Dissertations / Theses on the topic 'Adenosine receptors, A1, A2B'
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Halldner, 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 textBANGALORE, REVANNA CHANDRASHEKAR. "Ischemia/Reperfusion injury on mice steatotic Hapatocites and differential effect of adenosine A2A and A1 receptors stimulation." Doctoral thesis, Università del Piemonte Orientale, 2016. http://hdl.handle.net/11579/115194.
Full textStumpf, Anette D. [Verfasser], and Carsten [Gutachter] Hoffmann. "Development of fluorescent FRET receptor sensors for investigation of conformational changes in adenosine A1 and A2A receptors / Anette D. Stumpf. Gutachter: Carsten Hoffmann." Würzburg : Universität Würzburg, 2016. http://d-nb.info/1111887357/34.
Full textTikh, Eugene I. "Regulation of Contractility by Adenosine A1 and A2A Receptors in the Murine Heart: Role of Protein Phosphatase 2A: A Dissertation." eScholarship@UMMS, 2006. https://escholarship.umassmed.edu/gsbs_diss/130.
Full textPagnussat, Natália. "O envolvimento dos receptores de adenosina A1 e A2A na memória em camundongos machos adultos." reponame:Biblioteca Digital de Teses e Dissertações da UFRGS, 2015. http://hdl.handle.net/10183/131897.
Full textCaffeine, a non-selective adenosine receptor antagonist, prevents memory deficits, an effect mimicked by adenosine A2A receptor (A2AR), but not receptor A1 (A1R), antagonists upon aging and Alzheimer´s disease. We tested if A2AR were also necessary for the memory impairment upon direct perturbation of the cholinergic system with scopolamine and if A2AR activation was sufficient to trigger memory deficits in naive mice using 3 tests, to probe for short-term memory, namely the object recognition task, inhibitory avoidance and modified Y-maze. The intra-peritoneal (i.p.) administration of scopolamine (1.0 mg/kg) impaired short-term memory performance in 3 tests, namely the object recognition task, inhibitory avoidance and modified Y-maze. The scopolamine-induced amnesia was prevented by the A2AR (SCH 58261, 0.5 mg/kg, i.p.) as well as by A1R antagonist (DPCPX, 1 mg/kg, i.p.) in all tests, except for the modified Y-maze, and both antagonists were devoid of effects on memory or locomotion in naive rats. Notably, the activation of A2AR with CGS 21680 (0.1 mg/kg, i.p.) before the training session was sufficient to trigger memory impairment in the 3 tests in naive mice, and effect prevented by SCH 58261 (0.5 mg/kg, i.p.). Furthermore, the intracerebroventricular administration of CGS 21680 (50 nmol) also impaired recognition memory in the object recognition task. These results show that A2AR are necessary and sufficient to trigger memory impairment and they further suggest that A1R might also be selectively engaged to control the cholinergic driven memory impairment.
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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Hamil, 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 textWu, 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 textFinlayson, Keith. "Pharmacology and modulation of adenosine A1 receptors in the mammalian central nervous system." Thesis, University of Edinburgh, 1998. http://hdl.handle.net/1842/21241.
Full textMurphy, Cody. "Transregulation of Cardiac Ischaemic Tolerance and Stress Kinase Signalling by A1 Adenosine and ¿-Opioid Receptors." Thesis, Griffith University, 2018. http://hdl.handle.net/10072/382690.
Full textThesis (Masters)
Master of Medical Research (MMedRes)
School of Medical Science
Griffith Health
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Lanznaster, Débora. "Estudo da interação da guanosina com heterômeros de receptores A1+A2A e seu efeito neuroprotetor contra a toxicidade do peptídeo B-amiloide1-40." reponame:Repositório Institucional da UFSC, 2016. https://repositorio.ufsc.br/xmlui/handle/123456789/168138.
Full textMade available in DSpace on 2016-09-20T04:56:30Z (GMT). No. of bitstreams: 1 340495.pdf: 1662080 bytes, checksum: 079d7095f84db1f40c79acbdd2f1074c (MD5) Previous issue date: 2016
A guanosina, nucleosídeo derivado da purina guanina, exerce efeitos neuroprotetores e neurotróficos no Sistema Nervoso Central (SNC). Recentemente, um sistema de neurotransmissão purinérgica dos derivados da guanina, ou sistema guanosinérgico, foi proposto. Deste sistema de neurotransmissão, já são conhecidos transportadores de nucleosídeos e enzimas responsáveis pelo metabolismo intra e extracelular, porém os receptores de membrana seletivos para a guanosina ainda não foram claramente caracterizados. Alguns efeitos neuroprotetores da guanosina parecem depender da ativação dos receptores de adenosina A1R e A2AR. Nesta tese, foi avaliada (i) a interação da guanosina com oligômeros de receptores de adenosina A1RA2AR; e (ii) o efeito da guanosina em um modelo animal da doença de Alzheimer. No capítulo I, através da superexpressão heteróloga dos receptores A1 e A2A em células HEK293, demonstramos que a guanosina não altera a colocalização destes receptores na membrana celular e sua heteromerização, quando avaliada por BRET e complementação de fluorescência. A guanosina não tem efeito per se, mas inibe o aumento de Ca2+ intracelular induzido por agonista de A1R (CCPA) em células que expressam A1R. Em células que expressam A1R+A2AR guanosina previne a aumento de Ca2+ induzido por agonista de A1R ou de A2AR. Guanosina induz aumento de AMPc em células A2AR, mas inibe o aumento de AMPc na presença dos agonistas A2AR, adenosina e CGS21680. Experimentos de nanoBRET sugerem que a guanosina desloca a ligação do agonista A2AR (APEC) em células que expressam A2AR e oligômeros A1R+A2AR. O efeito neuroprotetor da guanosina, não é observado em um modelo de isquemia in vitro realizado em fatias hipocampais de camundongos knock-out para o A2AR. Os resultados sugerem que guanosina pode interferir com a sinalização celular ativada por A1R e A2AR, e na presença de agonistas A2AR, guanosina bloqueia a ativação deste receptor. Além disso, o efeito neuroprotetor da guanosina depende da expressão de A2AR. No capítulo II desta tese, o efeito neuroprotetor da guanosina foi avaliado em um modelo de toxicidade do peptídeo beta-amiloide (Aß1-40), um modelo animal da doença de Alzheimer. Guanosina administrada logo após a infusão i.c.v do Aß1-40 e durante 14 dias consecutivos reverteu o déficit cognitivo e o comportamento tipo-anedônico induzidos pelo Aß1- 40. Guanosina preveniu o aumento na captação de glutamato independente de Na+ induzido pelo Aß1-40. A análise dos níveis de purinas mostra que Aß1-40 aumentou os níveis de ADP e ATP no hipocampo dos animais, e que o tratamento com guanosina aumentou os níveis de GDP. Aß1-40 reduziu a expressão de GFAP na região CA1 do hipocampo dos camundongos e guanosina não alterou esse efeito. Não foi observada alteração nos níveis de sinaptofisina no hipocampo dos animais. Os resultados obtidos sugerem que guanosina previne alterações cognitivas e no transporte de glutamato induzidas pelo Aß1-40 em camundongos. Esta tese contribuiu para identificar os sítios extracelulares de interação da guanosina e adicionou evidências sobre o efeito neuroprotetor da guanosina.
