Dissertations / Theses on the topic 'Adenosine receptors'
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Svenningsson, Per. "Striatal adenosine A₂A receptors /." Stockholm, 1998. http://diss.kib.ki.se/search/diss.se.cfm?19981015sven.
Full textSTEFANELLI, Angela. "Adenosine receptors in health and disease." Doctoral thesis, Università degli studi di Ferrara, 2014. http://hdl.handle.net/11392/2388942.
Full textWang, Jianjie. "Modulation of coronary and skeletal muscle exchange by adenosine : role of adenosine receptors /." Free to MU Campus, others may purchase, 2005. http://wwwlib.umi.com/cr/mo/fullcit?p3204635.
Full textCohen, Fiona Rachel. "The allosteric regulation of adenosine receptors." Thesis, University College London (University of London), 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.309286.
Full textScammells, Peter J., and n/a. "Pyrazolo(3,4-d)Pyrimidines and adenosine receptors: a structure/activity study." Griffith University. Division of Science and Technology, 1990. http://www4.gu.edu.au:8080/adt-root/public/adt-QGU20050826.141630.
Full textScammells, Peter. "Pyrazolo(3,4-d)Pyrimidines and adenosine receptors: a structure/activity study." Thesis, Griffith University, 1990. http://hdl.handle.net/10072/365214.
Full textThesis (PhD Doctorate)
Doctor of Philosophy (PhD)
Division of Science and Technology
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Hussey, Martin John. "Adenosine Aâ‚‚A receptors and peripheral nociception." Thesis, University of Surrey, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.441903.
Full textGurden, Mark Francis. "Studies on the classification of adenosine receptors." Thesis, Open University, 1992. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.386645.
Full textTorvinen, Maria. "Adenosine receptor/dopamine receptor interactions : molecular and biochemical aspects /." Stockholm, 2002. http://diss.kib.ki.se/2002/91-7349-298-1/.
Full textCarlos, Carolina Dias. "Polimorfismos nos Receptores de Adenosina, suas Associações com Características Fisiopatológicas e Avaliação de Componentes na Biossíntese da Adenosina em Pacientes com Doença Falciforme." Universidade de São Paulo, 2011. http://www.teses.usp.br/teses/disponiveis/17/17135/tde-12062013-074600/.
Full textIn sickle cell disease in low oxygen tension, mutant hemoglobin S (HbS) undergoes polymerization promoting sickling of red blood cells that can adhere to vascular endothelium, causing vessel occlusion (VO) and tissue ischemia (painful crises) that characterize the clinical disease. In addition, sickle cell patients have other clinical manifestations such as priapism, bone disorders, certain pulmonary complications among others. In addition to the erythroid cells, endothelial cells, white cells and platelets also play a key role in the pathophysiology of sickle cell anemia. Hydroxyurea (HU) in sickle cell anemia, increases the production of fetal hemoglobin (HbF) in erythroid cells, reducing the HbS polymerization, reducing the clinical symptoms of patients. The increase in HbF, however, does not necessarily imply clinical improvement, thus indicating the potential effects of HU on other processes. Recent studies relating asthma and priapism with high levels of adenosine. Due to this importance of adenosine-related pathologies common to AF, we aimed to identify gene polymorphisms in adenosine receptors and adenosine deaminase and verify the possible association between clinical manifestations, and to investigate the role of HU in the modulation of markers involved synthesis and degradation of adenosine. We analyzed several polymorphic sites in genes that encode ADORA1, ADORA 2b, 3 and ADORA ADA, according to the genotype in patients with AF, comparing affected and unaffected. In addition we assessed the differential expression of ADA mRNA by HU in monocytes of these patients, comparing treated and untreated, and also evaluated by flow cytometry modulation of surface markers CD39, CD73 and CD26 by HU. Statistical analysis was performed using the software GenePop 3.4 for association analysis, calculation of HWE, GraphPad Prism 5, Arlequin for identification of linkage disequilibrium, haplotypes, heterozygosity and SAS 9.13 for association of haplotypes features. The results showed that patients treated with HU showed an increase in mRNA expression of ADA, increased expression of CD26 on monocytes and decreased CD39 on lymphocytes. No significant changes in relation to CD73. We also found an increased frequency of allele T (SNP rs1685103) present in a gene associated with ADORA affected patients with acute chest syndrome. Although not statistically significant, agrees with literature data. ADORA 2B gene, we found association of the SNP 1007 C> T in the development of STA indicating the T allele as a risk factor for the C allele and bone changes. For the SNP 968 G> T was associated with bone disorders. In haplotype analysis between SNPs 968 G> T and 1007 C> T found association of haplotypes ht2 and HT3 with STA as a risk factor for pulmonary hypertension ht2. ht1 for priapism, stenosis and bone disorders / stroke. The three haplotypes formed by SNPs 968 G> T, 1007 C> T and rs16851030, we found association between ht1, HT3 and HT4 among those affected with priapism, characterizing it as a risk haplotype and also ht1 ht6 associated with renal and / AVC. We conclude that hydroxyurea participates in modulating the expression of adenosine deaminase of CD26 on monocytes and CD39 on lymphocytes. Moreover, he showed the importance of polymorphic sites in this gene and ADORA 2B ADORA1 involved in the pathophysiology of clinical manifestations of sickle cell disease. Associations of SNPs in ADORA 1 and ADA should be better studied in a larger number of patients. The determination of these polymorphisms associated with different clinical characteristics can lead to a better understanding of the pathophysiological processes of sickle cell anemia, leading to the identification of patients at risk, enabling a rational handling of the same in terms of specific care, or even the determination of targets for the development of alternative therapies.
Wu, Weiping. "The role of adenosine and its receptor subtypes in nociception and neuropathic pain /." Stockholm, 2005. http://diss.kib.ki.se/2005/91-7140-298-5/.
Full textHarper, Laura. "A[2A subscript] adenosine receptors, dopamine and reward." Thesis, University of Nottingham, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.408638.
Full textOtley, Carolyn Elizabeth. "Adenosine receptors and regulation of the coronary circulation." Thesis, University of Cambridge, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.624702.
Full textBonyanian, Zeinab. "Adenosine Receptors And Endothelial Cell Mediated Wound Healing." Thesis, Griffith University, 2017. http://hdl.handle.net/10072/367912.
Full textThesis (PhD Doctorate)
Doctor of Philosophy (PhD)
School of Medical Science
Griffith Health
Full Text
Wright, Denis Matthew John, and mikewood@deakin edu au. "Potential antiarrhythmic and cardioprotective agents based on adenosine." Deakin University. School of Biological and Chemical Sciences, 1998. http://tux.lib.deakin.edu.au./adt-VDU/public/adt-VDU20050915.160941.
Full textHalldner, Henriksson Linda. "Physiology and pathophysiology of central adenosine A1 and A2A receptors /." Stockholm, 2003. http://diss.kib.ki.se/2003/91-628-5732-0/.
Full textArslan, Giulia. "Adenosine A₂A and ATP receptors in PC12 cells /." Stockholm, 2000. http://diss.kib.ki.se/2000/91-628-4028-2/.
Full textDixon, A. K. "Distribution and function of adenosine receptors in the rat." Thesis, University of Cambridge, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.598553.
Full textDavidson, H. J. "Adenosine receptors in the basilar artery of the rat." Thesis, University of Cambridge, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.598311.
