Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 720
Filtrar
1.
Int J Rheum Dis ; 21(12): 2128-2138, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30207074

RESUMO

BACKGROUND: Release of 5-hydroxytryptamine (5-HT; serotonin) from activated platelets following microvascular injury leads to tissue fibrosis. 5-HT strongly induces extracellular matrix synthesis in dermal fibroblasts in a transforming growth factor beta 1 (TGF-ß1)-dependent manner. AIM: To evaluate anti-fibrotic properties of inhibitors of 5-HT2 and 5-HT2B (terguride, SB204741) respectively in human adult dermal fibroblasts (HADF) derived from a patient with scleroderma. METHODS: Anti-fibrotic efficacy of 5-HT2 and 5-HT2B inhibitors was evaluated as per two strategies: HADF were incubated with 5-HT (1 µM)/TGF-ß1 (10 ng/mL) for 1 hour followed by 5-HT (1 µM)/TGF-ß1 (10 ng/mL) and terguride or SB204741 (1 µM, each) for 24 hours (post-treatment strategy) and HADF were treated with terguride or SB204741 (1 µM, each) for 1 hour followed by 5-HT (1 µM)/TGF-ß1 (10 ng/mL) for 24 hours (pre-treatment strategy). Real time quantitative polymerase chain reaction for expression of pro-fibrotic (TGFΒ1, COL1A1, COL1A2, ACTA2, CTGF and FN1) and anti-fibrotic genes (MMP2/TIMP1) was performed. Expression of type I collagen, alpha smooth muscle actin (α-SMA), phosphorylation of Smad3, ERK1/2 and STAT3 was examined by immunoblotting. RESULTS: Stimulation of HADF cells with 5-HT/TGF-ß1 led to the increased expression of pro-fibrotic genes which was significantly reduced by both terguride and SB204741. Expression of anti-fibrotic genes was not affected upon incubation with the inhibitors. In 5-HT-stimulated HADF, treatment with terguride and SB204741 decreased type I collagen and α-SMA. In 5-HT/TGF-ß1 stimulated HADF, terguride and SB204741 treatment reduced ERK1/2 and STAT3 phosphorylation but did not influence Smad3 phosphorylation. CONCLUSION: Terguride and SB204741 reduce pro-fibrotic potential of HADF cells and suppress TGF-ß1-mediated non-canonical pathways, ERK1/2 and STAT3 which have been implicated in the regulation of pro-fibrotic genes and in the development of fibrosis. Taken together, our data suggest that 5-HT inhibitors might reduce fibrosis via suppression of TGF-beta1-mediated non-canonical signaling pathways. These observations have important therapeutic implications for fibrotic disorders like scleroderma.


Assuntos
Fibroblastos/efeitos dos fármacos , Indóis/farmacologia , Lisurida/análogos & derivados , Receptor 5-HT2B de Serotonina/efeitos dos fármacos , Escleroderma Sistêmico/tratamento farmacológico , Antagonistas do Receptor 5-HT2 de Serotonina/farmacologia , Transdução de Sinais/efeitos dos fármacos , Pele/efeitos dos fármacos , Fator de Crescimento Transformador beta1/farmacologia , Ureia/análogos & derivados , Adulto , Células Cultivadas , Proteínas da Matriz Extracelular/genética , Proteínas da Matriz Extracelular/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Feminino , Fibroblastos/metabolismo , Fibroblastos/patologia , Fibrose , Regulação da Expressão Gênica , Humanos , Lisurida/farmacologia , Fenótipo , Fosforilação , Receptor 5-HT2B de Serotonina/metabolismo , Fator de Transcrição STAT3/metabolismo , Escleroderma Sistêmico/genética , Escleroderma Sistêmico/metabolismo , Escleroderma Sistêmico/patologia , Serotonina/farmacologia , Pele/metabolismo , Pele/patologia , Ureia/farmacologia
2.
Transpl Immunol ; 49: 43-53, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29649585

