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1.
Biol Psychiatry ; 70(8): 770-776, 2011 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-21802658

RESUMO

BACKGROUND: Preclinical data implicate the reinforcing effects of alcohol to be mediated by interaction between the opioid and dopamine systems of the brain. Specifically, alcohol-induced release of ß-endorphins stimulates µ-opioid receptors (MORs), which is believed to cause dopamine release in the brain reward system. Individual differences in opioid or dopamine neurotransmission have been suggested to be responsible for enhanced liability to abuse alcohol. In the present study, a single dose of the MOR agonist remifentanil was administered in detoxified alcohol-dependent patients and healthy control subjects to mimic the ß-endorphin-releasing properties of ethanol and to assess the effects of direct MOR stimulation on dopamine release in the mesolimbic reward system. METHODS: Availability of D(2/3) receptors was assessed before and after single-dose administration of the MOR agonist remifentanil in 11 detoxified alcohol-dependent patients and 11 healthy control subjects with positron emission tomography with the radiotracer [(18)F]fallypride. Severity of dependence as assessed with the Alcohol Use Disorders Identification Test was compared with remifentanil-induced percentage change in [(18)F]fallypride binding (Δ%BP(ND)). RESULTS: The [(18)F]fallypride binding potentials (BP(ND)s) were significantly reduced in the ventral striatum, dorsal putamen, and amygdala after remifentanil application in both patients and control subjects. In the patient group, ventral striatum Δ%BP(ND) was correlated with the Alcohol Use Disorders Identification Test score. CONCLUSIONS: The data provide evidence for a MOR-mediated interaction between the opioid and the dopamine system, supporting the assumption that one way by which alcohol unfolds its rewarding effects is via a MOR-(γ-aminobutyric acid)-dopamine pathway. No difference in dopamine release was found between patients and control subjects, but evidence for a patient-specific association between sensitivity to MOR stimulation and severity of alcohol dependence was found.


Assuntos
Alcoolismo/metabolismo , Benzamidas , Dopamina/metabolismo , Neuroimagem Funcional/estatística & dados numéricos , Sistema Límbico/metabolismo , Piperidinas/farmacologia , Tomografia por Emissão de Pósitrons/estatística & dados numéricos , Pirrolidinas , Adulto , Alcoolismo/diagnóstico , Alcoolismo/diagnóstico por imagem , Analgésicos Opioides/farmacologia , Comportamento Aditivo/diagnóstico por imagem , Comportamento Aditivo/metabolismo , Radioisótopos de Flúor , Neuroimagem Funcional/métodos , Humanos , Sistema Límbico/diagnóstico por imagem , Sistema Límbico/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Tomografia por Emissão de Pósitrons/métodos , Ensaio Radioligante/métodos , Ensaio Radioligante/estatística & dados numéricos , Receptores de Dopamina D2/efeitos dos fármacos , Receptores de Dopamina D2/metabolismo , Receptores Opioides mu/agonistas , Remifentanil , Índice de Gravidade de Doença
2.
Mol Immunol ; 46(13): 2533-8, 2009 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-19524301

RESUMO

Chemokine function in vivo depends on the presentation by structures of the extracellular matrix or on endothelial surfaces. CCL5 contains two clusters of basic amino acid residues ((44)RKNR(47) and (55)KKWVR(59)) implicated in presentation of the protein. While (44)RKNR(47) has been shown to moderate CCL5 binding to glycosaminoglycans (GAGs), no direct role for the basic residues in the so called 50s loop ((55)KKWVR(59)) as a presentation structure has been published to date. In ex vivo studies both regions were found to be necessary for direct tissue binding suggesting a role for (55)KKWVR(59). In vitroT lymphocyte and monocyte induced firm adhesion under flow, as well as leukocyte recruitment to the peritoneal cavity in vivo was reduced in the 50s mutant. The binding of the 50s mutant to endothelial cells was significantly reduced as compared to the wild type protein demonstrated by ELISA. The 50s mutant had little impact on GAG binding in vitro. These data suggest that functional CCL5 presentation is mediated through both the 40s as well as the 50s loop with differential functions of the two loops of clusters of basic residues.