Full textWinfield, Ian J. "Quantifying biased agonism of adenosine and calcitonin-like receptors." Thesis, University of Warwick, 2017. http://wrap.warwick.ac.uk/100406/.
Full textPaoletta, Silvia. "Designing adenosine receptors antagonists using an in silico approach." Doctoral thesis, Università degli studi di Padova, 2012. http://hdl.handle.net/11577/3422906.
Full textL’adenosina è un neuromodulatore che regola molti processi fisiopatologici attraverso l’attivazione di quattro diversi recettori accoppiati a proteine G (GPCRs), classificati come sottotipi A1, A2A, A2B e A3. I recettori adenosinici sono ubiquitari nell’organismo umano e la loro attivazione è responsabile di numerosi effetti in diversi organi. Proprio per questo motivo la regolazione dell’attività di questi recettori può avere interessanti applicazioni terapeutiche. Il principale obiettivo di questo progetto è stato l’analisi in silico a livello molecolare dei recettori adenosinici, ed in particolare dei recettori adenosinici umani A2A e A3, per guidare la scoperta e l’ottimizzazione strutturale di nuovi antagonisti adenosinici potenti e selettivi. Le strutture cristallografiche del recettore adenosinico umano A2A, recentemente pubblicate, forniscono dettagliate informazioni strutturali utili per supportare studi di homology modeling e approcci di drug design di tipo structure-based. In particolare, la struttura cristallografica del recettore adenosinico umano A2A, in complesso con l’antagonista potente e selettivo ZM241385, è stata utilizzata come templato per la costruzione di un modello per omologia del recettore adenosinico umano A3. Inoltre, con l’intento di selezionare il protocollo di docking molecolare più adatto per la famiglia dei recettori adenosinici, la struttura cristallografica del recettore adenosinico A2A è stata utilizzata per effettuare simulazioni di docking con diversi softwares in parallelo. Successivamente, le conformazioni ottenute dal docking sono state confrontate con la pose cristallografica di ZM241385 per selezionare il protocollo di docking che fosse in grado di riprodurre al meglio questo sistema molecolare e che potesse quindi essere usato per i successivi studi di docking. Sono stati quindi effettuati studi di docking molecolare di vari antagonisti adenosinici sul modello del recettore A3 e sulla struttura cristallografica del recettore A2A, in modo da ricavare informazioni che potessero facilitare il processo di ottimizzazione dei composti. Sono stati infatti analizzati numerosi nuovi composti appartenenti a classi note di antagonisti adenosinici, tra cui composti triazolotriazinici e tirazolotriazolopirimidinici, in modo da suggerire modifiche strutturali in grado di modularne l’affinità nei confronti dei vari sottotipi recettoriali adenosinici, di aumentarne la solubilità o di superarne i punti di instabilità metabolica. Diversi derivati con strutture semplificate, come per esempio composti pirazolopirimidinonici, ftalazinonici e triazolotriazinici, sono stati inoltre proposti come nuovi composti con attività antagonista nei confronti dei recettori adenosinici. Le informazioni ricavate grazie agli studi di docking hanno permesso l’identificazione di caratteristiche strutturali degli antagonisti adenosinici fondamentali per l’interazione con questi recettori. Queste informazioni sono state quindi applicate alla progettazione di derivati fluorescenti per il recettore adenosinico A3, che risultano particolarmente interessanti per il loro potenziale utilizzo in saggi farmacologici. In conclusione, quindi, questo studio sui recettori adenosinici dimostra come l’integrazione di metodologie computazionali con il lavoro sintetico e farmacologico risulta essere una strategia efficace per lo sviluppo di nuovi ligandi dei recettori adenosinici, a potenziale interesse terapeutico, e per il chiarimento di importanti aspetti strutturali riguardanti questa famiglia recettoriale e più in generale tutti i GPCRs.
Nanekar, R. (Rahul). "Biochemical and biophysical studies on adenosine receptors and their interaction partners." Doctoral thesis, Oulun yliopisto, 2016. http://urn.fi/urn:isbn:9789526211022.
Full textTiivistelmä Adenosiinireseptorit kuuluvat G-proteiinikytkeiset reseptorit (GPCR:t) proteiiniperheeseen. Adenosiinireseptorit välittävät endogeenisen ligandinsa adenosiinin vaikutuksia solukalvolta solunsisäisiin signaalijärjestelmiin. Adenosiini A3 reseptori (A3R) on adenosiinireseptorien neljästä alatyypistä (A1, A2A, A2B ja A3) vähiten tutkittu. Aikaisempien tutkimusten perusteella A3 reseptori yhdistetään sekä hermosoluja suojaaviin että rappeuttaviin tapahtumiin. Tässä työssä arvioitiin sekä ihmisen rekombinantti-A3R:n tuottumista hiiva- ja hyönteissoluissa että tutkittiin ihmisen adenosiini A2A reseptorin (A2AR) ja dopamiini D2 reseptorin (D2R) heteromerisoitumista. Rekombinantti A3 reseptori- vihreä fluoresoiva proteiini (GFP) fuusioproteiinia tuotettiin Saccharomyces cerevisiae -hiivassa 15 mg litrassa kasvatusliuosta. Pichia pastoris -hiivakanta taas kasvatti saman reseptorin tuottumista aina 108 mg/l saakka, kun tuotto tehtiin bioreaktorissa. Hyvin korkeasta tuottotasosta huolimattaA3R:n puhdistus hiivasta oli ylitsepääsemätön tehtävä, sillä reseptorin saostumista ei voinut välttää. Työssä havaittiin, että hyönteissolut sopivat paremmin A3R:n tuottoon: noin 10 µg monomeerista A3R:a voitiin puhdistaa litran hyönteissoluviljelmästä. Reseptorin stabiilisuuden lisääminen helpottaa reseptorin biokemiallista ja biofysikaalista karakterisointia. Tässä työssä osoitettiin, että T4L-proteiinin lisääminen A3R:n kolmannen solunsisäisen silmukan paikalle lisää reseptorin lämpöstabiilisuutta 10 °C. Jatkotutkimuksissa voitaisiin käyttää alaniiniskannausmutageneesiin perustuvien pistemutaatioiden ja fuusioproteiinin yhdistelmää A3R:n lisästabilointiin ja kiteytykseen. Tämän työn perusteella määrät, joilla A3R tuottuu hyönteissoluissa ja jotka saadaan eristettyä affiniteettipuhdistuksilla, muodostavat hyvän perustan proteiinin biokemialliselle karakterisoinnille. Reseptorin heteromerisoituminen on GPCR:en käyttämä mekanismi signalointiominaisuuksien ja toimintojen monipuolistamiseksi. Ihmisessä A2AR ja D2R heteromeereja on GABAergisissä enkefalinergisissä hermosoluissa. Molekyylien välisiin kontakteihin osallistuvat domeenit puhdistettiin Escherichia coli (E. coli) -bakteerista. Biokemiallisia ja biofysikaalisia tekniikoita kuten natiivi-PAGE:a ja massaspektrometriaa käyttäen vahvistettiin, että puhdistettu A2AR:n karboksiterminaalinen osa ja D2R:n kolmas solunsisäinen silmukka muodostavat heterodimeereja. Myös tutkittaessa puhdistetun kalmoduliini-proteiinin sitoutumista D2R:n kolmanteen solunsisäiseen silmukkaan osoitettiin proteiini-proteiini -vuorovaikutuksen olevan kalsiumista riippuvainen
Moscoso, Castro Maria 1988. "Study of the involvement of adenosine A2A receptors in the pathophysiology of schizophrenia." Doctoral thesis, Universitat Pompeu Fabra, 2016. http://hdl.handle.net/10803/565401.
