylxanthine, and (E)-1,3-diethyl-8 tion between the common consumption of coffee or other (KW-6002)-(3,4-dimethoxystyryl)-7-methyl-3,7-dihydro-1H- caffeinated beverages and a reduced risk of developing Parkin- purine-2,6-dione) (KW-6002) and by genetic inactivation of the A2A son’s disease (PD). To explore the possibility that caffeine helps receptor, but not by A1 receptor blockade with 8-cyclopentyl-1,3- prevent the dopaminergic deficits characteristic of PD, we in- dipropylxanthine, suggesting that caffeine attenuates MPTP tox- vestigated the effects of caffeine and the adenosine receptor icity by A2A receptor blockade. These data establish a potential subtypes through which it may act in the 1-methyl-4-phenyl- neural basis for the inverse association of caffeine with the devel- 1,2,3,6-tetrahydropyridine (MPTP) neurotoxin model of PD. opment of PD, and they enhance the potential of A2A antagonists Caffeine, at doses comparable to those of typical human ex- as a novel treatment for this neurodegenerative disease.
    [Show full text]
  • The Effects of Adenosine Antagonists on Distinct Aspects of Motivated Behavior: Interaction with Ethanol and Dopamine Depletion
    Facultat de Ciències de la Salut Departament de Psicologia Bàsica, Clínica i Psicobiologia The effects of adenosine antagonists on distinct aspects of motivated behavior: interaction with ethanol and dopamine depletion. PhD Candidate Laura López Cruz Advisor Dr. Mercè Correa Sanz Co-advisor Dr. John D.Salamone Castelló, May 2016 Als meus pares i germà A Carlos AKNOWLEDGEMENTS This work was funded by two competitive grants awarded to Mercè Correa and John D. Salamone: Chapters 1-4: The experiments in the first chapters were supported by Plan Nacional de Drogas. Ministerio de Sanidad y Consumo. Spain. Project: “Impacto de la dosis de cafeína en las bebidas energéticas sobre las conductas implicadas en el abuso y la adicción al alcohol: interacción de los sistemas de neuromodulación adenosinérgicos y dopaminérgicos”. (2010I024). Chapters 5 and 6: The last 2 chapters contain experiments financed by Fundació Bancaixa-Universitat Jaume I. Spain. Project: “Efecto del ejercicio físico y el consumo de xantinas sobre la realización del esfuerzo en las conductas motivadas: Modulación del sistema mesolímbico dopaminérgico y su regulación por adenosina”. (P1.1B2010-43). Laura López Cruz was awarded a 4-year predoctoral scholarship “Fornación de Profesorado Universitario-FPU” (AP2010-3793) from the Spanish Ministry of Education, Culture and Sport. (2012/2016). TABLE OF CONTENTS ABSTRACT ...................................................................................................................1 RESUMEN .....................................................................................................................3
    [Show full text]
  • Nivedita Singh
    Xanthine Based Inhibitors for Therapeutics Targeting Phosphodiesterase 9A A Thesis Submitted in Partial Fulfilment of the Requirements for the Degree of DOCTOR OF PHILOSOPHY BY NIVEDITA SINGH DEPARTMENT OF BIOSCIENCES & BIOENGINEERING INDIAN INSTITUTE OF TECHNOLOGY GUWAHATI GUWAHATI-781039, ASSAM, INDIA NOVEMBER 2016 Xanthine Based Inhibitors for Therapeutics Targeting Phosphodiesterase 9A A Thesis Submitted in Partial Fulfilment of the Requirements for the Degree of DOCTOR OF PHILOSOPHY BY NIVEDITA SINGH DEPARTMENT OF BIOSCIENCES & BIOENGINEERING INDIAN INSTITUTE OF TECHNOLOGY GUWAHATI GUWAHATI-781039, ASSAM, INDIA NOVEMBER 2016 TH-1894_11610615 TH-1894_11610615 INDIAN INSTITUTE OF TECHNOLOGY GUWAHATI DEPARTMENT OF BIOSCIENCE & BIOENGINEERING STATEMENT I do hereby declare that the matter embodied in this thesis entitled: “Xanthine based inhibitors for therapeutics targeting phosphodiesterase 9A”, is the result of investigations carried out by me in the Department of Biosciences & Bioengineering, Indian Institute of Technology Guwahati, India, under the guidance of Dr. Sanjukta Patra and co-supervision of Prof. Parameswar Krishnan Iyer. In keeping with the general practice of reporting scientific observations, due acknowledgements have been made wherever the work described is based on the findings of other investigators. November, 2016 Ms. Nivedita Singh Roll No. 11610615 TH-1894_11610615 INDIAN INSTITUTE OF TECHNOLOGY GUWAHATI DEPARTMENT OF BIOSCIENCE & BIOENGINEERING CERTIFICATE It is certified that the work described in this thesis, entitled: “Xanthine based inhibitors for therapeutics targeting phosphodiesterase 9A”, done by Ms Nivedita Singh (Roll No: 11610615), for the award of degree of Doctor of Philosophy is an authentic record of the results obtained from the research work carried out under my supervision in the Department of Biosciences & Bioengineering, Indian Institute of Technology Guwahati, India, and this work has not been submitted elsewhere for a degree.