Abstract : Guanosine, the guanine-based nucleoside, exerts neurotrophic and neuroprotective effects in the Central Nervous System (CNS). A guaninebased purinergic system - or guanosinergic system ? has been recently proposed. In this neurotransmitter system some components are known, as nucleosides transporters and enzymes responsible for intra and extracellular metabolism. However, a selective extracellular site for guanosine interaction or guanosine receptor has not yet been clearly characterized. Some of guanosine neuroprotective effects seem to be dependent upon the activation of adenosine A1 or A2A receptors. In this study, we investigated (i) the possible guanosine interaction with A1RA2AR oligomers, and (ii) guanosine neuroprotective effect in an animal model of Alzheimer´s disease. Using A1R and A2AR heterologous expression in HEK193 cells, we showed that guanosine did not alter the colocalization of these receptors at the cellular membrane. Guanosine also did not modify A1R-A2AR heteromeric formation, evaluated with BRET and bimolecular fluorescence complementation (BiFC) techniques. Guanosine alone had no effect on intracellular Ca2+ signaling, but it inhibited the increase in Ca2+ induced by an A1R agonist (CCPA) in A1Rcells. In A1R+A2AR-expressing cells, guanosine prevents Ca2+ signaling evoked by A1R or A2AR agonists. Guanosine increased cAMP levels in A2AR cells, but it inhibited cAMP increase induced by adenosine or CGS21680 (A2AR agonists). NanoBRET experiments suggested that guanosine displaced the binding of an A2AR agonist (APEC), both in A2AR and A2AR+A1R cells. Guanosine neuroprotective effect in an in vitro model of ischemia was not observed in hippocampal slices of A2ARknockout mice. Data presented here suggest that guanosine can interfere on A1R and A2AR activated signaling pathways. However, in the presence of an A2AR agonist, guanosine blocks A2AR activation. Furthermore, the neuroprotective effect of guanosine is dependent on A2AR expression. In chapter II, we assessed guanosine neuroprotective effects against amyloid-beta peptide (Aß1-40) intracerebroventricular infusion, an animal model of Alzheimer´s disease. Guanosine treatment soon after Aß1-40 i.c.v infusion and once a day during the 14 consecutive days, inhibited the cognitive deficit and the anhedonic-like behavior induced by Aß1-40. Guanosine prevented the impairment in Na+-independent glutamate transport induced by Aß1-40. Purines levels analysis showed that Aß1-40 increased ATP and ADP at mice hippocampus, and guanosine increased GDP levels. Aß1-40 infusion decreased GFAP at CA1 hippocampal region, an effect not modified by guanosine. No changes in synaptophysin levels were observed. Presented data show that guanosine prevents cognitive alterations and the unbalance in glutamate transmission evoked by Aß1-40 in mice. Therefore, this thesis has contributed to identify extracellular sites to guanosine action and add information on the neuroprotective effects of guanosine.
Afzal, Aqeela. "Reduction in pre-retinal neovascularization by ribozymes that cleave the A2B receptor mRNA." [Gainesville, Fla.] : University of Florida, 2003. http://purl.fcla.edu/fcla/etd/UFE0000624.
Full textAffini, Anna [Verfasser]. "Histamine H3 receptor antagonists in combination with monoamine oxidase B and adenosine A1/A2A receptor ligands as multi-target approach for the treatment of Parkinson´s disease / Anna Affini." Düsseldorf : Universitäts- und Landesbibliothek der Heinrich-Heine-Universität Düsseldorf, 2019. http://d-nb.info/1190350807/34.
Full textMilanez, Paula de Azevedo Oliveira. "A frutose-1, 6-bifosfato reduz dor neuropática via ativação dos receptores de adenosina A1 e A2A : participação da via de sinalização NO/GMPc/PKG/KATP." Universidade Estadual de Londrina. Centro de Ciências Biológicas. Programa de Pós-Graduação em Patologia Experimental, 2011. http://www.bibliotecadigital.uel.br/document/?code=vtls000170581.
Full textThere are several therapies for neuropathic pain control, but current treatments are lacking efficacy and have many side effects, so alternatives for this treatment are needed. Fructose-1, 6-bisphosphate (FBP) is an intermediate of the glycolytic pathway that has several pharmacological actions, and more recently it was demonstrated its anti-hyperalgesic effect in acute inflammatory pain model via production of adenosine. Interestingly, adenosine and adenosine A1 and A2A receptor agonists have anti-hyperalgesic effects in neuropathic pain models. Thus, we investigated the anti-hyperalgesic effect and mechanism of action of FBP in a model of chronic constriction injury (CCI) of sciatic nerve-induced neuropathic pain in Swiss mice. Seven days after surgery, animals were treated with FBP or adenosine in oral or intrathecal administration. Moreover, the oral treatments of FBP and adenosine were associated with A1 or A2A adenosine receptor antagonists in intraplantar or intrathecal administration. Finaly, oral treatment of FBP was associated with inhibitors of nitric oxide/cycle GMP/Protein Kinase G/Potassium Channels ATP-sensitive (NO/cGMP/PKG/KATP) signaling pathway, which was already demonstrated as mechanism of action of adenosine. The mechanical hyperalgesia was assessed by an electronic version of von Frey filaments 1, 3, 5 and 7 hours after treatments. FBP and adenosine inhibited the mechanical hyperalgesia induced by CCI in a similar profile. FBP mechanism of action seems to be dependent on adenosine production as its effect was inhibited by adenosine A1 and A2A receptors antagonists, and FBP treatment promote anti-hyperalgesia through NO/cGMP/PKG/KATP signaling pathway similarly to adenosine. Concluding, it was demonstrated that FBP has possible therapeutic application to reduce neuropathic pain, and its mechanisms involve adenosine activation of A1 and A2A receptors and the NO/cGMP/PKG/KATP signaling pathway.