RESUMO

BACKGROUND: Cardiac allograft vasculopathy (CAV) is the main obstacle for long-term survival after heart transplantation. Alloimmune mediated chronic vascular rejection results in several mechanisms like platelet activation, immigration of inflammatory cells through the endothelial layer and proliferation and migration of smooth muscle cells (SMCs). Serotonin (5-HT) promotes these processes via activation of 5-HT2 receptors. We hypothesized that inhibiting 5-HT2 receptors ameliorates the development of CAV. METHODS: CBA/JRj mice recieved aortic grafts from C57BL/6 mice. After transplantation until recovery of organs, recipients were treated with serotonin receptor antagonists: sarpogrelate (5-HT2A), SB 204741 (5-HT2B) or terguride (5-HT2A+B). Mice were sacrificed after 14 days for qRT-PCR analysis or after 30 days for histological evaluation. Serum serotonin ELISA was done at both time points. RESULTS: Elevated serum serotonin levels were significantly reduced after 5-HT2A antagonist treatment as was 5-HT2A receptor expression. This went along with reduced inflammation characterized by significantly fewer infiltrating macrophages and pro-inflammatory intragraft cytokines and with reduced tissue remodeling evident as significantly less neointima formation. CONCLUSION: Inhibition of the 5HT/5-HT2A receptor axis leads to significantly reduced neointima proliferation after aortic transplantation associated with reduced transendothelial migration of macrophages and decreased expression of inflammatory cytokines. These findings have translational implications as inhibitors of 5HT2A like sarpogrelate are already approved for clinical use.


Assuntos
Aorta/cirurgia , Rejeição de Enxerto/prevenção & controle , Transplante de Coração , Lisurida/análogos & derivados , Antagonistas do Receptor 5-HT2 de Serotonina/metabolismo , Antagonistas da Serotonina/uso terapêutico , Succinatos/uso terapêutico , Animais , Aorta/patologia , Proliferação de Células , Feminino , Rejeição de Enxerto/imunologia , Humanos , Indóis/uso terapêutico , Lisurida/uso terapêutico , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos CBA , Modelos Animais , Serotonina/metabolismo , Migração Transendotelial e Transepitelial , Transplante Homólogo , Ureia/análogos & derivados , Ureia/uso terapêutico
3.
Psychopharmacology (Berl) ; 235(1): 99-108, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-28971230

RESUMO

RATIONALE: 2-Bromoterguride, a dopamine D2 receptor partial agonist with antagonist properties at serotonin 5-HT2A receptors and α2C-adrenoceptors, meets the prerequisites of a putative atypical antipsychotic drug (APD). We recently showed that 2-bromoterguride is effective in tests of positive symptoms of schizophrenia in rats without inducing extrapyramidal side effects or metabolic changes. OBJECTIVE: In continuation of our recent work, we now investigated the effect of 2-bromoterguride on apomorphine and phencyclidine (PCP)-induced disruptions of prepulse inhibition (PPI) of the acoustic startle response, a measure of sensory gating. In addition, we used subchronic PCP treatment to produce cognitive deficits and social aversion, and assessed the effect of 2-bromoterguride on the performance in the novel object recognition (NOR) task (model for studying cognitive deficit symptoms of schizophrenia) and the social interaction test (model for studying negative symptoms of schizophrenia). Finally, we extended the side effect profile of 2-bromoterguride by measuring the prolactin response to systemic administration of the drug in rats. RESULTS: Treatment with 2-bromoterguride (0.1 and 0.3 mg/kg) reversed PPI deficits induced by apomorphine and PCP, respectively. Subchronic PCP induced impairments in object memory and social interaction behavior which were ameliorated by 2-bromoterguride but not by clozapine and aripiprazole, respectively. Prolactin concentration in blood serum was not elevated at 1, 2, or 4 h post-2-bromoterguride treatment, which further supports the safe and effective use of this drug. CONCLUSIONS: Our data support 2-bromoterguride as a promising APD candidate due to its beneficial effect on cognitive impairments and negative symptoms of schizophrenia.