Assuntos
Motivos de Aminoácidos , Quimiocina CCL5/metabolismo , Sequência de Aminoácidos , Animais , Adesão Celular , Linhagem Celular , Movimento Celular , Quimiocina CCL5/química , Quimiocina CCL5/genética , Células Endoteliais/citologia , Células Endoteliais/metabolismo , Feminino , Citometria de Fluxo , Glicosaminoglicanos/metabolismo , Humanos , Molécula 1 de Adesão Intercelular/metabolismo , Leucócitos/citologia , Leucócitos/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Mutação , Oligossacarídeos/metabolismo , Ligação Proteica
3.
J Cardiothorac Vasc Anesth ; 23(5): 614-8, 2009 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-19362018

RESUMO

OBJECTIVES: To investigate if the protective effects of xenon and isoflurane against myocardial ischemia-reperfusion damage would be additive. DESIGN: A prospective, randomized laboratory investigation. SETTING: An animal laboratory of a university hospital. PARTICIPANTS: Thirty-six pigs (female German landrace). INTERVENTIONS: In an open-chest preparation with thiopental anesthesia, the left anterior descending artery was occluded to produce ischemia for 60 minutes. One hour previously, ischemic preconditioning, isoflurane (0.55 minimum alveolar concentration [MAC]) alone, or isoflurane together with xenon (0.55 MAC each) were started in the respective groups. A fourth (control) group received no protective intervention. Myocardial ischemia was followed by 2 hours of reperfusion. MEASUREMENTS AND MAIN RESULTS: Hearts were excised and stained (Evans Blue/TTC) to measure infarct size as related to the area at risk. Myocardial infarct size was reduced (means +/- standard deviation) from 64% +/- 9% of the area at risk in the control group to 19% +/- 12% with ischemic preconditioning to 46% +/- 12% with isoflurane and to 39% +/- 13% with isoflurane and xenon. All intervention groups were significantly different from the control (p < 0.05), and both anesthetic groups were significantly different from ischemic preconditioning (p < 0.05). CONCLUSION: Combined isoflurane/xenon anesthesia reduced infarct size but not more than isoflurane alone. Ischemic preconditioning was more effective than the anesthetics.


Assuntos
Modelos Animais de Doenças , Isoflurano/administração & dosagem , Infarto do Miocárdio/prevenção & controle , Xenônio/administração & dosagem , Animais , Quimioterapia Combinada , Feminino , Precondicionamento Isquêmico Miocárdico/métodos , Isoflurano/uso terapêutico , Infarto do Miocárdio/patologia , Estudos Prospectivos , Suínos
4.
Anesth Analg ; 105(5): 1200-6, table of contents, 2007 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-17959941

RESUMO

BACKGROUND: Volatile anesthetics protect the myocardium from ischemia reperfusion damage. Our hypothesis for this study was that xenon reduces the size of myocardial infarction similar in extent to the reduction associated with ischemic preconditioning. METHODS: Thirty-six pigs weighing 30-35 kg were anesthetized with thiopental and then randomized into four groups: control (myocardial ischemia only), ischemic preconditioning (five 5-min episodes of intermittent myocardial ischemia), xenon preconditioning (three 10-min exposures to xenon 70% followed by myocardial ischemia), and xenon anesthesia (xenon 70%, continued before and after myocardial ischemia). Myocardial ischemia was induced by placing a tourniquet around the left anterior descending coronary artery for 60 min followed by 2 h of reperfusion. Myocardial infarct size and the area at risk for myocardial infarction were measured by Evans Blue and triphenyl tetrazolium chloride staining, respectively. RESULTS: Mean (sd) myocardial infarct size was reduced from 64% +/- 9% of the area at risk in the control group to 19% +/- 12% with ischemic preconditioning (P < 0.001), and to 50% +/- 9% with xenon anesthesia (P < 0.05 versus control, P < 0.001 versus ischemic preconditioning). Myocardial infarct size was not reduced with xenon preconditioning compared with the control group (59% +/- 11%, P = 0.41). CONCLUSION: Myocardial infarct size was reduced by ischemic preconditioning but less so by xenon anesthesia. Brief, intermittent exposure to xenon before myocardial ischemia did not reduce myocardial infarct size.