Klaft, Zin-Juan [Verfasser]. "Suppression of carbamazepine-resistant epileptiform activity by activation of adenosine A1 receptors in human neocortex slices from pharmacoresistant epilepsy patients / Zin-Juan Klaft." Berlin : Medizinische Fakultät Charité - Universitätsmedizin Berlin, 2017. http://d-nb.info/1148426124/34.
Full textGleizes, Marie. "Ectonucléotidases, adénosine et transmission synaptique." Thesis, Toulouse 3, 2017. http://www.theses.fr/2017TOU30306/document.
Full textThe functions of Tissue Nonspecific Alkaline Phosphatase (TNAP) in the brain are not clearly identified. The localization and expression of TNAP at the neuronal level, however, suggests that it plays a prominent role in the development and the function in the brain. This is supported by the presence of severe epileptic seizures in humans carrying TNAP mutation. These epileptic seizures are lethal in TNAP KO mice. Studies in mice show that TNAP could regulate GABA-mediated postsynaptic inhibition and may be involved in presynaptic inhibition mediated by adenosine. Adenosine is, partly, synthesized via the successive dephosphorylation of ATP to ADP and then to AMP by ectonucleotidases. Among them TNAP and ecto-5'-nucleotidase (NT5E) are able to hydrolyze AMP into adenosine. Adenosine acts mainly at the presynaptic level via A1 receptors activation. Adenosine has an influence on synaptic transmission and thus on synaptic plasticity. This could partly explain the epileptic seizures observed in TNAP knock-out mice. The two main purposes of my thesis were: (1) to evaluate the contribution of TNAP in adenosine production in the brain; (2) to study the influence of adenosine on synaptic plasticity. Firstly, the study of the contribution of TNAP in adenosine production in the brain was carried out using two complementary approaches. A metabolomic approach (proton NMR spectroscopy) on whole brains of TNAP KO mice showed that TNAP in involved in adenosine synthesis in the brain. In a second approach, in vitro electrophysiological recordings on mouse brain slices allowed us to examine the consequences of the inhibition of the ectonucleotidases involved in adenosine synthesis. This revealed that inhibition of ectonucleotidases (TNAP and NT5E) did not suppress the inhibitory effect of AMP mediated by A1 receptors. Secondly, we studied the influence of adenosine on short-term synaptic plasticity. Field potentials were recorded in response to electrical stimulations (3.125 to 100 Hz) applied with frequencies encompassing the range of physiological oscillation. Our results show that, with high adenosine concentrations, the facilitation is emphasized compared to that observed in the control situation. This effect is observed for frequencies greater than or equal to 25 Hz. In addition, the higher the frequency, the greater the facilitation. Finally, by blocking the action of endogenous adenosine, the opposite effect was observed: a deficient facilitation with respect to the control, whose defect was increasing with stimulation frequency. All these results converge towards the hypothesis that TNAP deficiency, expressed by absence of adenosine, could contribute to the maintenance of the epileptic processes generated by an imbalance of the neuronal inhibition and the excitation due to a decrease of GABA. AMP inhibitory effect mediated by A1 receptors, would not be sufficient to counteract epileptic seizures observed in hypophosphatasic patients and TNAP KO mice
Thomas, Jennifer Ann. "Engineering the angiotensin II type 1 receptor for structural studies." Thesis, University of Cambridge, 2015. https://www.repository.cam.ac.uk/handle/1810/247919.
Full textBETTI, MARCO. "Design, synthesis and pharmacological evaluation of new adenosine receptor ligands." Doctoral thesis, 2017. http://hdl.handle.net/2158/1076744.
Full textXavier, 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.
Katsidzira, Runako Masline. "Affinity of dihydropyrimidone analogues for adenosine A1 and A2A receptors / Runako Masline Katsidzira." Thesis, 2014. http://hdl.handle.net/10394/10747.
Full textMSc (Pharmaceutical Chemistry), North-West University, Potchefstroom Campus, 2014
Stumpf, Anette D. "Development of fluorescent FRET receptor sensors for investigation of conformational changes in adenosine A1 and A2A receptors." Doctoral thesis, 2015. https://nbn-resolving.org/urn:nbn:de:bvb:20-opus-125469.
