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1.
J Pharmacol Exp Ther ; 370(2): 137-147, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31085698

RESUMO

The Janus-activated kinase (JAK) family together with signal transducer and activator of transcription (STAT) signaling pathway has a key role in regulating the expression and function of many inflammatory cytokines. This has led to the discovery of JAK inhibitors for the treatment of inflammatory diseases, some of them already in the market. Considering the adverse effects associated with JAK inhibition by oral route, we wanted to explore whether JAK inhibition by inhaled route is enough to inhibit airway inflammation. The aim of this study was to characterize the enzymatic and cellular potency and the selectivity of LAS194046, a novel JAK inhibitor, compared with the reference compounds ruxolitinib and tofacitinib. The efficacy of this new JAK inhibitor is described in a model of ovalbumin (OVA)-induced airway inflammation in Brown Norway rats by inhaled administration. As potential markers of target engagement, we assessed the effect of LAS194046 on the STAT activation state. LAS194046 is a selective inhaled pan-JAK inhibitor that reduces allergen-induced airway inflammation, late asthmatic response, and phosphor-STAT activation in the rat OVA model. Our results show that topical inhibition of JAK in the lung, without relevant systemic exposure, is sufficient to reduce lung inflammation and improve lung function in a rat asthma model. In summary, JAK-STAT pathway inhibition by inhaled route constitutes a promising therapeutic option for lung inflammatory diseases.


Assuntos
Alérgenos/imunologia , Asma/tratamento farmacológico , Asma/imunologia , Inibidores de Janus Quinases/farmacologia , Janus Quinases/antagonistas & inibidores , Nitrilas/farmacologia , Fosfoproteínas/metabolismo , Piperidinas/farmacologia , Pirimidinas/farmacologia , Fatores de Transcrição STAT/metabolismo , Administração por Inalação , Animais , Asma/metabolismo , Asma/patologia , Inflamação/tratamento farmacológico , Isoenzimas/antagonistas & inibidores , Inibidores de Janus Quinases/administração & dosagem , Inibidores de Janus Quinases/farmacocinética , Inibidores de Janus Quinases/uso terapêutico , Masculino , Nitrilas/administração & dosagem , Nitrilas/farmacocinética , Nitrilas/uso terapêutico , Piperidinas/administração & dosagem , Piperidinas/farmacocinética , Piperidinas/uso terapêutico , Pirimidinas/administração & dosagem , Pirimidinas/farmacocinética , Pirimidinas/uso terapêutico , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Fatores de Tempo
2.
Pharmacol Res ; 111: 208-216, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27317944

RESUMO

The chemoattractant receptor-homologous molecule expressed on T-helper type 2 cells (CRTh2) is a G protein-coupled receptor expressed on the leukocytes most closely associated with asthma and allergy like eosinophils, mast cells, Th2-lymphocytes and basophils. At present it is clear that CRTh2 mediates most prostaglandin D2 (PGD2) pro-inflammatory effects and as a result antagonists for this receptor have reached asthma clinical studies showing a trend of lung function improvement. The challenge remains to identify compounds with improved clinical efficacy when administered once a day. Herein we described the pharmacological profile of LAS191859, a novel, potent and selective CRTh2 antagonist. In vitro evidence in GTPγS binding studies indicate that LAS191859 is a CRTh2 antagonist with activity in the low nanomolar range. This potency is also maintained in cellular assays performed with human eosinophils and whole blood. The main differentiation of LAS191859 vs other CRTh2 antagonists is in its receptor binding kinetics. LAS191859 has a residence time half-life of 21h at CRTh2 that translates into a long-lasting in vivo efficacy that is independent of plasma levels. We believe that the strategy behind this compound will allow optimal efficacy and posology for chronic asthma treatment.