Full textEl sistema adenosinèrgic és un neuromodulador que actua sobre quatre subtipus de receptors amb diferents distribucions en el sistema nerviós central. Aquest sistema contribueix a l’homeòstasi i a la vegada regula diverses funcions fisiològiques com per exemple la son, la funció motora, la plasticitat sinàptica o la cognició. L’adenosina pot exercir un control “upstream” sobre diferents sistemes de neurotransmissió, incloent la dopamina i el glutamat, neurotransmissors implicats en la fisiopatologia de les malalties neuropsiquiàtriques, especialment en la psicosis. L’esquizofrènia es considera una malaltia psicòtica que cursa de forma crònica i debilitant provocada per la interacció de diferents factors genètics, ambientals i del desenvolupament. La malaltia es manifesta en tres dominis de símptomes, incloent símptomes positius, negatius i cognitius, i actualment té importants limitacions terapèutiques. Estudis preclínics i clínics suggereixen que la disfunció en el sistema d’adenosina pot contribuir a la patofisiologia de l’esquizofrènia. Per tant, l’objectiu principal d’aquesta tesi és l’estudi dels efectes induïts per la supressió completa dels receptors A2A d’adenosina en la fisiopatologia de la malaltia, parant especial atenció al domini de símptomes cognitius. L’ús de mètodes bioquímics i comportamentals ens ha permès avaluar la validesa dels KO pel receptor A2A d’adenosina com a possible model animal per a l’estudi de l’esquizofrènia.
Casadó, Anguera Verònica. "Allosteric interactions between catecholamine receptors and other G protein-coupled receptors: Pharmacological and functional characterization." Doctoral thesis, Universitat de Barcelona, 2018. http://hdl.handle.net/10803/586262.
Full textLes catecolamines dopamina (DA) i norepinefrina (NE) tenen una funció clau en la regulació de processos fisiològics i en el desenvolupament de diverses patologies. Existeix una correlació entre gens relacionats amb la DA (com el receptor D4) i amb la NE (com el receptor α2A) i la vulnerabilitat per desenvolupar el trastorn per dèficit d’atenció i hiperactivitat (TDAH). A més, l’adenosina, actuant sobre els receptors d’adenosina (AR), és un modulador dels receptors de DA tipus D1 i D2, que controlen el moviment als ganglis basals, on també es troben implicats els adrenoreceptors. Els receptors de NE, DA i adenosina pertanyen a la família dels GPCR, que té una gran importància biomèdica, essent diana d’un 35% dels fàrmacs aprovats. És conegut que els GPCRs formen homodimers, heterodimers i oligòmers més complexos amb noves propietats farmacològiques i funcionals. En aquesta Tesi hem caracteritzat les interaccions moleculars entre receptors de catecolamines i entre receptors de catecolamines i d’adenosina, involucrats en patologies neurològiques relacionades amb l’atenció, la impulsivitat i el control motor. Concretament, hem donat evidències que els homodimers de GPCRs són les espècies predominants a l’organisme i que les interaccions alostèriques entre lligands ortostèrics dins un heteròmer tenen importants implicacions farmacològiques. També hem generat un protocol de síntesis de lligands bivalents molt eficient. Aquests lligands permeten actuar sobre un oligòmer concret, minimitzant els efectes secundaris en comparació amb fàrmacs dirigits a monomèrs. Hem demostrat que els receptors de catecolamines constitueixen una mateixa família funcional donada la promiscuïtat entre els seus lligands. Finalment, hem descrit l’existència de complexos entre els receptors D4 i D2S i entre D4 i α2A, trobant diferències funcionals segons la variant del receptor D4 involucrada. Donat que els receptors D2R, D4R i α2AR estan involucrats en el TDAH, aquests heteròmers poden ser una nova diana terapèutica per a aquesta patologia.
Beauglehole, Anthony Robert, and anthony@adenrx com. "N3-substituted xanthines as irreversible adenosine receptor antagonists." Deakin University. School of Biological and Chemical Sciences, 2000. http://tux.lib.deakin.edu.au./adt-VDU/public/adt-VDU20080612.084330.
Full textWebb, Rachel J. "Characterisation of P2-receptors on human platelets." Thesis, University of Oxford, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.342989.
Full textTARGA, Martina. "ADENOSINE RECEPTORS IN RESPIRATORY DISORDERS AS CHRONIC OBSTRUCTIVE PULMONARY DISEASE AND MALIGNANT PLEURAL MESOTHELIOMA." Doctoral thesis, Università degli studi di Ferrara, 2012. http://hdl.handle.net/11392/2388779.
Full textHamil, Nicola Elizabeth. "The neuromodulatory role of adenosine A1 receptors in status epilepticus." Thesis, St George's, University of London, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.526032.
Full textBlythe, Louise Jane. "Analysis of presynaptic metabotropic glutamate and adenosine A¦1 receptors." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1998. http://www.collectionscanada.ca/obj/s4/f2/dsk2/tape17/PQDD_0002/MQ33952.pdf.
Full textAl-Jarari, Nouh Mohamed Hamed. "Regulation of adenosine receptors in human SH-SY5Y neuroblastoma cells." Thesis, University of Nottingham, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.438430.
Full textTAFFI, MARIANNA. "Synthesis of heterocycles and nucleosides as ligands of adenosine receptors." Doctoral thesis, Università degli Studi di Camerino, 2006. http://hdl.handle.net/11581/401908.
Full textFOGLI, Eleonora. "Adenosine receptors modulation of inflammatory cells: the foam cells history." Doctoral thesis, Università degli studi di Ferrara, 2010. http://hdl.handle.net/11392/2389328.
Full textRAVANI, Annalisa. "Pharmacological characterization of adenosine receptors in chronic inflammatory rheumatic diseases." Doctoral thesis, Università degli studi di Ferrara, 2018. http://hdl.handle.net/11392/2478762.
Full textRheumatoid arthritis (RA), ankylosing spondylitis (AS) and psoriatic arthritis (PsA) are chronic inflammatory rheumatic diseases that affect joints, causing debilitating pain and disability. Adenosine receptors (ARs) play a key role in the mechanism of inflammation, and the activation of A2A and A3AR subtypes is often associated with a reduction of the inflammatory status. The first aim of this study was to investigate the involvement of ARs in patients suffering from early-RA (ERA), RA, AS and PsA. Messenger RNA (mRNA) analysis and saturation binding experiments indicated an upregulation of A2A and A3ARs in lymphocytes obtained from patients when compared with healthy subjects. A2A and A3AR agonists inhibited nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) activation and reduced inflammatory cytokines release, such as tumor necrosis factor-α (TNF-α), interleukin (IL)-1β and IL-6. Moreover, A2A and A3AR activation mediated a reduction of metalloproteinases (MMP)-1 and MMP-3. The effect of the agonists was abrogated by selective antagonists demonstrating the direct involvement of these receptor subtypes. These data confirmed the involvement of ARs in chronic autoimmune rheumatic diseases highlighting the possibility to exploit A2A and A3ARs as therapeutic targets, with the aim to limit the inflammatory responses usually associated with RA, AS and PsA. The purpose of the second chapter of this thesis, was to evaluate the modulation of A2A and A3ARs in patients suffering from RA, AS and PsA after different pharmacological treatments. We investigated A2A and A3AR density and functionality in pathologies progression by using a longitudinal study in RA, AS and PsA patients before and after methotrexate (MTX), anti-TNFa agents or rituximab treatments. A2A and A3ARs were analyzed by saturation binding assays in lymphocytes from patients throughout the 24-month study timeframe. In lymphocytes obtained from RA patients, the A2A and A3AR up-regulation was gradually reduced in function of the treatment time. Taken together, these data confirmed the involvement of A2A and A3ARs in chronic inflammatory rheumatic disease progression and highlighted that A2A and A3AR agonists could represent a physiological-like therapeutic alternative for RA treatment.