Assuntos
Anestésicos Inalatórios , Infarto do Miocárdio/patologia , Xenônio , Anestesia por Inalação/métodos , Animais , Modelos Animais de Doenças , Precondicionamento Isquêmico Miocárdico/métodos , Infarto do Miocárdio/prevenção & controle , Distribuição Aleatória , Suínos
5.
J Leukoc Biol ; 78(2): 435-41, 2005 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-15899984

RESUMO

Platelet-derived chemokines, such as regulated on activation, normal T expressed and secreted (RANTES; CC chemokine ligand 5), platelet factor 4 [PF4; CXC chemokine ligand 4 (CXCL4)], and epithelial neutrophil-activating protein 78 (ENA-78; CXCL5), or precursors, such as beta-thromboglobulin, which can be processed to neutrophil-activating protein-2 (NAP-2; CXCL7), may play an important role in monocyte recruitment during atherogenesis. Platelets can deposit chemokines on inflamed endothelium; however, little is known about differential or additive effects of platelet chemokines on monocyte arrest. Here, we demonstrate that preincubation of activated human microvascular endothelial cells (HMVECs) with RANTES, PF4, or NAP-2 but not ENA-78 dose-dependently increased surface immobilization and subsequent monocyte arrest in flow. RANTES was the most potent and efficient arrest chemokine. Pretreatment of HMVECs with beta-thromboglobulin enhanced monocyte arrest in the presence of cathepsin G generating NAP-2. Combined pretreatment of HMVECs with RANTES and PF4 at suboptimal concentrations synergistically increased arrest, and preincubation with chondroitinase ABC abrogated RANTES- and PF4-induced monocyte arrest. This was associated with reduced expression of chondroitin sulfate, RANTES, and PF4 on the HMVEC surface. Perfusion of HMVECs with platelets known to deposit RANTES and PF4 on the endothelial surface enhanced monocyte arrest, which was inhibited by Met-RANTES, chondroitinase, or a blocking antibody to PF4 but not to ENA-78. The relevance of platelet-derived chemokines was confirmed in adhesion assays with activated whole blood, where Met-RANTES and to a lesser extent, antibodies to PF4 and NAP-2 inhibited arrest of CD14-positive monocytes. Thus, multiple platelet-derived chemokines and processable precursors, which can be presented by specific endothelial proteoglycans, may contribute and cooperate differentially to induce monocyte recruitment.


Assuntos
Plaquetas/fisiologia , Quimiocinas/metabolismo , Endotélio Vascular/metabolismo , Migração e Rolagem de Leucócitos/fisiologia , Monócitos/fisiologia , Anticorpos Monoclonais/farmacologia , Arteriosclerose/metabolismo , Arteriosclerose/patologia , Adesão Celular/efeitos dos fármacos , Adesão Celular/fisiologia , Linhagem Celular , Quimiocinas/farmacologia , Condroitina ABC Liase/farmacologia , Sinergismo Farmacológico , Endotélio Vascular/patologia , Humanos , Inflamação/metabolismo , Inflamação/patologia , Migração e Rolagem de Leucócitos/efeitos dos fármacos , Receptores de Lipopolissacarídeos/metabolismo , Ativação de Macrófagos/efeitos dos fármacos , Ativação de Macrófagos/fisiologia
6.
Arterioscler Thromb Vasc Biol ; 25(4): 729-35, 2005 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-15681301