Assuntos
Antiasmáticos/farmacologia , Eosinófilos/efeitos dos fármacos , Antagonistas de Prostaglandina/farmacologia , Piridinas/farmacologia , Pirróis/farmacologia , Receptores Imunológicos/antagonistas & inibidores , Receptores de Prostaglandina/antagonistas & inibidores , Animais , Antiasmáticos/sangue , Antiasmáticos/química , Antiasmáticos/farmacocinética , Células CHO , Forma Celular/efeitos dos fármacos , Quimiotaxia de Leucócito/efeitos dos fármacos , Cricetulus , Cães , Relação Dose-Resposta a Droga , Desenho de Fármacos , Eosinófilos/metabolismo , Guanosina 5'-O-(3-Tiotrifosfato)/metabolismo , Cobaias , Meia-Vida , Cinética , Masculino , Camundongos , Antagonistas de Prostaglandina/sangue , Antagonistas de Prostaglandina/química , Antagonistas de Prostaglandina/farmacocinética , Ligação Proteica , Piridinas/sangue , Piridinas/química , Piridinas/farmacocinética , Pirróis/sangue , Pirróis/química , Pirróis/farmacocinética , Ratos Wistar , Receptores Imunológicos/sangue , Receptores Imunológicos/genética , Receptores de Prostaglandina/sangue , Receptores de Prostaglandina/genética , Transfecção
3.
Bioorg Med Chem Lett ; 24(21): 5111-7, 2014 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-25437503

RESUMO

Pyrrolopiperidinone acetic acids (PPAs) were identified as highly potent CRTh2 receptor antagonists. In addition, many of these compounds displayed slow-dissociation kinetics from the receptor. Structure-kinetic relationship (SKR) studies allowed optimisation of the kinetics to give potent analogues with long receptor residence half-lives of up to 23 h. Low permeability was a general feature of this series, however oral bioavailability could be achieved through the use of ester prodrugs.


Assuntos
Acetatos/química , Acetatos/farmacologia , Piperidinas/química , Pirazóis/química , Receptores Imunológicos/antagonistas & inibidores , Receptores de Prostaglandina/antagonistas & inibidores , Acetatos/síntese química , Acetatos/farmacocinética , Administração Oral , Animais , Células CACO-2 , Permeabilidade da Membrana Celular/efeitos dos fármacos , Meia-Vida , Humanos , Ratos , Receptores Imunológicos/metabolismo , Receptores de Prostaglandina/metabolismo , Relação Estrutura-Atividade
5.
Bioorg Med Chem Lett ; 24(21): 5123-6, 2014 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-25437505

RESUMO

Extensive structure-activity relationship (SAR) and structure-kinetic relationship (SKR) studies in the bicyclic heteroaromatic series of CRTh2 antagonists led to the identification of several molecules that possessed both excellent binding and cellular potencies along with long receptor residence times. A small substituent in the bicyclic core provided an order of magnitude jump in dissociation half-lives. Selected optimized compounds demonstrated suitable pharmacokinetic profiles.


Assuntos
Acetatos/química , Compostos Bicíclicos com Pontes/química , Receptores Imunológicos/antagonistas & inibidores , Receptores de Prostaglandina/antagonistas & inibidores , Acetatos/síntese química , Acetatos/farmacocinética , Animais , Meia-Vida , Humanos , Indóis/química , Injeções Intravenosas , Ratos , Ratos Wistar , Receptores Imunológicos/metabolismo , Receptores de Prostaglandina/metabolismo , Relação Estrutura-Atividade
7.
J Clin Invest ; 134(3)2024 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-38051587

RESUMO

Hidradenitis suppurativa (HS) is a chronic inflammatory disease characterized by abscesses, nodules, dissecting/draining tunnels, and extensive fibrosis. Here, we integrate single-cell RNA sequencing, spatial transcriptomics, and immunostaining to provide an unprecedented view of the pathogenesis of chronic HS, characterizing the main cellular players and defining their interactions. We found a striking layering of the chronic HS infiltrate and identified the contribution of 2 fibroblast subtypes (SFRP4+ and CXCL13+) in orchestrating this compartmentalized immune response. We further demonstrated the central role of the Hippo pathway in promoting extensive fibrosis in HS and provided preclinical evidence that the profibrotic fibroblast response in HS can be modulated through inhibition of this pathway. These data provide insights into key aspects of HS pathogenesis with broad therapeutic implications.