Higgins, Michael Joseph. "An investigation of paired pulse interactions between evoked field potentials in normal and bicuculline-superfused rat hippocampal slices." Thesis, University of Glasgow, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.320311.
Full textLandon, Linda A. Neighbors. "Salivary gland P2 nucleotide receptors : structure and function studies /." free to MU campus, to others for purchase, 1998. http://wwwlib.umi.com/cr/mo/fullcit?p9904855.
Full textKim, Douglas S. "Dopamine and adenosine receptor function in adult and developing dopamine-deficient mice /." Thesis, Connect to this title online; UW restricted, 2002. http://hdl.handle.net/1773/5063.
Full textAl-Hasani, Ream. "The involvement of adenosine A2a receptors in morphine and cocaine addiction." Thesis, University of Surrey, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.510572.
Full textFieger, Sarah M. "Adenosine receptors in cutaneous thermal hyperemia and active vasodilation in humans." Thesis, Kansas State University, 2011. http://hdl.handle.net/2097/8762.
Full textDepartment of Kinesiology
Brett J. Wong
Mechanisms underlying the cutaneous vasodilation response to local skin heating and whole body heating in humans remain unresolved. Although nitric oxide (NO) is known to contribute to these responses, it remains unclear as to the source of NO. Adenosine receptors induce vasodilation in many human tissues and may work, in part, through NO. As these receptors are also known to be located in the cutaneous vasculature, the studies contained in this thesis were designed to investigate a potential contribution of adenosine receptor activation to the rise in skin blood flow elicited by local skin and whole body heating. The study presented in chapter IV was designed to determine a potential role for adenosine receptors in contributing to cutaneous thermal hyperemia. Four cutaneous microdialysis sites were randomly assigned one of four drug treatments designed to elucidate the contribution of A[subscript]1/A[subscript]2 adenosine receptors during local skin heating. Each site was locally heated from a baseline temperature of 33°C to 42°C at a rate of 1°C/10 s and skin blood flow was monitored via laser-Doppler flowmetry (LDF). The data obtained from these experiments suggest A[subscript]1/A[subscript]2 adenosine receptor activation directly contributes to cutaneous thermal hyperemia. These data further suggest a portion of the NO response may be explained by A[subscript]1/A[subscript]2 adenosine receptor activation; however, a substantial portion of the NO response is independent of the adenosine receptor contribution. The study presented in chapter V was designed to determine a potential role for A[subscript]1/A[subscript]2 adenosine receptors in contributing to cutaneous active vasodilation. Four cutaneous microdialysis sites were randomly assigned one of four drug treatments, as above, and skin blood flow was monitored via LDF. Whole body heat stress, sufficient to raise oral temperature at least 0.8°C above baseline, was induced via water-perfused suits. The data obtained from these experiments suggest A[subscript]1/A[subscript]2 adenosine receptor activation does not directly contribute to cutaneous active vasodilation; however, a role for A[subscript]1/A[subscript]2 adenosine receptor activation is unmasked when NO synthase is inhibited. The data from this study further suggest that A[subscript]1/A[subscript]2 adenosine receptor activation may be responsible for a portion of the known NO component of cutaneous active vasodilation.
NGOUADJEU, NGNINTEDEM MICHAEL ALLIANCE. "Synthesis and Biological Evaluation of new Ligands for the Adenosine Receptors." Doctoral thesis, Università degli Studi di Camerino, 2019. http://hdl.handle.net/11581/428735.
Full textSAPONARO, Giulia. "Design and Synthesis of New A2A and A3 Adenosine Receptors Antagonists." Doctoral thesis, Università degli studi di Ferrara, 2009. http://hdl.handle.net/11392/2388703.
Full textNadal, Magriñà Laura. "Muscarinic, adenosine and tropomyosin-related kinase B receptors modulate the neuromuscular developmental synapse elimination process." Doctoral thesis, Universitat Rovira i Virgili, 2017. http://hdl.handle.net/10803/441749.
Full textEl desarrollo del sistema nervioso periférico implica una inicial exuberante producción de neuronas y, una posterior reducción dependiente de actividad del número de sinapsis en las uniones neuromusculares (NMJ). Este proceso se denomina eliminación sináptica. Al final de la segunda semana postnatal, cada fibra muscular esta inervadas por una solo motoneurona. Los receptores muscarínicos de acetilcolina (mAChR), los receptores de adenosina (AR) y el receptor quinasa de tropomiosina B (TrkB) podrían permitir la competición entre los terminales nerviosos durante el proceso de eliminación sináptica mediante la modulación en la liberación de acetilcolina. En esta tesis se ha investigado, mediante microscopía confocal y un análisis morfológico cuantitativo, el papel de los receptores mAChRs (M1, M2 y M4), de los receptores de adenosina (A1 y A2A) y del receptor TrkB en el del proceso de eliminación en el desarrollo de la NMJ. Los resultados muestran que los receptores mAChRs, AR y el receptor TrkB promueven una desconexión axonal al inicio de la segunda semana postnatal independientemente de la maduración de los receptores de acetilcolina postsinápticos. En resumen, los receptores mAChRs, AR y el receptor TrkB retrasan el proceso de eliminación sináptica en P7 pero lo aceleran en P9. En la cooperación de estos receptores, se ha demostrado que M4 produce un efecto oclusivo sobre M1 y aditivo sobre A1 en P7. La cooperación entre M1, A1 y A2A promueve la pérdida axonal en P9, mientras que M2 es independiente de los otros receptores. M1 y TrkB cooperan para incrementar la pérdida axonal en P9 independientemente de M2 y TrkB. En conclusión, la eliminación sináptica postnatal está regulada por un mecanismo que depende de varios receptores, involucrando la cooperación de diferentes subtipos de receptores muscarínicos, de adenosina y el receptor TrkB, los cuales garantizan la monoinnervación de las sinapsis neuromusculares al final del proceso. saludable.