Assuntos
Antipsicóticos/farmacologia , Transtornos Cognitivos/psicologia , Agonistas de Dopamina/farmacologia , Lisurida/análogos & derivados , Receptores de Dopamina D2/agonistas , Comportamento Social , Animais , Apomorfina/farmacologia , Transtornos Cognitivos/induzido quimicamente , Agonistas de Dopamina/efeitos adversos , Lisurida/efeitos adversos , Lisurida/farmacologia , Masculino , Transtornos da Memória/induzido quimicamente , Transtornos da Memória/psicologia , Fenciclidina/farmacologia , Prolactina/metabolismo , Ratos , Ratos Sprague-Dawley , Reconhecimento Psicológico/efeitos dos fármacos , Reflexo de Sobressalto/efeitos dos fármacos , Psicologia do Esquizofrênico
4.
Eur J Pharmacol ; 814: 114-123, 2017 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-28821451

RESUMO

The neurotransmitter 5-hydroxytryptamine (5-HT) is involved in regulation of local tissue inflammation and repair through a set of receptors (5-HT1-7 receptors), which are expressed in the lung. Considering the protective importance of 5-HT receptor antagonists against development of pulmonary fibrosis, we evaluated whether 5-HT7 receptor antagonist (SB-269970) modulates lung inflammatory and fibrogenic processes in comparison with 5-HT2A/B receptor antagonist (terguride), in bleomycin (BLM)-induced idiopathic pulmonary fibrosis (IPF) model. IPF model induced by a single dose of intra-tracheal BLM instillation (5mg/kg), and rats were treated with intraperitoneal injection of SB-269970 (1mg/kg day) or terguride (1.2mg/kg/d). The experiment was carried out on two separate sets of rats that were killed at day 7th and day 21st to evaluate the endpoint of the IPF inflammatory and fibrogenic phases, respectively. During the inflammatory phase 5-HT2A/B and 5-HT7 receptor antagonists attenuated the BLM-induced increase in the lung fluid content, the inflammatory cytokines levels and oxidative stress burden. In the fibrogenic phase, both SB-269970 and terguride reduced the serotonin concentrations in lung homogenates and significantly protected against IPF fibrogenic phase by attenuating collagen deposition and mRNA expression of both transforming growth factor-ß1 (TGF- ß1), and procollagen type Ӏ (PINP). 5-hydroxytryptamine 5-HT7 receptor antagonist showed more benefits than 5-HT2A/B receptor antagonist on the deleterious effects accompanied BLM instillation. The present study showed involvement of 5-HT7 receptor in the pathophysiology of BLM-induced IPF in rats and identified it as a potential therapeutic target in lung fibrotic disorders.


Assuntos
Bleomicina/efeitos adversos , Regulação para Baixo/efeitos dos fármacos , Lisurida/análogos & derivados , Estresse Oxidativo/efeitos dos fármacos , Fenóis/farmacologia , Fibrose Pulmonar/tratamento farmacológico , Receptores de Serotonina/metabolismo , Sulfonamidas/farmacologia , Animais , Colágeno/metabolismo , Inflamação/metabolismo , Interleucina-6/metabolismo , Lisurida/farmacologia , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Pulmão/patologia , Masculino , Fenóis/uso terapêutico , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/metabolismo , Fibrose Pulmonar/patologia , Ratos , Sulfonamidas/uso terapêutico , Fator de Necrose Tumoral alfa/metabolismo , Água/metabolismo
5.
Neuropharmacology ; 117: 14-20, 2017 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-28131770

RESUMO

Dopamine (DA) contributes to the regulation of voluntary movement, and a deficiency in DAergic neurons leads to movement disorders. The objective of this study was to examine the neuroprotective effect of DA D2-like receptor agonist, lisuride, and the role of DA receptors in this protection. Treatment with lisuride alleviated loss of tyrosine hydroxylase (TH) both direct and intraperitoneal injection in 6-hydroxydopamine (6-OHDA) mouse model. Similar results were obtained in primary neuronal cultures treated with lisuride. Lisuride protected TH expression against 6-OHDA-induced cytotoxicity in a concentration-dependent manner. Then, we evaluated the role of DA D2 and D3 receptor in neuroprotective effect of lisuride. Treatment of neuronal cultures with L-741,626, a DA D2 receptor-selective antagonist, did not alter neuroprotective effect of lisuride. However, protective effect of lisuride on TH expression was abolished when cells were treated with GR103691, a D3 receptor selective antagonist. Furthermore, whether lisuride can alleviate mitochondrial damage of DAergic neurons induced by 6-OHDA, we investigated the expression of the mitochondrial regulatory protein, paraplegin, and changes in mitochondria morphology. Treatment with lisuride countered a 6-OHDA-induced reduction in paraplegin and TH expression, and co-treatment with GR103691 blocked this effect of lisuride. Transmission electron microscopy confirmed the lisuride mitigation of 6-OHDA-induced damage to the mitochondrial membrane and cristae. These results suggest that the DA D3 receptor mediates the neuroprotective effects of lisuride by preventing mitochondrial damage.