Assuntos
Hidradenite Supurativa , Humanos , Hidradenite Supurativa/genética , Via de Sinalização Hippo , Fibrose
9.
Sci Rep ; 12(1): 5132, 2022 03 24.
Artigo em Inglês | MEDLINE | ID: mdl-35332239

RESUMO

Non-T2 severe asthma and chronic obstructive pulmonary disease (COPD) are airway chronic inflammatory disorders with a poor response to corticosteroids. LAS194046, a novel pan-Janus kinase (JAK) inhibitor, shows inhibitory effects on T2 allergic lung inflammation in rats. In this work we analyze the effects of LAS194046, fluticasone propionate and their combination in neutrophils from non-T2 severe asthma and COPD patients in vitro. Neutrophils from 23 healthy subjects, 23 COPD and 21 non-T2 severe asthma patients were incubated with LAS194046 (0.01 nM-1 µM), fluticasone propionate (0.1 nM-1 µM) or their combination and stimulated with lipopolysaccharide (LPS 1 µM). LAS194046 shows similar maximal % inhibition and potency inhibiting IL-8, MMP-9 and superoxide anion release in neutrophils from healthy, COPD and asthma. Fluticasone propionate suppresses mediator release only in neutrophils from healthy patients. The combination of LAS194046 with fluticasone propionate shows synergistic anti-inflammatory and anti-oxidant effects. The mechanisms involved in the synergistic effects of this combination include the increase of MKP1 expression, decrease of PI3Kδ, the induction of glucocorticoid response element and the decrease of ERK1/2, P38 and JAK2/STAT3 phosphorylation compared with monotherapies. In summary, LAS194046 shows anti-inflammatory effects in neutrophils from COPD and severe non-T2 asthma patients and induces synergistic anti-inflammatory effects when combined with fluticasone propionate.


Assuntos
Asma , Inibidores de Janus Quinases , Doença Pulmonar Obstrutiva Crônica , Administração por Inalação , Androstadienos/farmacologia , Animais , Anti-Inflamatórios/farmacologia , Asma/tratamento farmacológico , Asma/metabolismo , Fluticasona/farmacologia , Fluticasona/uso terapêutico , Humanos , Ativação de Neutrófilo , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Ratos
10.
PLoS One ; 14(1): e0210188, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30608978

RESUMO

Recent evidence indicates that AZD8999 (LAS190792), a novel muscarinic acetylcholine receptor antagonist and ß2-adrenoceptor agonist (MABA) in development for chronic respiratory diseases, induces potent and sustained relaxant effects in human bronchi by adressing both muscarinic acetylcholine receptors and ß2-adrenoceptor. However, the anti-inflammatory effects of the AZD8999 monotherapy or in combination with corticosteroids are unknown. This study investigates the anti-inflammatory effects of AZD8999 in monotherapy and combined with fluticasone propionate in neutrophils from healthy and chronic obstructive pulmonary disease (COPD) patients. Peripheral blood neutrophils from healthy and COPD patients were incubated with AZD8999 and fluticasone propionate, individually or in combination, for 1h followed by lipopolysaccharide (LPS) stimulation for 6h. The IL-8, MMP9, IL-1ß, and GM-CSF release was measured in cell culture supernatants. AZD8999 shows ~ 50% maximum inhibitory effect and similar potency inhibiting the released cytokines in neutrophils from healthy and COPD patients. However, while fluticasone propionate suppresses mediator release in neutrophils from healthy patients, COPD neutrophils are less sensitive. The combination of non-effective concentrations of AZD8999 (0.01nM) with non-effective concentrations of fluticasone propionate (0.1nM) shows synergistic anti-inflammatory effects. The studied mechanisms that may be involved in the synergistic anti-inflammatory effects of this combination include the increase of glucocorticoid receptor (GR)α and MKP1 expression, the induction of glucocorticoid response element (GRE) activation and the decrease of ERK1/2, P38 and GR-Ser226 phosphorylations compared with monotherapies. In summary, AZD8999 shows anti-inflammatory effects in neutrophils from COPD patients and induces synergistic anti-inflammatory effects when combined with fluticasone propionate, supporting the use of MABA/ICS combination therapy in COPD.