The development of the peripheral nervous system involves an initially exuberant production of neurons and a subsequent activity-dependent reduction in the number of synapses at the neuromuscular junctions (NMJ). This process is called synaptic elimination. At the end of the first postnatal week, each muscle fiber is innervated by a single motoneuron. Muscarinic acetylcholine receptors (mAChR), adenosine receptors (AR) and the tropomyosin-related kinase B (TrkB) receptor may allow the direct competition between nerve endings during synapse elimination through the modulation of acetylcholine release. Here, it has been investigated by confocal microscopy and quantitative morphological analysis the involvement of the individual and synergic or oclusive effect of M1-, M2- and M4-subtypes of mAChRs, A1 and A2A of ARs and TrkB in the control of the axonal elimination in developing NMJ. The results show that mAChRs, ARs and TrkB promote axonal disconnection at the beginning of the second postnatal week without affecting the postsynaptic maturation of the nicotinic receptor cluster. In summary, mAChRs, ARs and TrkB delay axonal loss at P7 but accelerate it at P9. In terms of receptor cooperation, M4 produces some occlusion of the M1 pathway and some addition to the A1 pathway at P7. The cooperation between M1, A1 and A2A receptors promotes axonal loss at P9, whereas the effect of M2 is independent of the other receptors. M1 and TrkB receptors work together to increase axonal loss rate at P9 but the effect of M2 is largely independent of the TrkB receptor. In conclusion, postnatal synapse elimination is a regulated multireceptor mechanism involving the cooperation of several muscarinic, adenosine and TrkB receptor subtypes that guarantees the monoinnervation of the neuromuscular synapses in the end of the process.
Sorrentino, Claudia. "Role of CD73 - A2A/A2B receptors axis in cancer." Doctoral thesis, Universita degli studi di Salerno, 2018. http://hdl.handle.net/10556/3116.
Full textThe adenosinergic pathway plays a critical role in cancer development and progression, as well as in drug resistance to chemotherapy and/or targeted-therapy. The goal of this PhD thesis was to investigate and fully characterize the role of CD73/adenosine A2A-A2B receptors axis in cancer, highlighting the therapeutic potential of inhibitors of the adenosinergic pathway. We firstly characterized the mechanism/s by which A2BR promotes immunosuppression and angiogenesis in tumor-bearing hosts, focusing on the role of myeloid-derived suppressor cells (MDSCs) and cancer-associated fibroblasts (CAFs). The results revealed that treatment of melanoma-bearing mice with Bay60-6583, a selective A2BR agonist, is associated with 1. increased tumor VEGF-A expression and vessel density, and 2. increased accumulation of tumor-infiltrating CD11b+Gr1+cells (MDSCs). MDSCs strongly contribute to the immunosuppressive and angiogenic effects of Bay60-6583. Melanoma-bearing mice treated with a selective A2BR antagonist PSB1115 showed reduced tumor growth compared to controls and this effect was associated with reduced tumor angiogenesis, low levels of MDSCs and increased number of tumor-infiltrating CD8+ T cells. Furthermore, blockade of A2BR increased the anti-tumor effects of VEGF-A inhibitors. Next, we verified that A2BR activation also drives fibroblasts activation within melanoma tissues, by increasing the number of FAP positive cells within tumor lesions. FAP is a common marker of activated fibroblasts also named cancer-associated fibroblasts. These cells produce and secrete various tumor-promoting factors, including fibroblast growth factor (FGF)-2 and CXCL12 or stromal-derived factor 1 α (SDF1α), that were increased both in melanoma tissue and fibroblasts isolated from melanoma tissue or from skin upon Bay60-6583 treatment. Bay60-6583-induced FGF-2 from fibroblasts contributed to melanoma cells proliferation. The CXCL12/CXCR4 pathway, instead, was involved in the pro-angiogenic effects of A2BR agonist, but not in its immunosuppressive effects. These effects were significantly blocked by the A2BR antagonists PSB1115. Taken together, these data elucidate the pivotal role of A2BR in establishing a positive cross-talk between tumor-infiltrating immune cells, fibroblasts and endothelial cells that sustain tumor growth, reinforcing the therapeutic potential of A2BR blockers for cancer therapy. ... [edited by Author]
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BENCIVENNI, SERENA. "Glial cells and neuroinflammation: the adenosinergic contribution." Doctoral thesis, Università degli studi di Ferrara, 2018. http://hdl.handle.net/11392/2478763.
Full textThe hallmark of neuroinflammation is the activation of microglia, the immunocompetent cells of the CNS, releasing a number of pro-inflammatory mediators implicated in the pathogenesis of several neurological diseases such as AD, PD, MS and ischemic stroke. The innate immune TLR4, localized on the surface of microglia, is a first-line host defense receptor against invading microorganisms and LPS, a component of the cell wall of gram-negative bacteria, was first identified as the TLR ligand. ARs interacting with TLR4 influence on many immune properties of microglia and are implicated in numerous physiological and pathophysiological states in CNS. Indeed, Ado, a ubiquitous nucleoside with important immunomodulatory functions, has been found to take part in the principal microglial activation processes spanning from proliferation, process extension, retraction, migration and cytokine production. On this background, the aim of this study was to investigate the adenosinergic contribution to glial cell mediated-neuroinflammation by analyzing the expression of ARs and the signalling pathways, transcription factors and cytokines activated by them in different pathophysiological conditions linked to hypoxic and inflammatory conditions. The aim of studies reported in chapter 1 was to investigate whether Ado may affect microglia functions by acting on HIF-1α modulation, the main transcription factor of hypoxia-inducible genes, involved in the immune response, being regulated in normoxia by inflammatory mediators. Primary murine microglia were activated with LPS with or without Ado, Ado receptor agonists and antagonists and HIF-1α accumulation and downstream genes regulation were determined. Ado increased LPS-induced HIF-1α accumulation leading to an increase in HIF-1α target genes involved in cell metabolism and pathogens killing but did not induce HIF-1α dependent genes related to angiogenesis and inflammation. The stimulatory effect of Ado on HIF-1α and its target genes was essentially exerted by activation of A2A through ERK1/2 (or p44/42) and A2B subtypes via p38 MAPKs and Akt phosphorylation. Furthermore, the nucleoside raised VEGF and decreased TNF-α levels, by activating A2B subtypes. Our results show that Ado increases GLUT-1 and iNOS gene expression in a HIF-1α-dependent way, through A2A and A2B ARs, suggesting their role in the regulation of microglial cells function following injury. However, inhibition of TNF-α adds an important anti-inflammatory effect only for the A2B subtype. The aim of studies reported in chapter 2 was to indagate the potential role of ARs in the modulation of IL-6 secretion and cell proliferation in primary microglial cells. The A2B AR agonist BAY 60-6583 stimulated IL-6 increase under normoxia and hypoxia, in a dose- and time-dependent way. In cells incubated with the blockers of PLC, PKC-ε and PKC-delta the IL-6 increase due to A2B AR activation was strongly reduced, whilst it was not affected by the inhibitor of AC. Investigation of cellular signalling involved in the A2B AR effect revealed that only the inhibitor of p38 MAPK was able to block the agonist effect on IL-6 secretion, whilst inhibitors of ERK1/2, JNK1/2 MAPKs and Akt were not. Stimulation of p38 by BAY 60-6583 was A2B AR dependent, through PLC, PKC-ɛ and PKC-delta but not AC pathway, in both normoxia and hypoxia. Finally, BAY 60-6583 increased microglial cell proliferation involving A2B AR, PLC, PKC-ε PKC-delta and p38 signalling. Our results show for the first time that Ado by activating A2B ARs increases IL-6 protein levels and cell proliferation through a pathway dependent on PLC, PKC-ε, PKC-delta, and p38 signalling. These findings add new molecular pathways activated by Ado in microglia to give a reduction of genes and cytokines involved in inflammation and hypoxic injury that may cohexist in stroke, ischemia and other CNS disorders.
Poulsen, Sally-Ann, and n/a. "Pyrazolo(3,4-d)pyrimidines: Synthesis and Structure-Activity Relationships for Binding to Adenosine Receptors." Griffith University. School of Science, 1996. http://www4.gu.edu.au:8080/adt-root/public/adt-QGU20050901.161632.