    [Show full text]
  • (12) United States Patent (10) Patent No.: US 7,160,899 B2 Peters Et Al
    US007160899B2 (12) United States Patent (10) Patent No.: US 7,160,899 B2 Peters et al. (45) Date of Patent: Jan. 9, 2007 (54) ADENOSINE AA RECEPTOR (56) References Cited ANTANGONSTS COMBINED WITH NEUROTROPHIC ACTIVITY COMPOUNDS U.S. PATENT DOCUMENTS IN THE TREATMENT OF PARKINSONS 2001/0027.196 A1 10, 2001 Borroni et al. DISEASE FOREIGN PATENT DOCUMENTS (75) Inventors: Dan Peters, Malmö (SE); Lars Christian B. Ronn, Vekse (DK); Karin DE 43 25 254 A1 2, 1994 Sandager Nielsen, Fredensborg (DK) WO WO 97/40035 * 10/1997 WO WO99/43678 A1 9, 1999 (73) Assignee: Neurosearch A/S, Ballerup (DK) WO WO 99,53909 A2 10, 1999 (*) Notice: Subject to any disclaimer, the term of this WO WO 01/82946 A2 4/2001 patent is extended or adjusted under 35 U.S.C. 154(b) by 342 days. OTHER PUBLICATIONS Beers, M. H. and Berkow, R., Editors-in-chief, The Merck Manual (21) Appl. No.: 10/473,809 of Diagnosis and Therapy, 17th Edition, pp. 1466-1473, 1999.* Hess, Expert Opinion Ther. Patents, vol. 11, No. 10, pp. 1533-1561 (22) PCT Filed: Apr. 4, 2002 (2001). Lee et al., PNAS, vol. 98, No. 6, pp. 3555-3560 (2001). (86). PCT No.: PCT/DKO2/OO228 Kiec-Kononowicz et al., Pure Appl. Chem... vol. 73, No. 9, pp. 1411–1420 (2001). S 371 (c)(1), Ongini et al., Annals NY Academy of Sciences, pp. 30-49, 1997. (2), (4) Date: Oct. 2, 2003 Heese et al., Neuroscience Letters, vol. 231, pp. 83-86 (1997). Bennett, The Neuroscientist, vol. 7, No.
    [Show full text]
  • Agomelatine and Tianeptine Antidepressant Activity in Mice Behavioral
    Pharmacological Reports 71 (2019) 676–681 Contents lists available at ScienceDirect Pharmacological Reports journal homepage: www.elsevier.com/locate/pharep Short communication Agomelatine and tianeptine antidepressant activity in mice behavioral despair tests is enhanced by DMPX, a selective adenosine A2A receptor antagonist, but not DPCPX, a selective adenosine A1 receptor antagonist a, a a b a _ Aleksandra Szopa *, Karolina Bogatko , Anna Serefko , Elzbieta Wyska , Sylwia Wosko , a c d e Katarzyna Swia˛der , Urszula Doboszewska , Aleksandra Wlaz , Andrzej Wróbel , c f a Piotr Wlaz , Jarosław Dudka , Ewa Poleszak a Department of Applied Pharmacy, Medical University of Lublin, Lublin, Poland b Department of Pharmacokinetics and Physical Pharmacy, Collegium Medicum, Jagiellonian University, Kraków, Poland c Department of Animal Physiology, Institute of Biology and Biochemistry, Faculty of Biology and Biotechnology, Maria Curie-Skłodowska University, Lublin, Poland d Department of Pathophysiology, Medical University of Lublin, Lublin, Poland e Second Department of Gynecology, Medical University of Lublin, Lublin, Poland f Chair and Department of Toxicology, Medical University of Lublin, Lublin, Poland A R T I C L E I N F O A B S T R A C T Article history: Background: Adenosine, an endogenous nucleoside, modulates the release of monoamines, e.g., Received 9 October 2018 noradrenaline, serotonin, and dopamine in the brain. Both nonselective and selective stimulation of Received in revised form 12 February 2019 adenosine receptors produce symptoms of depression in some animal models. Therefore, the main Accepted 11 March 2019 objective of our study was to assess the influence of a selective adenosine A1 receptor antagonist (DPCPX) Available online 16 March 2019 and a selective adenosine A2A receptor antagonist (DMPX) on the activity of agomelatine and tianeptine.