Assuntos
Anti-Inflamatórios/farmacologia , Cicloexanos/farmacologia , Neutrófilos/efeitos dos fármacos , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Quinolinas/farmacologia , Tiofenos/farmacologia , Agonistas de Receptores Adrenérgicos beta 2/farmacologia , Agonistas de Receptores Adrenérgicos beta 2/uso terapêutico , Idoso , Anti-Inflamatórios/uso terapêutico , Cicloexanos/uso terapêutico , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Quimioterapia Combinada/métodos , Feminino , Fluticasona/farmacologia , Fluticasona/uso terapêutico , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Antagonistas Muscarínicos/farmacologia , Antagonistas Muscarínicos/uso terapêutico , Neutrófilos/imunologia , Neutrófilos/metabolismo , Doença Pulmonar Obstrutiva Crônica/imunologia , Quinolinas/uso terapêutico , Receptores Adrenérgicos beta 2/metabolismo , Receptores Muscarínicos/metabolismo , Tiofenos/uso terapêutico
11.
J Med Chem ; 62(20): 9045-9060, 2019 10 24.
Artigo em Inglês | MEDLINE | ID: mdl-31609613

RESUMO

Janus kinases (JAKs) have a key role in regulating the expression and function of relevant inflammatory cytokines involved in asthma and chronic obstructive pulmonary disease. Herein are described the design, synthesis, and pharmacological evaluation of a series of novel purinone JAK inhibitors with profiles suitable for inhaled administration. Replacement of the imidazopyridine hinge binding motif present in the initial compounds of this series with a pyridone ring resulted in the mitigation of cell cytotoxicity. Further systematic structure-activity relationship (SAR) efforts driven by structural biology studies led to the discovery of pyridone 34, a potent pan-JAK inhibitor with good selectivity, long lung retention time, low oral bioavailability, and proven efficacy in the lipopolysaccharide-induced rat model of airway inflammation by the inhaled route.


Assuntos
Imidazóis/química , Inibidores de Janus Quinases/farmacologia , Janus Quinases/antagonistas & inibidores , Piridinas/química , Piridonas/química , Doenças Respiratórias/tratamento farmacológico , Administração por Inalação , Animais , Humanos , Inibidores de Janus Quinases/administração & dosagem , Inibidores de Janus Quinases/química , Inibidores de Janus Quinases/uso terapêutico , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Ratos , Relação Estrutura-Atividade
12.
Biomark Res ; 6: 14, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29651336

RESUMO

BACKGROUND: Inhaled allergen challenges are often used to evaluate novel asthma treatments in early phase clinical trials. Current novel therapeutic targets in asthma include phosphoinositide 3-kinases (PI3K) delta and gamma, p38 mitogen-activated protein kinase (p38) and Janus kinase/Signal Transducer and Activator of Transcription (JAK/STAT) signalling pathways. The activation of these pathways following allergen exposure in atopic asthma patients it is not known. METHODS: We collected bronchial biopsies from 11 atopic asthma patients at baseline and after allergen challenge to investigate biomarkers of PI3K, p38 MAPK and JAK/STAT activation by immunohistochemistry. Cell counts and levels of eosinophil cationic protein and interleukin-5 were also assessed in sputum and bronchoalvelar lavage. RESULTS: Biopsies collected post-allergen had an increased percentage of epithelial cells expressing phospho-p38 (17.5 vs 25.6%, p = 0.04), and increased numbers of sub-epithelial cells expressing phospho-STAT5 (122.2 vs 540.6 cells/mm2, p = 0.01) and the PI3K marker phospho-ribosomal protein S6 (180.7 vs 777.3 cells/mm2,p = 0.005). Type 2 inflammation was increased in the airways post allergen, with elevated levels of eosinophils, interleukin-5 and eosinophil cationic protein. CONCLUSIONS: Future clinical trials of novel kinase inhibitors could use the allergen challenge model in proof of concept studies, while employing these biomarkers to investigate pharmacological inhibition in the lungs.