Full textPoulsen, Sally-Ann. "Pyrazolo(3,4-d)pyrimidines: Synthesis and Structure-Activity Relationships for Binding to Adenosine Receptors." Thesis, Griffith University, 1996. http://hdl.handle.net/10072/365893.
Full textThesis (PhD Doctorate)
Doctor of Philosophy (PhD)
School of Science
Science, Environment, Engineering and Technology
Full Text
Henriques, Ana Margarida Cardoso. "Modulation of NMDA receptor currents by adenosine A2A receptors in the Schaffer collaterals-CA1 synapses." Master's thesis, 2017. http://hdl.handle.net/10316/83240.
Full textAdenosine is a neuromodulator able to control the balance between neuronal excitation and inhibition, throughout the central nervous system (CNS). Adenosine acts onto a G protein–coupled receptors (GPCRs) subfamily called P1 adenosine receptors: A1R, A2AR, A2BR and A3R. Adenosine type 2A receptor (A2AR) is highly expressed in striatum, whereas in other brain regions A2AR is expressed at lower levels. One of these regions is the hippocampus, a central brain region enrolled in learning and memory processes as well as spatial recognition. Moreover, it was discovered that A2AR modulate reference memory. Additionally, A2AR can facilitate synaptic transmission since it can fine-tune other neuromodulatory systems, by controlling neurotransmitter release and modulating metabotropic or ionotropic receptors. It was also described that A2AR can interact with NMDA receptor (NMDAR), that is an ionotropic receptor. Therefore, given the particular importance of NMDAR in the hippocampal neurotransmission phenomena, in this work, we explore how A2AR can modulate NMDAR-dependent currents in hippocampal Schaffer collaterals - CA1 synapses. We showed that exogenous activation of A2AR, with its selective agonist CGS21680, decreases NMDAR-dependent evoked excitatory postsynaptic currents (eEPSCs) and that this effect is no longer observed in the presence of the selective A2AR antagonist, SCH58261. However, the superfusion of SCH58261 alone also decreases NMDAR-eEPSCs, suggesting that A2AR may exert a tonic control of these currents in CA1 pyramidal cells. Finally, this study revealed that our slice preparations contained high levels of endogenous adenosine which, once removed, does not prevent the A2AR antagonist-induced decrease in NMDAR-eEPCSs in SC-CA1 synapses. Our main hypothesis to explain these results is based in the possibility of existing two sub-populations of A2AR that may have antagonistic effects upon NMDA-dependent currents. Nevertheless, this hypothesis and mechanisms remain to be clarified, which can be the foundation for future work.
A adenosina é um neuromodulador capaz de controlar o balanço entre excitação e inibição ao longo de todo o sistema nervoso central. Este controlo é feito através da activação da subfamília de receptores acoplados a proteínas G (GPCRs), os receptores de adenosina P1: A1R, A2AR, A2BR and A3R. O receptor de adenosina do tipo 2A (A2AR) é abundantemente expresso no estriado e é menos expresso noutras regiões do cérebro. Uma destas regiões é o hippocampo, uma região cerebral central envolvida nos processos de aprendizagem, memória e reconhecimento espacial. Foi descoberto que os A2AR podem modular a memória de referência. Além disso, os A2AR estão maioritariamente descritos como facilitadores da transmissão sináptica, sendo que as suas principais funções são o refinamento de outros sistemas neuromodulatórios, o controlo da libertação de neurotransmissores e ainda a modulação da actividade de outros receptores, quer metabotrópicos quer ionotrópicos.O receptor de NMDA (NMDAR) é um receptor ionotrópico com o qual o A2AR pode interagir. Deste modo, dada a particular importância do NMDAR para o fenómeno de neurotransmissão no hippocampo, este trabalho explora de que forma é que os A2AR modulam as correntes dependentes de NMDAR nas sinapses entre os neurónios piramidais do CA1 e as colaterais de Schaffer (SC) no hipocampo.Mostrou-se que a activação exógena do A2AR com o seu agonista selectivo CGS21680 diminui as correntes excitatórias pós-sinápticas evocadas (eEPSC) dependentes do receptor de NMDA, um efeito que deixa de ser observado na presença do antagonista selectivo dos A2AR, SCH58261. Além disso, SCH58261 diminui a amplitude dos eEPSCs em condições basais o que sugere que os A2AR poderão exercer um controlo tónico destas correntes nos neurónios piramidais do CA1. Finalmente, com este trabalho observou-se ainda, que as preparações in vitro utilizadas têm uma grande quantidade de adenosina endógena. A sua remoção, porém, não previne o efeito induzido pelo antagonista selectivo dos A2AR, continuando a observar-se uma diminuição na amplitude de eEPSC dependentes de NMDAR nas sinapses CA1-SC.A principal hipótese para explicar esta aparente contradição de resultados tem a ver com a possível existência de duas sub-populações de A2AR que podem afectar as correntes dependentes de NMDAR de maneira oposta. Contudo, o estudo de qual a população de A2AR que é responsável por cada um dos efeitos, assim como quais os mecanismos por detrás desta evidente modulação dos A2AR sobre os NMDAR permanece por clarificsr, o que poderá servir de basede trabalho futuro.
Outro - 016684 - PTDC/NEU-NMC/4154/2014 (POCI-01-0145-FEDER-016684) - Papel dos astrócitos no controlo da memória- foco nos recetores adenosina A2A - Fundação para a Ciência e a Tecnologia
Outro - COMPETE POCI-01-0145-FEDER-007440 - Trabalho multidisciplinar no âmbito da neurociência cognitiva na saúde e na doença - Fundação para a Ciência e a Tecnologia
Hettinger, Barbara D. "Regulation of neuronal A��� adenosine receptors." Thesis, 1997. http://hdl.handle.net/1957/33807.
Full text"Adenosine receptors : pharmacology and adaptive change." Chinese University of Hong Kong, 1986. http://library.cuhk.edu.hk/record=b5885665.
Full textAlfaro, Tiago Manuel Pombo. "Adenosine receptors in inflammatory lung diseases." Doctoral thesis, 2018. http://hdl.handle.net/10316/84773.