Full textAdenosin Rezeptoren, die zur Gruppe der Rhodopsin-ähnlichen G Protein-gekoppelten Rezeptoren (GPCRs) gehören, sind in eine Vielzahl regulatorischer Prozesse eingebunden und weit im Körper verbreitet. Das macht sie zu einer interessanten Zielstruktur für Arzneistoffe. Das Wissen über die Struktur der Adenosin Rezeptoren ist jedoch noch begrenzt. Ein großer Fortschritt zu mehr strukturellem Wissen war die Entwicklung der ersten Kristallstruktur des Adenosin A2A Rezeptors im Jahr 2008. Mit der Kristallstruktur wurden die Aminosäuren bekannt, die die Ligandenbindetasche dieses Rezeptors formen. Zudem gab die Kristallstruktur Einblick in den Endpunkt der dynamischen Rezeptorbewegung nach Ligandenbindung. Im Rahmen der hier vorgestellten Arbeit wurden zwei Mitglieder der Adenosin Rezeptor Familie, der Adenosin A1 Rezeptor und der Adenosin A2A Rezeptor (A1R, A2AR), genauer untersucht. Der A1R wurde auf Basis des vor kurzem veröffentlichten A2AR entwickelt. Die Rezeptoren wurden mit Fluorophoren versehen, zum einen mit dem cyan fluoreszierenden Protein (CFP) am C-Terminus des Rezeptors und zum anderen mit der Bindesequenz des kleinen Fluorophors "Fluorescein Arsenical Hairpin binder" (FlAsH) in der dritten intrazellulären Schleife des Rezeptors. Die daraus resultierenden Rezeptorsensoren A1 Fl3 CFP und A2A Fl3 CFP wurden mit Hilfe des Fluoreszenz Resonanz Energie Transfers (FRET) in lebenden Zellen erforscht. FRET Messungen ermöglichen es, eine Änderung der Distanz zwischen den beiden Fluorophoren und damit Rezeptorbewegungen zu untersuchen. Um A1R und A2AR bezüglich dynamischer Rezeptorbewegungen nach Ligandenbindung vergleichen zu können, wurden die fluoreszierenden Rezeptorsensoren A1 Fl3 CFP und A2A Fl3 CFP mit verschiedenen Liganden umspült. Die Ergebnisse der FRET Messungen bezüglich ihrer Höhe des FRET Ratio wurden verglichen, welche mit der Konformationsänderung des Rezeptors nach Ligandenbindung zusammenhängt. Neben der unterschiedlichen Richtung des FRET Ratio nach Ligandenbindung am A1R und A2AR Sensor waren Unterschiede bezüglich der Signalhöhe und der Bindungs- und Dissoziationskinetiken feststellbar, wenn die verschiedenen Liganden miteinander verglichen wurden. Unterschiede zwischen den Adenosin Rezeptor Subtypen waren speziell für den A1R subtypselektiven Agonist CPA und für den A2AR subtypselektiven Agonist CGS 21680 feststellbar. Einen weiteren Punkt in diesem Projekt stellte die Erforschung des Einflusses, den einzelne Aminosäuren im fluoreszierenden A1R Sensor auf den Prozess der Ligandenbindung haben, dar. Die Position der Aminosäuren wurde der Kristallstruktur des A2AR entnommen und entsprechende Aminosäuren im A1R mutiert. Die konfokalmikroskopische Analyse des A1R Sensors und seiner Mutanten ergab, dass einige Aminosäuren direkt an der zellulären Expression des Rezeptors beteiligt waren. Wurden diese Aminosäuren mutiert, wurde der Rezeptor nicht in der Plasmamembran der Zellen exprimiert. Einige Aminosäuren die untersucht wurden,hatten einen generellen Einfluss auf die Bindung der Liganden, andere Aminosäuren hatten mehr Einfluss auf die Bindung bestimmter struktureller Gruppen der untersuchten Liganden. In einem weiteren Schritt wurden A1R und A2AR am N-terminalen Rezeptorende mit SNAP oder CLIP versehen, was eine Markierung der Rezeptoren mit einer Vielzahl an Fluorophoren erlaubt. Mit Hilfe dieser Technik konnte die Verteilung der Rezeptoren in der Zelle mit konfokaler Mikroskopie untersucht werden. Des Weiteren wurde die Bindung von fluoreszierenden Adenosin Rezeptor Liganden und deren Verdrängung mit einem nicht-fluoreszierenden Adenosin Rezeptor Antagonist erforscht. Am Ende des Projekts wurden die zuvor beschriebenen fluoreszierenden Rezeptorsensoren zu dreifach fluorophormarkierten Rezeptorsensoren kombiniert, was zu den Sensoren SNAP A1 Fl3 CFP und SNAP A2A Fl3 CFP führte. Beide Rezeptorsensoren waren funktionell bezüglich FRET Experimenten und der Expression in der Plasmamembran der Zellen. In Zukunft können mit dieser Methode gleichzeitig die Bindung von fluoreszierenden Liganden am SNAP-markierten Rezeptor, so wie die Rezeptorbewegung beobachtet werden, die durch eine Distanzänderung zwischen CFP und FlAsH angezeigt wird. Das kann zu einem besseren Verständnis der Rezeptorfunktion und der dynamischen Rezeptorbewegung nach Ligandenbindung führen, die in Zukunft zur Entwicklung spezifischerer Wirkstoffe am A1R und A2AR beitragen könnte
Ramos, Gonçalo Luis Monteiro 1988. "A1 and A2A Adenosine receptors expression in ALS transgenic mice for the human gene SOD1." Master's thesis, 2012. http://hdl.handle.net/10451/7946.
Full textA Esclerose Lateral Amiotrópica (ELA) é uma doença progressiva e fatal caracterizada pela degeneração selectiva dos neurónios motores do córtex motor, tronco cerebral e medula espinal, que provoca atrofia muscular, paralesia e morte por falha respiratória. A etiologia da doença continua desconhecida, mas com um consenso de que o dano dos neurónios motores é causado por uma rede de processos patológicos complexos. Os mecanismos envolvidos na degeneração dos neurónios motores são melhor conhecidos num subtipo da doença causada por mutações na enzima superóxido dismutase 1 (SOD1). Esta enzima actua na eliminação de radicais livres de oxigénio e na ELA o processo de degeneração neuronal deve-se a um ganho de função da SOD1. A adenosina tem uma função importante na modulação da transmissão sináptica no SNC e SNP, actuando a dois níveis: inibitório, modulado pelos receptores do subtipo A1 e excitatório, mediado pelos receptores do subtipo A2A. É conhecido que a expressão dos receptores A1 e A2A da adenosina está alterada nalgumas doenças neurodegenerativas, mas o seu papel na ELA é ainda muito pouco conhecido. O objectivo deste trabalho foi determinar o efeito da ELA na expressão proteica e de mRNA dos receptors A1 e A2A da adenosina no decurso da doença. O modelo de murganhos transgénicos para o gene SOD1 humano com a mutação G93A foi usado neste trabalho. Os níveis proteicos e de mRNA de ambos os receptores foram quantificados através das técnicas de immunoblotting e PCR quantitativo em tempo real, respectivamente. Foram estudados diferentes tecidos do SNC e SNP, nomeadamente, córtex e medula espinal (apenas immunoblotting) e nervo frénico-diafragama, de animais selvagens e portadores da doença nas fases pre-sintomática (4-6 semanas) e sintomática (13-14 semanas). Resultados deste estudo indicaram níveis proteicos não alterados nos SNC e SNP do receptor A1 ao longo da progressão da doença. No entanto, observou-se uma sobreexpressão dos receptores A2A no córtex na fase pre-sintomática e um decréscimo na fase sintomática. Os outros tecidos mantiveram-se inalterados no que se refere aos receptores A2A em ambas as fases da doença. A avaliação da expressão de mRNA no diafragma não revelou quaisquer alterações em ambos os receptores da adenosina durante a progressão da doença. Assim, no que se refere aos receptores da adenosina em ELA, as primeiras alterações parecem ocorrer logo no início da doença nos receptores A2A do SNC.