13.
J Med Chem ; 61(21): 9551-9567, 2018 11 08.
Artigo em Inglês | MEDLINE | ID: mdl-30351000

RESUMO

Oral PI3Kδ inhibitors such as Idelalisib and Duvelisib have shown efficacy as anticancer agents and Idelalisib has been approved for the treatment of three B-cell cancers. However, Idelalisib has a black box warning on its product label regarding the risks of fatal and serious toxicities including hepatic toxicity, severe diarrhea, colitis, pneumonitis, infections, and intestinal perforation. Some of these side effects are mechanism-related and could hinder the development of Idelalisib for less severe conditions. For respiratory diseases, compounds administered by inhalation are delivered directly to the site of action and may improve the therapeutic index of a drug, minimizing undesired side effects. This work describes the discovery and optimization of inhaled PI3Kδ inhibitors intended for the treatment of severe asthma and COPD. Once the potency was in the desired range, efforts were focused on identifying the particular physicochemical properties that could translate into better lung retention. This medicinal chemistry exercise led to the identification of LAS195319 as a candidate for clinical development.


Assuntos
Asma/tratamento farmacológico , Classe I de Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Descoberta de Drogas , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/farmacologia , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Administração por Inalação , Classe I de Fosfatidilinositol 3-Quinases/química , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/uso terapêutico , Humanos , Concentração Inibidora 50 , Modelos Moleculares , Conformação Proteica
14.
J Med Chem ; 50(11): 2732-6, 2007 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-17469811

RESUMO

A novel series of N-heteroaryl 4'-(2-furyl)-4,5'-bipyrimidin-2'-amines has been identified as potent and selective A(2B) adenosine receptor antagonists. In particular, compound 5 showed high affinity for the A(2B) receptor (Ki = 17 nM), good selectivity (IC(50): A(1) > 1000 nM, A(2A) > 2500 nM, A3 > 1000 nM), displayed a favorable pharmacokinetic profile in preclinical species, and showed efficacy in functional in vitro models.


Assuntos
Antagonistas do Receptor A2 de Adenosina , Furanos/síntese química , Piridinas/síntese química , Pirimidinas/síntese química , Animais , Linhagem Celular , Cricetinae , Cricetulus , Cães , Furanos/farmacocinética , Furanos/farmacologia , Camundongos , Piridinas/farmacocinética , Piridinas/farmacologia , Pirimidinas/farmacocinética , Pirimidinas/farmacologia , Ensaio Radioligante , Ratos , Relação Estrutura-Atividade
15.
Eur J Med Chem ; 113: 102-33, 2016 May 04.
Artigo em Inglês | MEDLINE | ID: mdl-26922232

RESUMO

Monocyclic and bicyclic ring systems were investigated as the "core" section of a series of diphenylsulphone-containing acetic acid CRTh2 receptor antagonists. A range of potencies were observed and single-digit nanomolar potencies were obtained in both the monocyclic and bicyclic cores. Residence times for the monocyclic compounds were very short. Some of the bicyclic cores displayed better residence times. A methyl group in the northern part of the core, between the head and tail was a necessary requirement for the beginnings of long residence times. Variations of the tail substitution maximised potencies and residence times.


Assuntos
Receptores Imunológicos/antagonistas & inibidores , Receptores de Prostaglandina/antagonistas & inibidores , Sulfonas/química , Sulfonas/farmacologia , Relação Dose-Resposta a Droga , Humanos , Cinética , Estrutura Molecular , Relação Estrutura-Atividade , Sulfonas/síntese química
16.
Brain Res Mol Brain Res ; 122(2): 133-50, 2004 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-15010206

RESUMO

In an attempt to elucidate the molecular basis of neuronal migration and corticogenesis, we performed subtractive hybridization of mRNAs from the upper cortical layers (layer I and upper cortical plate) against mRNAs from the remaining cerebral cortex at E15-E16. We obtained a collection of subtracted cDNA clones and analyzed their 3' UTR sequences, 47% of which correspond to EST sequences, and may represent novel products. Among the cloned sequences, we identified gene products that have not been reported in brain or in the cerebral cortex before. We examined the expression pattern of 39 subtracted clones, which was enriched in the upper layers of the cerebral cortex at embryonic stages. The expression of most clones is developmentally regulated, and especially high in embryonic and early postnatal stages. Four of the unknown clones were studied in more detail and identified as a new member of the tetraspanin superfamily, a putative RNA binding protein, a specific product of the adult dentate gyrus and a protein containing a beta-catenin repeat. We thus cloned a collection of subtracted cDNAs coding for protein products that may be involved in the development of the cerebral cortex.