Assuntos
Lisurida/farmacologia , Fármacos Neuroprotetores/farmacologia , Receptores de Dopamina D3/agonistas , ATPases Associadas a Diversas Atividades Celulares , Animais , Compostos de Bifenilo/farmacologia , Antagonistas dos Receptores de Dopamina D2/farmacologia , Relação Dose-Resposta a Droga , Feminino , Indóis/farmacologia , Lisurida/antagonistas & inibidores , Masculino , Metaloendopeptidases/metabolismo , Camundongos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/ultraestrutura , Fármacos Neuroprotetores/antagonistas & inibidores , Oxidopamina/antagonistas & inibidores , Piperazinas/farmacologia , Piperidinas/farmacologia , Cultura Primária de Células , Receptores de Dopamina D3/antagonistas & inibidores , Tirosina 3-Mono-Oxigenase/metabolismo
6.
Expert Rev Clin Immunol ; 13(5): 469-482, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-27899043

RESUMO

INTRODUCTION: Systemic sclerosis (SSc) is a systemic autoimmune disease characterized by vasculopathy, inflammation and fibrosis. These three main disease-determining pathways are the target of the currently available treatments used to possibly modify the progression of disease-related manifestations, although this synergy has not been fully applied on SSc joint, skin or lung involvement yet. Areas covered: we describe the current status of SSc treatment/therapy performing a literature search in MEDLINE/Pubmed and Thomson Reuter's Web of Science for articles published until March 2016. Moreover, ongoing registered clinical trials (RCTs) on SSc were searched through clinicaltrials.gov website. Expert commentary: presently, promising drugs are under evaluation to target the different pathogenic pathways of systemic sclerosis: Tocilizumab and Abatacept for skin and lung fibrosis; Riociguat and Selexipag are approved for pulmonary arterial hypertension but promising anti-fibrotic effects are now being studied. Finally, several anti-fibrotic molecules are currently involved in RCTs, such as Nintedanib, IVA-337, Terguride.


Assuntos
Produtos Biológicos/uso terapêutico , Fibrinolíticos/uso terapêutico , Hipertensão Pulmonar/tratamento farmacológico , Articulações/patologia , Pulmão/patologia , Escleroderma Sistêmico/tratamento farmacológico , Pele/patologia , Abatacepte/uso terapêutico , Acetamidas/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Ensaios Clínicos como Assunto , Fibrose , Humanos , Indóis/uso terapêutico , Inflamação , Lisurida/análogos & derivados , Lisurida/uso terapêutico , PubMed , Pirazinas/uso terapêutico , Pirazóis/uso terapêutico , Pirimidinas/uso terapêutico
7.
Psychopharmacology (Berl) ; 233(15-16): 3041-50, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-27317020

RESUMO

RATIONALE: Recently, we showed that 2-bromoterguride acted as a dopamine D2 receptor partial agonist, a serotonin 5-HT2A and α2C-adrenergic receptor antagonist, and exhibited antidopaminergic efficacy in amphetamine-induced locomotion (AIL) in rats without inducing catalepsy. OBJECTIVE: To extend our knowledge on the antipsychotic effects of 2-bromoterguride, we used convergent preclinical animal models and tests; i.e., conditioned avoidance response (CAR), predictive of antipsychotic-like effects; Fos protein expression, a molecular marker for (atypical) antipsychotic activity; wet dog shake behavior, a test for the in vivo effects of drugs acting on central 5-HT2A receptors; and investigated metabolic changes as a common side effect of atypical antipsychotic drugs (APDs). RESULTS: Acute treatment with 2-bromoterguride (0.1 and 0.3 mg/kg) decreased the CAR at 30, 90, and 270 min post-injection in rats without inducing escape failures at any time. Fos protein expression, as shown by Western blotting, was enhanced by 2-bromoterguride in the nucleus accumbens (NAc), the dorsolateral striatum (dStr), and the medial prefrontal cortex (mPFC). (±)-2,5-Dimethoxy-4-iodoamphetamine (DOI)-induced wet dog shakes in rats were reduced by 2-bromoterguride. Chronic treatment with 2-bromoterguride did not affect metabolic parameters such as body weight development and body fat composition as well as behavioral parameters such as food intake and locomotor activity. CONCLUSIONS: Our data suggest that 2-bromoterguride is a promising candidate in the treatment of schizophrenia due to its atypical antipsychotic-like activity and its inability to induce weight gain.