Amyothrophic Lateral Sclerosis (ALS) is a progressive and fatal disease categorized by a selective degeneration of motor neurons from the cerebral cortex, brainstem and spinal cord that provokes muscle atrophy, progressive paralysis and death due to respiratory failure. The etiology of most ALS cases remains unknown but there is a current consensus that motor neuron degeneration is caused by a complex interaction between multiple pathogenic processes. The mechanisms of motor neuron degeneration are best understood in the subtype of disease caused by mutations in the enzyme superoxide dismutase 1. This enzyme is enrolled in the degradation of free oxygen radicals and in ALS neuronal damage is due to its gain-of-function. Adenosine has a central role as a neuromodulator of the CNS and PNS synaptic transmission. Adenosine acts at two levels: inhibitory through the subtype A1 receptor and excitatory through the subtype A2A receptor. Variation on the expression of A1 and A2A receptors has been identified in some neurodegenerative diseases, but their role in ALS is not yet understood. The objective of this work was to determine the effect of ALS on the protein and mRNA expression of A1 and A2A adenosine receptors through disease progression. The transgenic model of mice carrying the human SOD1 gene with the G93A mutation was used in this work. Protein and mRNA levels of both receptors were quantified through immunblotting and quantitative real time PCR, respectively. Different tissues of the CNS and PNS, namely cortex and spinal cord (immunoblotting only) and phrenic nerve-diaphragm were studied in wild-type and transgenic mice in the pre-symptomatic (4-6 weeks) and symptomatic (13-14 weeks) phases of the disease. Results from this study indicate unaltered A1 receptor protein levels at the CNS and PNS through disease progression. However, there is an overexpression of A2A receptors in the cortex of pre-symptomatic mice and a decrease in the symptomatic phase. The A2A receptors are unaltered in the other tissues in both phases of the disease. The mRNA evaluation does not reveal significant alterations in both adenosine receptors during disease progression. Thus, regarding adenosine receptors in ALS, the first changes seem to occur early in the disease at the CNS in A2A receptors.
Bulli, Irene. "Adenosine A2B receptors and carbonic anhydrase: new therapeutic targets for cerebral ischemia." Doctoral thesis, 2022. http://hdl.handle.net/2158/1265035.
Full textGaviano, Lisa. "Adenosine a2b receptors and carbonic anhydrase: new therapeutic targets for cerebral ischemia and demyelination." Doctoral thesis, 2020. http://hdl.handle.net/2158/1188740.
Full textYang, Su-Ching, and 楊素卿. "Presynaptic adenosine A1 receptors modulate excitatory synaptic transmission in the posterior piriform." Thesis, 2007. http://ndltd.ncl.edu.tw/handle/88078507724153165851.
Full text國立陽明大學
生理學研究所
95
Abstract The effect of adenosine on the fEPSP was examined in lateral olfactory tract (Ia input) and associative tract (Ib input) in rat piriform cortex. The fEPSP evoked in Ia input showed paired-pulse (PP) facilitation, and in Ib input it showed PP depression, suggesting a lower resting release probability in the Ia input. This was supported by results showing that MK801 blocked the NMDA-receptor fEPSP at a faster rate in the Ib input. Adenosine caused a dose-dependent inhibition of the fEPSP in both inputs, the sensitivity being higher in the Ib input. This effect was mimicked by the A1 receptor agonist, CHA, and antagonized by co-application of the antagonist, DPCPX, showing that adenosine was acting at A1 receptors. Application of DPCPX alone increased the fEPSP, the increase being larger in the Ia input. DPCPX also caused PP depression in both inputs, and the PP ratios measured in its presence were very similar in both inputs. These results suggest a lower endogenous concentration of adenosine in the Ib sublayer than the Ia sublayer, which might account for the native difference in the resting release probability of the two inputs. The inhibition of the fEPSP in both inputs by adenosine was associated with an increase in the PP ratio and with significant lowering of the MK801 blocking rate of the NMDA-receptor fEPSP, suggesting a presynaptic location of the A1 receptors. Blocking of N-, P/Q-type calcium channels occluded the inhibition by adenosine, indicating a downregulation of presynaptic calcium channels by A1 receptors.
"The chemistry of an active adenosine A1 receptor ligand and its related analogs." Chinese University of Hong Kong, 1992. http://library.cuhk.edu.hk/record=b5887067.
Full textOn t.p. "1" is subscript following A in the title.
Thesis (Ph.D.)--Chinese University of Hong Kong, 1992.
Includes bibliographical references (leaves 138-139).