Assuntos
Diferenciação Celular/genética , Movimento Celular/genética , Córtex Cerebral/embriologia , DNA Complementar/genética , Proteínas do Tecido Nervoso/genética , Neurônios/metabolismo , Sequência de Aminoácidos , Animais , Animais Recém-Nascidos , Sequência de Bases , Córtex Cerebral/citologia , Córtex Cerebral/metabolismo , DNA Complementar/isolamento & purificação , Giro Denteado/citologia , Giro Denteado/embriologia , Giro Denteado/metabolismo , Feminino , Feto , Biblioteca Genômica , Substâncias de Crescimento/genética , Substâncias de Crescimento/isolamento & purificação , Proteínas de Membrana/genética , Proteínas de Membrana/isolamento & purificação , Camundongos , Dados de Sequência Molecular , Proteínas do Tecido Nervoso/isolamento & purificação , Neurônios/citologia , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/isolamento & purificação , Homologia de Sequência de Aminoácidos , Homologia de Sequência do Ácido Nucleico
17.
Eur J Med Chem ; 71: 168-84, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24292338

RESUMO

In this manuscript, the synthesis and biological activity of a series of pyrazole acetic acid derivatives as CRTh2 antagonists is presented. Biological evaluation in vitro revealed that the pyrazole core showed in several cases a different structure-activity relationship (SAR) to that of related indole acetic acid. A potent series of ortho-sulfonyl benzyl substituents was found, from which compounds 27 and 63 were advanced to in vivo profiling.


Assuntos
Acetatos/química , Acetatos/farmacologia , Pirazóis/química , Pirazóis/farmacologia , Receptores Imunológicos/antagonistas & inibidores , Receptores de Prostaglandina/antagonistas & inibidores , Acetatos/síntese química , Humanos , Pirazóis/síntese química , Receptores Imunológicos/metabolismo , Receptores de Prostaglandina/metabolismo , Relação Estrutura-Atividade
18.
Int Immunopharmacol ; 11(11): 1773-9, 2011 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-21798372

RESUMO

Agonists of the sphingosine-1-phosphate (S1P) receptors, like fingolimod (FTY720), are a novel class of immunomodulators. Administration of these compounds prevents the egress of lymphocytes from primary and secondary lymphoid organs causing peripheral blood lymphopenia. Although it is well established that lymphopenia is mediated by S1P receptor type 1 (S1P1), the exact mechanism is still controversial. The most favored hypothesis states that S1P1 agonists cause internalization and loss of the cell surface receptor on lymphocytes, preventing them to respond to S1P. Hence, S1P1 agonists would behave in vivo as functional antagonists of the receptor. For this hypothesis to be valid, a true S1P1 antagonist should also induce lymphopenia. However, it has been reported that S1P1 antagonists fail to show this effect, arguing against the concept. Our study demonstrates that a S1P1 antagonist, W146, induces a significant but transient blood lymphopenia in mice and a parallel increase in CD4+ and CD8+ lymphocytes in lymph nodes. Treatment with W146 also causes the accumulation of mature T cells in the medulla of the thymus and moreover, it induces lung edema. We show that both the S1P1 antagonist and a S1P1 agonist cause lymphopenia in vivo in spite of their different effects on receptor expression in vitro. Although the antagonist purely blocks the receptor and the agonist causes its disappearance from the cell surface, the response to the endogenous ligand is prevented in both cases. Our results support the hypothesis that lymphopenia evoked by S1P1 agonists is due to functional antagonism of S1P1 in lymphocytes.