    [Show full text]
  • Insight of Captagon Abuse by Chemogenomics Knowledgebase
    www.nature.com/scientificreports OPEN Insight of Captagon Abuse by Chemogenomics Knowledgebase- guided Systems Pharmacology Received: 25 April 2018 Accepted: 10 September 2018 Target Mapping Analyses Published: xx xx xxxx Nan Wu1,2,3,4, Zhiwei Feng1,2,3,4, Xibing He1,2,3,4, William Kwon1,2,3,4, Junmei Wang1,2,3,4 & Xiang-Qun Xie1,2,3,4 Captagon, known by its genetic name Fenethylline, is an addictive drug that complicates the War on Drugs. Captagon has a strong CNS stimulating efect than its primary metabolite, Amphetamine. However, multi-targets issues associated with the drug and metabolites as well as its underlying mechanisms have not been fully defned. In the present work, we applied our established drug-abuse chemogenomics-knowledgebase systems pharmacology approach to conduct targets/of-targets mapping (SP-Targets) investigation of Captagon and its metabolites for hallucination addiction, and also analyzed the cell signaling pathways for both Amphetamine and Theophylline with data mining of available literature. Of note, Amphetamine, an agonist for trace amine-associated receptor 1 (TAAR1) with enhancing dopamine signaling (increase of irritability, aggression, etc.), is the main cause of Captagon addiction; Theophylline, an antagonist that blocks adenosine receptors (e.g. A2aR) in the brain responsible for restlessness and painlessness, may attenuate the behavioral sensitization caused by Amphetamine. We uncovered that Theophylline’s metabolism and elimination could be retarded due to competition and/or blockage of the CYP2D6 enzyme by Amphetamine; We also found that the synergies between these two metabolites cause Captagon’s psychoactive efects to act faster and far more potently than those of Amphetamine alone.
    [Show full text]
  • (12) Patent Application Publication (10) Pub. No.: US 2013/0224110 A1 Bynoe (43) Pub
    US 201302241 10A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2013/0224110 A1 Bynoe (43) Pub. Date: Aug. 29, 2013 (54) USE OF ADENOSINE RECEPTOR Publication Classification SIGNALING TO MODULATE PERMEABILITY OF BLOOD-BRAIN (51) Int. Cl. BARRIER A 6LX3 L/7076 (2006.01) A 6LX3/59 (2006.01) A6II 45/06 (2006.01) (75) Inventor: Margaret S. Bynoe, Ithaca, NY (US) A613 L/437 (2006.01) (52) U.S. Cl. CPC ........... A6 IK3I/7076 (2013.01); A61 K3I/437 (73) Assignee: CORNELL UNIVERSITY, Ithaca, NY (2013.01); A61 K3I/519 (2013.01); A61 K (US) 45/06 (2013.01) USPC ............ 424/1.49; 514/303: 514/45: 514/267; (21) Appl. No.: 13/823,266 424/649; 424/94.5; 424/133.1: 514/17.7: 514/8.6; 424/85.4; 424/143.1; 424/141.1; (22) PCT Fled: Sep. 16, 2011 424/147.1:435/375 (86) PCT NO.: PCT/US 11/51935 (57) ABSTRACT The present invention relates to a method of increasing blood S371 (c)(1), brain barrier (“BBB) permeability in a subject. This method (2), (4) Date: May 14, 2013 involves administering to the Subject an agentoragents which activate both of the A1 and A2A adenosine receptors. Also disclosed is a method to decrease BBB permeability in a Related U.S. Application Data Subject. This method includes administering to the Subject an agent which inhibits or blocks the A2A adenosine receptor (60) Provisional application No. 61/383,628, filed on Sep. signaling. Compositions relating to the same are also dis 16, 2010.