Acknowledgements --- p.i
List of Nomenclature --- p.ii-ix
"Abstracts (for Chapter 2,Chapter 3,and Chapter 4)" --- p.x
Chapter Chapter 1. --- General Introduction --- p.1-8
Chapter Chapter 2. --- Synthesis of 5-(3-Hydroxypropyl)-7-methoxy-2-(3'-methoxy-4'- hydroxyphenyl)-benzo[b]furan-3-carbaldehyde (XH14) (18)
Chapter 2.1. --- Introduction --- p.9-12
Chapter 2.2. --- Isolation and Structure Elucidation of XH14 (18)
Chapter 2.2.1. --- Material and method --- p.13-17
Chapter 2.2.2. --- Structure elucidation --- p.18-23
Chapter 2.3. --- Results and Discussion
Chapter 2.3.1. --- Total synthesis of XH14 (18) --- p.24-52
Chapter 2.3.2. --- Chemical modification of XH14 (18)
Chapter (a) --- Synthesis of 3-hydroxymethyl-5-(3-hydroxypropyl)- 7-methoxy-2-(3'-methoxy-4'-hydroxy phenyl)-benzo[b] furan(49) and 3-hydroxymethyl-5-(2-methoxycarbonyl ethyl)-7-methoxy-2-(3'-methoxy-4'-hydroxy phenyl)- benzo[b]furan (66) --- p.53-54
Chapter (b) --- Synthesis of 5-(2-carboxyethyl)-7-methoxy-2-(3'- methoxy-4'-hydroxyphenyl)-benzo[b]furan-3- carbaldehyde (67) --- p.54
Chapter (c) --- Synthesis of 5-(3-Hydroxypropyl)-7-methoxy-3- methyl-2-(3'-methoxy-4'-hydroxyphenyl)- benzo[b]furan (68) and 5-(2-methoxycarbonylethyl)-7- methoxy-3-methyl-2-(3'-methoxy-4'-hydroxyphenyl)- benzo[b]furan (69) --- p.54-55
Chapter (d) --- Synthesis of 5-(2-carboxy-trans-ethenyl)-7- methoxy-2-(3'-methoxy-4'- hydroxy phenyl) benzo[b]furan-3-carbaldehyde (70) --- p.55-56
Chapter (e) --- Synthesis of 4-bromo-5-(3-hydroxypropyI)-7- methoxy-2-(3'-methoxy-4'- hydroxy phenyl)- benzo[b]furan-3-carbaldehyde (72) --- p.56-57
Chapter (f) --- Synthesis of 4-acetyl-5-(3-hydroxypropyl)-7- methoxy-2-(3'-methoxy-4'-hydroxyphenyl)-benzo [b]furan (73) and 3-acetyI-5-(3-hydroxypropyl)-7- methoxy-2-(3'-methoxy-4'-hydroxy phenyl)- benzo[b]furan (75) --- p.57-61
Chapter (g) --- Synthesis of 3-nitro-5-(3-hydroxypropyl)-7- methoxy -2-(3'-methoxy-4'-hydroxyphenyl)- benzo[b]furan (77) and 4-nitro-5-(3-hydroxyphenyl)-7- methoxy-2-(3'-methoxy-4'-hydroxyphenyl)- benzo[b]furan (78) --- p.61-64
Chapter (h) --- Synthesis of 3-(α-hydroxyethyl)-5-(3-hydroxy propyl) -7-methoxy-2- (3'-methoxy-4' -hydroxyphenyl) - benzo[b]furan (81) --- p.64
Chapter (i) --- Synthesis of 5-(3-hydroxypropyl)-7-methoxy-2-(3'- methoxy-4'-benzyloxyphenyl )-benzo[b]furan-4- carbaldehyde (82) --- p.64
Chapter 2.4. --- Structure-activity Relationship of A1 Antagonists --- p.65-71
Chapter 2.5. --- Conclusion --- p.72
Chapter 2.6. --- Experimental Section --- p.73-97
Chapter 2.7. --- References --- p.98-103
Chapter Chapter 3. --- "Synthesis of 9,10-Dihydro-10,10-dimethoxyanthracen-9-one"
Chapter 3.1. --- Introduction --- p.104
Chapter 3.2 --- Results and Discussion --- p.105-118
Chapter 3.3. --- Experimental Section --- p.119-124
Chapter 3.4. --- References --- p.125-128
Chapter Chapter 4. --- "Synthesis of 10,11-Dimethoxydibenz[b,f]oxep in"
Chapter 3.1. --- Introduction --- p.129
Chapter 3.2. --- Results and Discussion --- p.130-133
Chapter 3.3. --- Experimental Section --- p.134-137
Chapter 3.4. --- References --- p.138-139
Appendix
Spectra --- p.140-145
Rebelo, Patricia Celeste Soares. "Alterações dos receptores A1 e A2a da adenosina num modelo animal da doença de Parkinson : função neuroprotectora?" Master's thesis, 2010. http://hdl.handle.net/10316/28813.
Full textOs receptores A2a da adenosina são actualmente considerados um alvo terapêutico na doença de Parkinson pois, devido à co-localização e interacção funcional com os receptores D2 da dopamina nos neurónios do estriado, a modulação com antagonistas A2a tem um efeito compensatório do défice de dopamina causado pela degeneração dos neurónios dopaminérgicos que projectam da substantia nigra para o estriado, melhorando a disfunção motora. Por outro lado, os antagonistas dos receptores A2a também mostraram efeitos neuroprotectores contra a degeneração dopaminérgica induzida por toxinas em modelos animais da doença de Parkinson, um efeito atribuído à inibição de mecanismos neuro-inflamatórios. No entanto, a activação dos receptores A2a é requerida para alguns efeitos do GDNF (Glial cell line-Derived Neurotrophic Factor), um factor neurotrófico amplamente reconhecido como protector e indutor da regeneração dos neurónios dopaminérgicos. O nosso grupo mostrou recentemente que a lesão selectiva dos neurónios dopaminérgicos em culturas de células da substantia nigra pode induzir o aumento da expressão de GDNF em astrócitos. No presente estudo utilizámos um rato modelo da doença de Parkinson, induzido pela injecção de 6-hidroxidopamina (6-OHDA) no estriado, para investigar a relação entre receptores da adenosina, expressão de GDNF e protecção dos neurónios dopaminérgicos. Em estudos de imunohistoquímica após a lesão da via nigra-estriatal, observámos um aumento significativo da expressão dos receptores A2a em astrócitos no estriado, particularmente em astrócitos que proliferaram nas zonas de transição entre zonas lesadas e zonas não afectadas. A observação, também nestas zonas, do aumento da expressão da tirosina hidroxilase (TH), um marcador dos terminais dopaminérgicos, sugere uma relação entre aumento dos receptores A2a e sobrevivência dos neurónios dopaminérgicos, e não apoia a ideia de que a activação dos receptores A2a em situações de lesão é deletéria para a sobrevivência dosneurónios dopaminérgicos. No entanto, em estudos preliminares em culturas de células da substantia nigra, observámos que a inibição dos receptores A2a teve efeitos protectores na sobrevivência dos neurónios dopaminérgicos contra a toxicidade da 6-OHDA. Nos estudos in vivo não observámos aumento da expressão de GDNF, avaliados por Western blot em extractos proteicos do estriado. No rato modelo da doença de Parkinson, observámos também um aumento marcado dos receptores A1 da adenosina no estriado, em terminais dopaminérgicos e em corpos celulares que expressam TH. A aquisição de fenótipo dopaminérgico por neurónios GABAérgicos do estriado lesado foi descrito por outros investigadores, e o nosso trabalho sugere que estes neurónios expressam também receptores A1 da adenosina. Observámos também que a degeneração da via nigra-estriatal está associada ao aumento da expressão dos receptores A1 na substantia nigra em neurónios não-dopaminérgicos cujos corpos celulares estão segregados dos corpos celulares dopaminérgicos nas regiões dendríticas da substantia nigra pars reticulata. Em conclusão, os nossos resultados num modelo animal da doença de Parkinson mostram que a lesão dos neurónios dopaminérgicos pode induzir o aumento da expressão dos receptores A2a da adenosina em astrócitos, e dos receptores A1 em terminais dopaminérgicos no estriado, em zonas de transição da lesão, onde parecem ocorrer tentativas de reparação evidenciadas pelo aumento da expressão da TH. Embora os resultados não provem uma relação entre a expressão dos receptores da adenosina e protecção dos neurónios dopaminérgicos, os nossos resultados não apoiam a ideia de que a activação dos receptores A2a contribua para a degeneração dopaminérgica.