Assuntos
Anilidas/farmacologia , Linfócitos/efeitos dos fármacos , Linfopenia/induzido quimicamente , Organofosfonatos/farmacologia , Receptores de Lisoesfingolipídeo/agonistas , Receptores de Lisoesfingolipídeo/antagonistas & inibidores , Anilidas/sangue , Animais , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Quimiotaxia/efeitos dos fármacos , Citometria de Fluxo , Linfonodos/citologia , Linfonodos/efeitos dos fármacos , Linfonodos/imunologia , Contagem de Linfócitos , Linfócitos/citologia , Linfócitos/imunologia , Linfopenia/imunologia , Masculino , Camundongos , Organofosfonatos/sangue , Timo/citologia , Timo/efeitos dos fármacos , Timo/imunologia , Fatores de Tempo
19.
Mol Cell Neurosci ; 30(3): 465-75, 2005 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-16182561

RESUMO

Cortistatin-14 (CST) is a neuropeptide expressed in cortical and hippocampal interneurons that shares 11 of 14 residues with somatostatin. In contrast to somatostatin, infusion of CST decreases locomotor activity and selectively enhances slow wave sleep. Here, we show that transgenic mice that overexpress cortistatin under the control of neuron-specific enolase promoter do not express long-term potentiation in the dentate gyrus. This blockade of dentate LTP correlates with profound impairment of hippocampal-dependent spatial learning. Exogenously applied CST to slices of wild-type mice also blocked induction of LTP in the dentate gyrus. Our findings implicate cortistatin in the modulation of synaptic plasticity and cognitive function. Thus, increases in hippocampal cortistatin expression during aging could have an impact on age-related cognitive deficits.


Assuntos
Hipocampo/metabolismo , Deficiências da Aprendizagem/genética , Aprendizagem/fisiologia , Potenciação de Longa Duração/genética , Peptídeos/metabolismo , Transmissão Sináptica/genética , Envelhecimento/genética , Envelhecimento/metabolismo , Animais , Giro Denteado/metabolismo , Giro Denteado/fisiopatologia , Feminino , Regulação da Expressão Gênica no Desenvolvimento/genética , Peptídeos e Proteínas de Sinalização Intercelular , Deficiências da Aprendizagem/metabolismo , Deficiências da Aprendizagem/fisiopatologia , Masculino , Transtornos da Memória/genética , Transtornos da Memória/metabolismo , Transtornos da Memória/fisiopatologia , Camundongos , Camundongos Transgênicos , Peptídeos/genética , Regiões Promotoras Genéticas/genética
20.
J Neurochem ; 90(4): 883-93, 2004 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-15287894

RESUMO

Nucleoside transport processes regulate the levels of adenosine available to modulate neurotransmission, vascular tone and other physiological events. However, although equilibrative transporter transcripts or proteins have been mapped in the central nervous system of rats and humans, little is known about the presence and distribution of the complete family of nucleoside transporters in brain. In this study, we analysed the distribution of the transcript encoding the high affinity adenosine-preferring concentrative transporter CNT2 in the rat central nervous system and compared it with that of the equilibrative transporter ENT1. Furthermore, we evaluated the changes in expression of these two transporters in a situation of increased extracellular levels of adenosine, such as sleep deprivation. CNT2 mRNA was widespread in rat brain, although most prevalent in the amygdala, the hippocampus, specific neocortical regions and the cerebellum. The distribution of CNT2 mRNA only partially overlapped that of ENT1. Most of the cells labelled were neurones. Total sleep deprivation dramatically diminished the amounts of CNT2 mRNA, whereas ENT1 mRNA remained unchanged. This specific decrease in CNT2 transcript suggests a new physiological role for the transporter in the modulation of extracellular adenosine levels and the sleep/wakefulness cycle.


Assuntos
Encéfalo/metabolismo , Proteínas de Transporte/genética , Proteínas de Membrana Transportadoras/genética , RNA Mensageiro/biossíntese , Privação do Sono/metabolismo , Animais , Córtex Cerebral/metabolismo , Transportador Equilibrativo 1 de Nucleosídeo , Hibridização In Situ , Masculino , Proteínas de Transporte de Nucleosídeos/genética , Ratos , Ratos Wistar , Reação em Cadeia da Polimerase Via Transcriptase Reversa
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