RESUMO

OBJECTIVE: The junctional adhesion molecule (JAM)-A on endothelium contributes to the inflammatory recruitment of mononuclear cells involving engagement of its integrin receptor lymphocyte function-associated antigen (LFA)-1. It is unknown whether these functions can be inhibited by soluble forms of JAM-A, whether JAM-A is expressed on atherosclerotic endothelium, and whether it participates in atherogenic recruitment of mononuclear cells. METHODS AND RESULTS: Adhesion assays revealed that LFA-1-mediated binding of mononuclear cells to intercellular adhesion molecule (ICAM)-1 or cytokine-costimulated endothelium was dose-dependently inhibited by soluble JAM-A.Fc (sJAM-A.Fc). Similarly, sJAM-A.Fc reduced stromal cell-derived factor (SDF)-1alpha-triggered transendothelial chemotaxis of activated T cells and their SDF-1alpha-triggered arrest on cytokine-costimulated endothelium under flow conditions. Immunofluorescence analysis revealed an upregulation of JAM-A on early atherosclerotic endothelium of carotid arteries from apolipoprotein E-deficient (apoE-/-) mice fed an atherogenic diet. In ex vivo perfusion assays, pretreatment of mononuclear cells with sJAM-A.Fc inhibited their very late antigen (VLA)-4-independent accumulation on atherosclerotic endothelium of these arteries. CONCLUSIONS: Soluble forms of JAM-A can be effectively applied to inhibit distinct steps of mononuclear cell recruitment on inflamed or atherosclerotic endothelium. In conjunction with its expression on atherosclerotic endothelium, this suggests a functional contribution of JAM-A to atherogenesis.


Assuntos
Arteriosclerose/imunologia , Moléculas de Adesão Celular/imunologia , Endotélio Vascular/imunologia , Receptores de Superfície Celular/imunologia , Linfócitos T/imunologia , Vasculite/imunologia , Animais , Apolipoproteínas E/genética , Arteriosclerose/tratamento farmacológico , Arteriosclerose/metabolismo , Células CHO , Adesão Celular/imunologia , Moléculas de Adesão Celular/metabolismo , Moléculas de Adesão Celular/farmacologia , Movimento Celular/efeitos dos fármacos , Movimento Celular/imunologia , Quimiocina CXCL12 , Quimiocinas CXC/farmacologia , Cricetinae , Endotélio Vascular/citologia , Endotélio Vascular/metabolismo , Humanos , Memória Imunológica , Células Jurkat , Antígeno-1 Associado à Função Linfocitária/imunologia , Antígeno-1 Associado à Função Linfocitária/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Receptores de Superfície Celular/metabolismo , Proteínas Recombinantes de Fusão/imunologia , Proteínas Recombinantes de Fusão/metabolismo , Proteínas Recombinantes de Fusão/farmacologia , Solubilidade , Linfócitos T/citologia , Linfócitos T/metabolismo , Veias Umbilicais/citologia , Vasculite/tratamento farmacológico , Vasculite/metabolismo
7.
Blood ; 102(6): 1985-8, 2003 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-12763925

RESUMO

Chemokines control inflammatory leukocyte recruitment. The propensity of chemokines such as CC chemokine ligand 5 (CCL5)/RANTES (regulated on activation, normal T cell expressed and secreted) to bind to glycosaminoglycans and to form higher order oligomers has been shown to be essential for its in vivo activity. However, the specific functional relevance of RANTES oligomerization for distinct steps of leukocyte recruitment on inflamed endothelium mediated by the RANTES receptors CC chemokine receptor 1 (CCR1) and CCR5 remains undefined. We studied RANTES mutants with deficient oligomerization in an assay in which recruitment of monocytes and CD45RO+ CD4+ T cells is triggered by RANTES immobilized on activated endothelium under flow conditions. Notably, the formation of higher order RANTES oligomers was crucial for CCR1-mediated arrest but not for CCR5-mediated spreading/transmigration in flow or transendothelial chemotaxis of leukocytes. Efficient leukocyte arrest in flow but not transmigration may thus require the presentation of RANTES oligomers to bridge surface-bound RANTES and CCR1.


Assuntos
Movimento Celular/imunologia , Quimiocina CCL5/metabolismo , Endotélio Vascular/imunologia , Receptores CCR5/metabolismo , Receptores de Quimiocinas/metabolismo , Células Cultivadas , Endotélio Vascular/citologia , Endotélio Vascular/metabolismo , Glicosaminoglicanos/imunologia , Glicosaminoglicanos/metabolismo , Humanos , Microcirculação , Monócitos/citologia , Monócitos/imunologia , Receptores CCR1 , Vasculite/imunologia , Vasculite/metabolismo
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