Świrski, Mateusz. "Synteza innowacyjnych małocząsteczkowych modulatorów immunosupresyjnego szlaku adenozyny." Praca doktorska, 2022. https://ruj.uj.edu.pl/xmlui/handle/item/289708.
Full textGalanis, Victor Chris. "Modulation of an acidosis-evoked current by A1 adenosine receptors in the CA1 region of the mouse Hippocampus." 2005. http://edissertations.library.swmed.edu/pdf/GalanisV051506/GalanisVictor.pdf.
Full textVisser, Susanna Salomina. "Effects of adenosine receptor agonists of the A1, A2A and A3 subtypes on the proinflammatory activity of human neutrophils in vitro." Thesis, 2002. http://hdl.handle.net/2263/29077.
Full textLong, Xin. "Role of Adenosine A1 Receptors in Native Coronary Atherosclerosis, In-stent Stenosis, and Coronary Blood Flow Regulation in Metabolic Syndrome and Exercise." Thesis, 2010. http://hdl.handle.net/1805/2121.
Full textAdenosine is widely thought to elicit coronary vasodilation and attenuate smooth muscle cell (SMC) proliferation, thereby providing cardioprotection. We cloned the porcine adenosine A1 receptor (A1R) subtype and found that it paradoxically stimulated proliferation of cultured coronary SMC by the extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) signaling pathways, thus suggesting A1R dysregulation could play a role in coronary artery disease (CAD), restenosis, and regulation of coronary blood flow (CBF). We utilized the Ossabaw swine model of metabolic syndrome (MetS) to test the hypothesis that A1R activation contributes to development of CAD, in-stent stenosis, and CBF regulation. Swine were fed standard chow (Lean) or excess calorie atherogenic diet for over 20 weeks, which elicited MetS characteristics and coronary atherosclerosis compared to Lean. We observed increased A1R in native CAD in MetS, which was reversed by exercise training, and upregulation of A1R expression and A1R-ERK1/2 activation in an in vitro organ culture model of CAD. Intracoronary stent deployment followed by different durations of recovery showed A1R upregulation occurred before maximal in-stent stenosis in vi vivo. More importantly, selective A1R antagonism with 8-cyclopentyl-1, 3-dipropylxanthine (DPCPX)-eluting stents decreased coronary ERK1/2 activation and reduced in-stent stenosis comparable to Taxus® (paclitaxel-eluting stents). A1R antagonism potentiated vasodilatory effects of some vasodilators other than adenosine in porcine coronary microcirculation under basal conditions. Short-term exercise training around stenting prevented stent-induced microvascular dysfunction and attenuated native atheroma in the genetically lean Yucatan swine. Conclusions: A1R upregulation and activation contributes to coronary in-stent stenosis in vivo in MetS, plays a role in the development of coronary atherosclerosis in vitro, and might involve in CBF dysregulation in dyslipidemia and stenting. Exercise training decreased A1R expression in atherosclerosis, reduced native atheroma, and prevented stent-induced microvascular dysfunction. Selective pharmacological antagonism of A1R holds promise for treatment of CAD.
Costa, Ana Filipa Silva. "Inhibition of cholinergic neurotransmission by β3-adrenoceptors in the rat urinary bladder: Role of adenosine release and A1 receptors activation." Master's thesis, 2016. https://hdl.handle.net/10216/90943.
Full textCosta, Ana Filipa Silva. "Inhibition of cholinergic neurotransmission by β3-adrenoceptors in the rat urinary bladder: Role of adenosine release and A1 receptors activation." Dissertação, 2016. https://hdl.handle.net/10216/90943.
Full textRial, Ana Cristina Figueiredo de Lemos. "Metabolic modifications associated with memory deficits." Doctoral thesis, 2016. http://hdl.handle.net/10316/30530.
Full textEste trabalho foi iniciado partindo da premissa em como, no cérebro, a glucose disponível regula a memória e a cognição em humanos saudáveis e pacientes com demência. Para além disso, a desregulação da glucose cerebral tem sido associada a doenças neuropsiquiátricas e as alterações na captação de glucose em áreas cerebrais específicas são considerados marcadores seletivos no diagnóstico de doenças neuropsiquiátricas. O trabalho experimental apresentado nesta tese de doutoramento teve como objetivo revelar como os neuromoduladores, incluindo a insulina, regulam o metabolismo da glicose no cérebro e quais as consequências dos danos ao nível do metabolismo da glicose cerebral em modelos animais. Para concretizar este objectivo, efetuamos estudos bioquímicos e eletrofisiológicos em estruturas cerebrais que se correlacionam com a cognição e personalidade, que são, o hipocampo e o córtex frontal. Também procedemos a uma bateria de testes comportamentais em roedores. Primeiro, optimizamos vários métodos in vitro para medições espaço-temporais e quantitativas da captação e metabolismo da glucose em fatias de hipocampo, fatias do córtex frontal e em culturas celulares. Depois, exploramos as características básicas da captação de glucose e metabolismo em fatias de hipocampo, incluindo o papel das vias de sinalização da insulina e de duas outras importantes famílias de neuromoduladores. Aqui, reportamos que a administração sistémica de streptozotocina (induzindo diabetes tipo 1) afecta tanto o repouso como a despolarização induzida pela captação e metabolismo da glucose dependente do receptor de canabinóides CB1 no hipocampo. Notavelmente, esta área cerebral é responsável pela formação e evocação da memória, que é regulada pela sinalização da insulina. Usando o mesmo composto diabetogénico mas agora administrado intracerebroventricularmente, obtivemos um modelo animal previamente caracterizado como diabetes cerebral, evitando a interferência de modificações periféricas. Além disso, os resultados apontaram para que a disfunção sináptica observada nas experiências de eletrofisiologia tenham ocorrido antes da perda sináptica e coincidiu com a disfunção metabólica. Em seguida, outro modelo animal foi utilizado, associado com disfunção metabólica, um modelo pré-diabético induzido pelo consumo de uma dieta rica em sacarose (Hsu). Este modelo tem a vantagem de ser menos invasivo do que a injeção cerebral de STZ e melhor mimetizar as doenças associadas ao estilo de vida humano, e para além disso permitir ainda o estudo da fase inicial da doença, a fase anterior à ocorrência da diabetes. De acordo com a análise de hipocampo por espectroscopia de elevada resolução por rotação em ângulo mágico (HRMAS) em tecidos de animais Hsu, a dieta Hsu