Full textAs doenças pulmonares inflamatórias crónicas, incluindo a asma, a doença pulmonar obstrutiva crónica e doenças pulmonares intersticiais são uma causa crescente e significativa de incapacidade e mortalidade precoce à escala global. Há uma necessidade urgente e reconhecida de novas terapêuticas, mas os alvos identificados nos estudos in vitro e modelos animais não têm sido aplicados com sucesso em humanos. A modulação dos recetores purinérgicos é uma abordagem particularmente promissora no controlo da inflamação e promoção da homeostasia. Um conjunto extenso e robusto de dados pré-clínicos demonstraram a presença e atividade destes recetores em células e tecidos envolvidos na inflamação pulmonar e a sua modulação foi eficaz em modelos animais de doença. No entanto, a aplicação destes resultados em ensaios clínicos tem sido dececionante. Alguns autores argumentam que essa ineficácia resulte de diferenças na distribuição e efeitos dos recetores purinérgicos entre as espécies. O objectivo deste estudo foi a avaliação dos efeitos dos recetores da adenosina na doença pulmonar humana. Em última análise pretende-se obter uma prova de conceito na manipulação dos recetores da adenosina para o tratamento de doenças pulmonares humanas. Foi aplicada uma estratégia de três passos. Primeiro, estudaram-se os efeitos do consumo crónico de doses moderadas de cafeína, um antagonista não seletivo dos recetores A1 e A2A da adenosina, na saúde respiratória, possibilitando assim um estudo não intervencional do efeito destes recetores em humanos. De seguida, avaliaram-se os níveis pulmonares dum percursor da adenosina, permitindo a avaliação da ativação endógena dos recetores purinérgicos na doença pulmonar humana. Finalmente, desenvolveu-se um método laboratorial que avalia um marcador robusto de ativação celular em macrófagos alveolares humanos frescos e não modificados. Salienta-se que o macrófago alveolar apresenta especial importância na patogénese das doenças pulmonares inflamatórias. Os estudos epidemiológicos mostraram efeitos globalmente benéficos da cafeína nas doenças respiratórias, incluindo na asma e na tosse pós-infeciosa, bem como na função respiratória e na mortalidade de causa respiratória. Os efeitos na DPOC e sarcoidose não foram claros. Não se observou correlação entre o consumo de cafeína e o risco ou gravidade da apneia do sono. Quando se mediram os níveis pulmonares de trifosfato de adenosina (ATP), encontraram-se níveis elevados em doentes com sarcoidose, comparativamente àqueles com pneumonite de hipersensibilidade, sugerindo que o ATP pode ser útil como biomarcador auxiliar de diagnóstico. Finalmente, em macrófagos alveolares humanos, os recetores A2A da adenosina sofreram alterações adaptativas da sua densidade e a sua ativação reduziu os transientes de cálcio livre intracelular causados pela exposição a um estímulo inflamatório. Estes resultados suportam a proposta de que os recetores A2A da adenosina são um alvo promissor no tratamento das doenças respiratórias inflamatórias, desde que seja utilizada uma dose suficientemente eficaz. Em conclusão, foram realizados dois estudos laboratoriais e quatro estudos epidemiológicos focados nos efeitos da adenosina em doença respiratória humana e obteve-se evidência que suporta um papel relevante das purinas na patogénese das doenças pulmonares inflamatórias humanas. Estes resultados sustentam a realização de ensaios clínicos com agonistas dos recetores A2A da adenosina em doenças pulmonares inflamatórias.
Chronic inflammatory lung diseases, such as asthma, chronic obstructive pulmonary disease and interstitial lung diseases are a major and rising global source of disability and early death. An urgent need for new therapies is widely recognized, but the identification of therapeutic targets in in vitro and animal studies has not been successfully translated into effective human treatments. The modulation of purinergic receptors is a particularly promising new strategy for the control of inflammation and promotion of homeostasis. A breadth of preclinical data has shown that adenosine receptors are active in cells and tissues with a role in pulmonary inflammation and their modulation leads to functional improvements in animal models. The application of these strategies in clinical trials was, however, disappointing. Some authors argue that this lack of effectiveness is related to inter-specific differences in distribution and effects of adenosine receptors. This study aimed to assess the effects of adenosine receptors in human disease. The final objective was to obtain a proof-of-concept for the use of adenosine receptor modulation for the treatment of human disease. A three-step approach was used. First the effects of chronic consumption of caffeine, a non-selective antagonist of the A1 and A2A adenosine receptors, were studied, allowing for a non-interventional evaluation of their effects on human respiratory disease. The levels of an adenosine precursor in the lung were then assessed, allowing for an appraisal of the expected endogenous activation of purinergic receptors in human disease. Finally, a laboratory method was developed for the study of a robust marker of cell activation in fresh, unchanged human alveolar macrophages, which have a prominent role in the pathogenesis of inflammatory pulmonary disease. The epidemiological studies showed that caffeine intake has positive effects in some lung diseases, such as asthma and post-infectious cough, as well as in lung function and respiratory mortality. The results on COPD and sarcoidosis were less clear. No correlation was found between caffeine consumption and the risk or severity of sleep apnoea. The measurement of the lung levels of adenosine triphosphate (ATP), revealed higher levels in patients with sarcoidosis compared to those with hypersensitivity pneumonitis, suggesting that ATP could useful as a diagnosis biomarker. Finally, adenosine A2A receptors underwent adaptive changes of density and their activation reduced the intracellular free calcium transients resulting from exposure to an inflammatory stimulus in human alveolar macrophages. This supports the contention that adenosine A2A receptors are a promising therapeutic target for treating inflammatory lung disorders in humans, provided that a sufficiently effective dose of agonist is used. In conclusion, these two laboratory and four epidemiological studies focused on the effects of adenosine in human lung disease found evidence that supports a relevant role for purines in the pathogenesis of human inflammatory lung disease. These results support the further testing of adenosine A2A receptor agonists for the treatment of inflammatory lung diseases.
This project was funded by Fundação para a Ciência e Tecnologia (FCT) through Grants SFRH/BD/69640/2010 (funded by POPH-QREN) and project grant PIC/IC/83290/2007, which is supported by FEDER (POFC e COMPETE) (PIC/IC/82390/2007) and FCT.
Xavier, Ana Carolina Gonçalves de Almeida. "Role of adenosine receptors in suicide." Master's thesis, 2014. http://hdl.handle.net/10316/31207.
Full textMajor depressive disorder (MDD), the most prevalent mental illness, is a chronic and recurrent condition (Lucas et al., 2011). MDD seems to be associated with abnormalities in regions that mediate emotional and stress responses (Manji et al., 2001). A strong link between suicide and depression has been showed, with more than 86% of suicide victims having a depressive disorder, and committing suicide most often after a major depressive episode (Coryell & Young, 2005; Rihmer, 2007). So, it is possible to study the brain tissue from suicide completers, in order to understand the neurobiological basis of depression. Suicide has been identified as a serious public health problem. Risk factors, such as biological, psychiatric and cultural, interact in a complex manner to this pathology (Bertolote & Fleischmann, 2005). Adenosine is an endogenous nucleoside that influences many functions in the central nervous system (CNS) (Fredholm et al., 2005), acting as a homeostatic modulator and also as a neuromodulator at the synaptic level, where it modulates the release of neurotransmitters, the post-synaptic responsiveness and the action of other receptor systems (Cunha, 2001). Adenosine acts via activation of four G-protein coupled receptors (GPCRs) (Fredholm, 1997), in the brain, it acts especially through activation of two adenosine receptors (ARs), inhibitory A1 (A1R) and facilitatory A2A (A2AR) receptors (Cunha, 2005; Wei et al., 2011). The interest in the role of adenosine in mood disorders arised from previous studies that have recognized a relationship between caffeine intake, mood changes and specific psychiatric symptoms (Kawachi et al., 1996; Lara, 2010; Lucas et al., 2011; Lucas et al., 2013), since caffeine has biological effects as competitive antagonist of A1R and A2AR (Chen et al., 2013; Cunha et al., 2008; El Yacoubi et al., 2003; Fredholm et al., 2005; Fredholm, 2007). There is also evidence that different therapeutic strategies used to control mood disorders are related to the adenosine modulation system (Chen et al., 2013; Cunha et al., 2008; El Yacoubi et al., 2001; Gomes et al., 2011). In animal models of manipulation of ARs, there are modified behavioral responses considered relevant for mood in humans (Gomes et al., 2011). The main goal of this study was to understand the differences in the localization, density and function of both A1R and A2AR between control subjects and suicide completers, in brain areas affected by depression. Also, we aimed to comprehend if these alterations are related with synaptic changes. For this purpose, a postmortem study was performed in male subjects who died by suicide, aged-matched with nonsuicide controls who died by natural causes or accidents. Human brain samples were obtained at autopsies performed in Instituto Nacional de Medicina Legal e Ciências Forenses, I. P. (INMLCF), Coimbra, Portugal. Several brain areas were studied: Brodmann area 25 (BA25); medial caudate nucleus (MC); posterior caudate nucleus (PC) and hippocampus. To comprehend the normal localization of A1R and A2AR we compared the relative abundance of A1R and A2AR in total extracts (TE) and in nerve terminals (NT), isolated using an adapted discontinuous Percoll gradient protocol (Dunkley et al., 1986, 2008), from human brain areas of the same sample. In all brain areas studied, both receptors were found enriched in NT. We then refined the information on ARs subsynaptic localization, using a fractionation method (Phillips et al., 2001; Rebola et al., 2005), and it was observed that A2AR are mainly located outside the active zone and A1R are present in all synaptic fractions. Synaptic changes present in the brain of suicide completers were then studied and it was observed a down-regulation of synaptosomal-associated protein 25 (SNAP25) on BA25 and MC together with a decrease in postsynaptic density protein 95 (PSD95) levels on PC and hippocampus. Astrocytic marker glial fibrillary acidic protein (GFAP) down-regulation was observed in BA25 and hippocampus. Several alterations in the density of ARs, in the different brain regions, were observed in suicide completers when compared with age-matched controls. We described: an up-regulation of A2AR in TE, on BA25 and PC; an up-regulation of A1R in TE, on MC; a down-regulation of A1R in NT, on PC. Due to their particular distribution in the brain and their functional properties, ARs constitute an attractive opportunity for developing innovative compounds for the treatment of specific neurodegenerative and psychiatric disorders, such as MDD. Our work has provided information about changes present in the brains of suicide completers and might contribute to better understand the modulatory role of ARs in depression. There are still numerous questions that demand careful attention to further explore this system and develop novel strategies to control mood disorders, particularly MDD.