    [Show full text]
  • Role of Adenosine A2 Receptors in Brain Stimulation Reward Under Baseline Conditions and During Cocaine Withdrawal in Rats
    The Journal of Neuroscience, December 15, 1999, 19(24):11017–11026 Role of Adenosine A2 Receptors in Brain Stimulation Reward under Baseline Conditions and during Cocaine Withdrawal in Rats Brian A. Baldo, George F. Koob, and Athina Markou Division of Psychopharmacology, Department of Neuropharmacology, The Scripps Research Institute, La Jolla, California 92037, and Program in Neurosciences, Department of Neuroscience, University of California, San Diego School of Medicine, La Jolla, California 92093 The present experiments tested the hypothesis that adenosine alter thresholds or latencies, but DMPX (1.0, 10.0 mg/kg) A2 receptors are involved in central reward function. Adenosine blocked the threshold-elevating effect of APEC (0.03 mg/kg). In receptor agonists or antagonists were administered to animals another study, repeated administration of cocaine (eight co- that had been trained to self-stimulate in a rate-free brain stimu- caine injections of 15 mg/kg, i.p., administered over 9 hr) lation reward (BSR) task that provides current thresholds as a produced elevations in thresholds at 4, 8, and 12 hr after measure of reward. The adenosine A2A receptor-selective ago- cocaine. DMPX (3 and 10 mg/kg), administered before both the nists 2-p-(2-carboxyethyl)phenethylamino-59-N-ethylcarbox- 8 and 12 hr post-cocaine self-stimulation tests, reversed the amido adenosine hydrochloride (CGS 21680) (0.1–1.0 mg/kg) and threshold elevation produced by cocaine withdrawal. These 9 2-[(2-aminoethylamino)carbonylethyl phenylethylamino]-5 -N- results indicate that stimulating adenosine A2A receptors dimin- ethylcarboxamido adenosine (APEC) (0.003–0.03 mg/kg) elevated ishes BSR without producing performance deficits, whereas reward thresholds without increasing response latencies, a mea- blocking adenosine receptors reverses the reward impairment sure of performance.
    [Show full text]
  • Subject Index
    Subject Index l\1 receptor 33,255 -- on surfactant secretion 242 - in lipolysis 385 -- on ventilation 244-251 - in the renal system 33-48 - half-life 313 -- blood flow 35 - in inflammation 303-314 -- distribution 33 - inhibition of respiration 246 -- renal diseases 42-48 -- adult animals 251 -- renin release 36 -- fetal hypoxia 248 -- signalling 34, 35 -- in neonates 250 -- tubular transport 39 - interaction with other mediators l\2 receptor -- with excitatory amino acids 414 - l\2A 103,113 -- lung 264,265 -- knockouts 123,408 -- neutrophils 306 - l\2B 103,157,249,252,255,262,311 -- NO 258 -- agonist 413 - metabolism 241 - in endothelium 102 - protective effect -- rat aorta 103 -- in gastric ulcer 196 - in the renal system -- in hearing loss 419 -- distribution 48 -- in ischemia 414 -- tubular transport 48 -- in inflammation 303 l\3 receptor 261,264,313 -- in kidney 46,47 l\3P5PS 130 - reduction of vascular resistance, lung l\Bl\ 4 253 - I-l\Bl\ 264 - regulation of vascular tone, lung l\BC proteins 74, 82 252 l\BT-702 418 - release acidosis, l\TP-induced 84 -- in asthmatics 239 l\Dl\ 6 -- by bacteria 307 adenolytics 42 -- in hypoxic brain 250 adenosine -- in bronchoconstriction 239 - adenosine a,J3-methylene diphosphate -- endothelium 107 46 -- kidney 37 - anti adrenergic effect 8 -- renal ischemia/hypoxia 46 - 5' -p-(fluorosulfonyl)benzoyl adenosine - stimulation of chemoreceptors 247, 344 249,269 - biphasic responses, airway smooth adenosine-brake hypothesis 37 muscle tone 256 adenosine deaminase 5,43,111,124, - effects 196,243 -- on
    [Show full text]