induziu modificações metabólicas periféricas sem um impacto aparente no metabolismo cerebral, apesar destes animais exibirem danos na memória. Procuramos também modificações nos circuitos da via hipocampal Schaffer-CA1, que está conectada com tarefas dependentes de memória hipocampal e não foram detetadas alterações. Posteriormente, questionamos se a dieta Hsu afectaria outra via mediadora da consolidação da memória espacial e o processo de reconhecimento em ratos, nomeadamente a via temporomónica. Observamos que a dieta Hsu danifica a plasticidade sináptica na via temporomonica-CA1 das sinapses piramidais. Adicionalmente, testamos o papel do receptor adenosinérgico nestas vias e observamos que, no hipocampo, a dieta Hsu regula para cima o receptor A1. Seguidamente, investigamos a hipótese de que a ativação do receptor A2B com baixa afinidade para a adenosina pudesse promover a captação de glucose em neurónios e astrócitos relacionando atividade cerebral com o metabolismo energético. Desenvolvemos um protocolo para a medição fluorescente em tempo real da captação de deoxiglucose em fatias de hipocampo, um complemento ideal das análises quantitativas. Verificamos que a ativação do receptor A2B está associada com o aumento tónico e instantâneo do transporte de glucose para os neurónios e astrócitos no cérebro de ratinho, levantando a possibilidade de em futuras investigações se avaliar o potencial clínico deste novo mecanismo glucoregulador. Em conclusão, este trabalho de tese contribuiu para elucidar os mecanismos pouco definidos que regulam o metabolismo da glucose cerebral. Encontramos novas provas que ligam a deficiência da plasticidade sináptica hipocampal e de memória às doenças metabólicas. Também identificamos o receptor A2B como um possível novo alvo terapêutico para estimular o metabolismo da glucose cerebral com o objectivo de atenuar o aparecimento de doenças cerebrais.
This work started from the known premise that, in the brain, glucose availability regulates memory and cognition in both healthy humans and dementia patients. Furthermore, cerebral glucose deregulation has been associated with neuropsychiatric disorders, and alterations in glucose uptake in specific brain areas are selective hallmarks for the diagnosis of neuropsychiatric diseases. The experimental work presented in this doctoral thesis aimed at unveiling how neuromodulators including insulin regulate glucose metabolism in the brain and what are the consequences of impaired brain glucose metabolism in animal models. To this aim, biochemical and electrophysiological studies were performed in brain structures that correlate with cognition and personality, that is, the hippocampus and the frontal cortex. Also a battery of behavioural studies was carried out in laboratory rodents. To begin with, various in vitro methods for both the spatiotemporal and the quantitative measurement of glucose uptake and metabolism in acute hippocampal and frontocortical slices and cell cultures were optimized. Then the basic characteristics of glucose uptake and metabolism in the hippocampal slice were explored, including the role of the insulin signalling pathway and the role of two other important neuromodulator families. We found and report for the first time that systemic streptozotocin-induced untreated type-1 diabetes affects both the resting and depolarization-induced glucose uptake and metabolism in a fashion dependent on the cannabinoid CB1 receptor in the hippocampus. Notably, this brain area is responsible for the formation and recall of memory, which is regulated by insulin signalling. Using the same diabetogenic compound but now intracerebroventricularly administered, we achieved a previously characterized animal model of cerebral diabetes, thus avoiding confounding peripheral changes. This procedure led to the impairment of hippocampusdependent memory. Furthermore, the results pointed out that synaptic dysfunction observed in the electrophysiological experiments occurred before the loss of synapses and coincided with metabolic dysfunction. Next, we moved to another animal model associated with metabolic dysfunction, a prediabetic model induced through the consumption of a high sucrose diet (HSu). This model has the advantage of being less invasive than cerebral STZ-injection, and mimics better human lifestyle-dependent disorders; furthermore it enables the study of the initial phase of the disease, prior to the occurrence of diabetes. According to the highresolution magic angle spinning spectroscopic analysis of the hippocampal tissue, HSuinduced peripheric metabolic modifications did not cause an apparent impact on cerebral metabolism, albeit these HSu animals exhibited memory impairment. We looked for circuitry modifications in the hippocampal Schaffer-CA1 pathway, which is connected to hippocampal-dependent memory task, but none was found. Subsequently, we asked if HSu affected another pathway mediating spatial memory consolidation and recognition process of rats, namely, the temporoammonic branch of the perforant path. We observed that high sucrose consumption impairs synaptic plasticity at the temporoammonic pathway-CA1 pyramidal synapses. Additionally, we tested the role of adenosine receptors in those pathways and observed that high sucrose consumption upregulates adenosine A1R in the hippocampus. Next we investigated the hypothesis that the activation of the low-affinity adenosine A2B receptor (A2BR) could promote glucose uptake in neurons and astrocytes, thereby possibly linking brain activity with energy metabolism. We developed a protocol for real-time fluorescent measurement of deoxyglucose uptake in hippocampal slices, ideal to complement quantitative analyses. We found that A2BR activation is associated with an instant and tonic increase of glucose transport into neurons and astrocytes in the mouse brain. These prompt further investigations to evaluate the clinical potential of this novel glucoregulator mechanism. In conclusion, the present thesis work has contributed to the elucidation the illdefined mechanisms that regulate brain glucose metabolism. We have found additional proofs linking impaired hippocampal synaptic plasticity and memory with metabolic disorders. We also identified the A2BR as a possible novel therapeutic target to boost brain glucose metabolism with the objective of mitigating the outcome of brain disorders.
NARSAD
Santa Casa da Misercórdia
DARPA
Fundação para a Ciência e Tecnologia