A perturbação depressiva major (MDD), a mais predominante das doenças mentais, é uma condição crónica e recorrente (Lucas et al., 2011). A MDD parece estar associada com alterações nas regiões que medeiam as respostas emocionais e de stress (Manji et al., 2001). Uma forte ligação entre o suicídio e a depressão foi demonstrada, uma vez que mais de 86% das vítimas de suicídio apresentavam uma perturbação depressiva, na maioria dos casos, ocorrendo o suicídio depois de um episódio depressivo major (Coryell et al., 2005; Rihmer, 2007). Assim, o tecido cerebral de vítimas de suicídio pode ser utilizado para estudar a neurobiologia da depressão. O suicídio foi identificado como um problema sério de saúde pública. Vários fatores de risco biológicos, psiquiátricos e culturais interagem de uma maneira complexa para esta patologia (Bertolote & Fleischmann, 2005). A adenosina é um nucleósido endógeno que influencia muitas funções do sistema nervoso central (CNS), agindo como modulador homeostático e também como neuromodulador ao nível sináptico, onde modula a libertação de neurotransmissores, a capacidade de resposta pós-sináptica e a ação de outros sistemas receptores (CNS) (Cunha, 2001; Fredholm et al., 2005). A adenosina actua em quatro receptores acoplados à proteína G (GPCRs) (Fredholm, 2007), no cérebro age especialmente através da activação de dois receptores de adenosina (ARs), inibitório A1 (A1R) e facilitatório A2A (A2AR) receptores (Cunha, 2005; Wei et al., 2011). O interesse do papel da adenosina nos distúrbios de humor surgiu de numerosos estudos que reconheceram uma relação entre o consumo de cafeína, alterações de humor e sintomas psiquiátricos específicos (Kawachi et al., 1996; Lara, 2010; Lucas et al., 2011; Lucas et al., 2013), uma vez que a cafeína tem efeitos biológicos como antagonista competitivo dos A1R e A2AR (Chen et al., 2013; Cunha et al., 2008; El Yacoubi et al., 2003; Fredholm et al., 2005; Fredholm, 2007). Também há evidências de que as estratégias terapêuticas utilizadas para controlar distúrbios de humor estão relacionados com o sistema modulatório de adenosina (Chen et al., 2013; Cunha et al., 2008; El Yacoubi et al., 2001; Gomes et al., 2011). Em modelos animais de manipulação de ARs há respostas comportamentais consideradas relevantes para o humor nos humanos (Gomes et al., 2011). O principal objectivo deste estudo era perceber as diferenças na localização, densidade e função dos A1R e A2AR, entre vítimas de suicídio e controlos, em áreas afectadas pela depressão. Além disso, tentámos compreender se essas alterações estão relacionadas com modificações sinápticas. Para este propósito foi realizado um estudo postmortem em sujeitos do sexo masculino suicidas, pareados com controlos da mesma idade que morreram de causas naturais ou acidentes. As amostras de cérebro humano foram obtidas em autópsias realizadas no Instituto Nacional de Medicina Legal e Ciências Forenses, I. P. (INMLCF), Coimbra, Portugal. Foram estudadas diversas áreas cerebrais: área de Brodmann 25 (BA25); núcleo caudado médio (MC); núcleo caudado posterior (PC) e hipocampo. Para compreender a localização normal dos A1R e do A2AR comparámos a abundância relativa dos ARs em extratos totais (TE) e em terminais nervosos (NT), isolados usando um protocolo adaptado de gradiente de Percoll discontínuo (Dunkley et al., 1986, 2008), das áreas cerebrais da mesma amostra. Em todas as áreas estudadas os dois receptores encontram-se enriquecidos nos NT. De seguida, refinámos a informação acerca da localização subsináptica dos ARs, usando um método de fracciomento (Phillips et al., 2001; Rebola et al., 2005) e foi observado que os A2AR estão maioritariamente localizados fora da zona activa da sinapse e os A1R estão presentes em todas as fracções sinápticas. Foram então estudadas alterações sinápticas presentes no cérebro de suicidas e foi observada uma diminuição de densidade da synaptosomal-associated protein 25 (SNAP-25) na BA25 e no MC juntamente com um decréscimo nos níveis de postsynaptic density protein 95 (PSD-95) no PC e no hipocampo. Foi observado uma diminuição da densidade do marcador astrocítico glial fibrillary acidic protein (GFAP) na BA25 e no hipocampo. Várias alterações na densidade dos ARs, nas diferentes regiões do cérebro, foram observadas nas amostras de suicidas quando comparadas com os controlos. Nós descrevemos: aumento da densidade de A2AR em TE, na BA25 e no PC; aumento de densidade de A1R em TE, no MC; diminuição de densidade de A1R em NT, no PC. Devido à sua particular distribuição no cérebro e as suas propriedades funcionais, os ARs constituem uma oportunidade atrativa para desenvolver compostos inovadores para o tratamento de distúrbios psiquiátricos e neurodegenerativos, como a MDD. O nosso trabalho forneceu informação sobre as mudanças presentes no cérebro de suicidas e pode contribuir para uma melhor compreensão do papel modulador dos ARs na depressão. Há ainda numerosas questões, que requerem atenção cuidadosa, para continuar a explorar este sistema e desenvolver novas estratégias para controlar os distúrbios de humor, particularmente, a MDD.