Assuntos
Antipsicóticos/farmacologia , Comportamento Animal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Condicionamento Clássico/efeitos dos fármacos , Lisurida/análogos & derivados , Proteínas Proto-Oncogênicas c-fos/efeitos dos fármacos , Antagonistas de Receptores Adrenérgicos alfa 2/farmacologia , Anfetaminas/farmacologia , Animais , Encéfalo/metabolismo , Agonistas de Dopamina/farmacologia , Lisurida/farmacologia , Masculino , Neostriado/efeitos dos fármacos , Neostriado/metabolismo , Núcleo Accumbens/efeitos dos fármacos , Núcleo Accumbens/metabolismo , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Proteínas Proto-Oncogênicas c-fos/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores de Dopamina D2/agonistas , Antagonistas do Receptor 5-HT2 de Serotonina/farmacologia , Agonistas do Receptor de Serotonina/farmacologia
8.
Pharmacol Ther ; 164: 195-203, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27133570

RESUMO

The past three decades have witnessed a welcome expansion of the therapeutic armamentarium for the management of pulmonary arterial hypertension (PAH). However, against this backdrop, there have been some notable disappointments in drug development. Here we use these as case studies to emphasize the importance of informed drug target selection, the early evaluation of dose-response relationships in human studies, and the value of the deep phenotyping of patients in clinical studies to better understand inter-individual variation in patient response. The integration of "omics" technologies and advanced clinical imaging offer the potential to reduce the risk, and so cost, of drug development in PAH and bring much needed new medicines to those patients most likely to benefit with greater efficiency.


Assuntos
Estudos Clínicos como Assunto/métodos , Hipertensão Pulmonar/tratamento farmacológico , Animais , Biomarcadores , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Combinação de Medicamentos , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Hipertensão Pulmonar/patologia , Hipertensão Pulmonar/fisiopatologia , Lisurida/análogos & derivados , Lisurida/farmacologia , Fenótipo , Fentolamina/farmacologia , Proteínas Tirosina Quinases/antagonistas & inibidores , Peptídeo Intestinal Vasoativo/farmacologia
9.
Mol Cell Proteomics ; 13(5): 1273-85, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24637012

RESUMO

The serotonin 5-HT(2A) receptor is a primary target of psychedelic hallucinogens such as lysergic acid diethylamine, mescaline, and psilocybin, which reproduce some of the core symptoms of schizophrenia. An incompletely resolved paradox is that only some 5-HT(2A) receptor agonists exhibit hallucinogenic activity, whereas structurally related agonists with comparable affinity and activity lack such a psychoactive activity. Using a strategy combining stable isotope labeling by amino acids in cell culture with enrichment in phosphorylated peptides by means of hydrophilic interaction liquid chromatography followed by immobilized metal affinity chromatography, we compared the phosphoproteome in HEK-293 cells transiently expressing the 5-HT(2A) receptor and exposed to either vehicle or the synthetic hallucinogen 1-[2,5-dimethoxy-4-iodophenyl]-2-aminopropane (DOI) or the nonhallucinogenic 5-HT(2A) agonist lisuride. Among the 5995 identified phosphorylated peptides, 16 sites were differentially phosphorylated upon exposure of cells to DOI versus lisuride. These include a serine (Ser(280)) located in the third intracellular loop of the 5-HT(2A) receptor, a region important for its desensitization. The specific phosphorylation of Ser(280) by hallucinogens was further validated by quantitative mass spectrometry analysis of immunopurified receptor digests and by Western blotting using a phosphosite specific antibody. The administration of DOI, but not of lisuride, to mice, enhanced the phosphorylation of 5-HT(2A) receptors at Ser(280) in the prefrontal cortex. Moreover, hallucinogens induced a less pronounced desensitization of receptor-operated signaling in HEK-293 cells and neurons than did nonhallucinogenic agonists. The mutation of Ser(280) to aspartic acid (to mimic phosphorylation) reduced receptor desensitization by nonhallucinogenic agonists, whereas its mutation to alanine increased the ability of hallucinogens to desensitize the receptor. This study reveals a biased phosphorylation of the 5-HT(2A) receptor in response to hallucinogenic versus nonhallucinogenic agonists, which underlies their distinct capacity to desensitize the receptor.


Assuntos
Anfetaminas/farmacologia , Alucinógenos/farmacologia , Lisurida/farmacologia , Receptor 5-HT2A de Serotonina/metabolismo , Serina/metabolismo , Agonistas do Receptor 5-HT2 de Serotonina/farmacologia , Animais , Células Cultivadas , Regulação da Expressão Gênica/efeitos dos fármacos , Células HEK293 , Humanos , Camundongos , Neurônios/metabolismo , Fosforilação , Córtex Pré-Frontal/metabolismo , Proteômica/métodos , Transdução de Sinais/efeitos dos fármacos
10.
Psychopharmacology (Berl) ; 231(3): 581-91, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24030470

RESUMO

RATIONALE: The contribution of dopamine receptor subtypes in mediating the discriminative stimulus effects of cocaine is not fully established. Many drug discrimination studies use food to maintain responding, necessitating food restriction, which can alter drug effects. OBJECTIVE: This study established stimulus control with cocaine (10 mg/kg) in free-feeding and food-restricted rats responding under a schedule of stimulus shock termination (SST) and in food-restricted rats responding under a schedule of food presentation to examine whether feeding condition or the reinforcer used to maintain responding impacts the effects of cocaine. METHOD: Dopamine receptor agonists and antagonists were examined for their ability to mimic or attenuate, respectively, the effects of cocaine. RESULTS: Apomorphine, quinpirole, and lisuride occasioned >90 % responding on the cocaine-associated lever in free-feeding rats responding under a schedule of SST; apomorphine, but not quinpirole or lisuride, occasioned >90 % responding on the cocaine lever in food-restricted rats responding under a schedule of SST. In food-restricted rats responding for food these drugs occasioned little cocaine lever responding and were comparatively more potent in decreasing responding. In free-feeding rats, the effects of cocaine were attenuated by the D2/D3 receptor antagonist raclopride and the D3 receptor-selective antagonist PG01037. In food-restricted rats, raclopride and the D2 receptor-selective antagonist L-741,626 attenuated the effects of cocaine. Raclopride antagonized quinpirole in all groups while PG01037 antagonized quinpirole only in free-feeding rats. CONCLUSION: These results demonstrate significant differences in the discriminative stimulus of cocaine that are due to feeding conditions and not to the use of different reinforcers across procedures.


Assuntos
Cocaína/farmacologia , Discriminação Psicológica/efeitos dos fármacos , Agonistas de Dopamina/farmacologia , Antagonistas de Dopamina/farmacologia , Inibidores da Captação de Dopamina/farmacologia , Privação de Alimentos/fisiologia , Animais , Apomorfina/farmacologia , Benzamidas/farmacologia , Condicionamento Operante/efeitos dos fármacos , Condicionamento Operante/fisiologia , Discriminação Psicológica/fisiologia , Eletrochoque , Indóis/farmacologia , Lisurida/farmacologia , Masculino , Piperidinas/farmacologia , Piridinas/farmacologia , Quimpirol/farmacologia , Racloprida/farmacologia , Ratos Sprague-Dawley , Reforço Psicológico
11.
Psychopharmacology (Berl) ; 231(4): 651-62, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24057816

RESUMO

RATIONALE: Inactivating dopamine (DA) receptors in the caudate-putamen (CPu) attenuates basal and DA agonist-induced behaviors of adult rats while paradoxically increasing the locomotor activity of preweanling rats. OBJECTIVE: The purpose of this study was to determine (a) whether D1 or D2 receptor inactivation is responsible for the elevated locomotion shown by preweanling rats and (b) whether DA receptor inactivation produces a general state in which any locomotor-activating drug will cause a potentiated behavioral response. METHODS: Dimethyl sulfoxide (DMSO) or N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) was bilaterally infused into the CPu on postnatal day (PD) 17. In experiment 1, DA receptors were selectively protected from EEDQ-induced alkylation by pretreating rats with D1 and/or D2 antagonists. On PD 18, rats received bilateral microinjections of the DA agonist R(-)-propylnorapomorphine into the dorsal CPu, and locomotor activity was measured for 40 min. In subsequent experiments, the locomotion of DMSO- and EEDQ-pretreated rats was assessed after intraCPu infusions of the selective DA agonists SKF82958 and quinpirole, the partial agonist terguride, or after systemic administration of nonDAergic compounds. RESULTS: Experiment 1 showed that EEDQ's ability to enhance the locomotor activity of preweanling rats was primarily due to the inactivation of D2 receptors. Consistent with this finding, only drugs that directly or indirectly stimulated D2 receptors produced a potentiated locomotor response in EEDQ-treated rats. CONCLUSIONS: These results show that DA receptor inactivation causes dramatically different behavioral effects in preweanling and adult rats, thus providing additional evidence that the D2 receptor system is not functionally mature by the end of the preweanling period.


Assuntos
Núcleo Caudado/metabolismo , Putamen/metabolismo , Receptores de Dopamina D2/metabolismo , Envelhecimento , Alquilantes/farmacologia , Animais , Apomorfina/análogos & derivados , Apomorfina/farmacologia , Benzazepinas/farmacologia , Núcleo Caudado/efeitos dos fármacos , Núcleo Caudado/crescimento & desenvolvimento , Dimetil Sulfóxido/farmacologia , Agonistas de Dopamina/farmacologia , Antagonistas de Dopamina/farmacologia , Antagonistas dos Receptores de Dopamina D2 , Feminino , Lisurida/análogos & derivados , Lisurida/farmacologia , Masculino , Atividade Motora/efeitos dos fármacos , Atividade Motora/fisiologia , Putamen/efeitos dos fármacos , Putamen/crescimento & desenvolvimento , Quinolinas/farmacologia , Quimpirol/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores de Dopamina D1/agonistas , Receptores de Dopamina D1/antagonistas & inibidores , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D2/agonistas , Desmame
12.
Artigo em Inglês | MEDLINE | ID: mdl-23909604

RESUMO

Cutaneous fibrosis seen in systemic sclerosis (SSc) is a generalized connective tissue disorder, characterized by a wide spectrum of microvascular and immunological abnormalities. Serotonin (5-hydroxytryptamine; 5-HT) is a neurotransmitter and immune modulator, is also an important mediator of bidirectional interactions between the vasoactive amines and the skin.5-HT, a commonly secreted amine, is a known inducer of fibrosis, although the mechanistic basis for it and growth factors regulating fibrosis and proliferation in the microenvironment are unclear. We review that as serotonin has powerful vasodilator, immunomodulator, and growth factor actions, this pathway could be involved in skin fibrotic. Since serotoninergic system play a role in skin fibrotic, and 5-HTs drugs, an usual treatment for this type of patients. These provides a future perspective for research and drug development.


Assuntos
Agonistas de Dopamina/uso terapêutico , Lisurida/análogos & derivados , Escleroderma Sistêmico/tratamento farmacológico , Inibidores de Captação de Serotonina/uso terapêutico , Serotonina/metabolismo , Pele/patologia , Animais , Processos de Crescimento Celular/efeitos dos fármacos , Fibrose , Humanos , Lisurida/uso terapêutico , Medicina de Precisão , Receptor 5-HT1A de Serotonina/metabolismo , Pele/efeitos dos fármacos
13.
J Pharmacol Exp Ther ; 347(1): 57-68, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23863695

RESUMO

Dopaminergic, serotonergic, and adrenergic receptors are targets for therapeutic actions in schizophrenia. Dopamine D2 receptor partial agonists such as aripiprazole represent a treatment option for patients with this severe disorder. The ineffectiveness of terguride, another D2 receptor partial agonist, in treating schizophrenia was recently attributed to its considerably high intrinsic activity at D2 receptors. In this study, we used functional assays for recombinant D2 receptors and native 5-hydroxytryptamine 2A (5-HT2A), α2C-adrenergic, and histamine H1 receptors to compare the pharmacological properties of terguride and three of its halogenated derivatives (2-chloro-, 2-bromo-, 2-iodoterguride) with those of aripiprazole. Subsequently, we studied the antidopaminergic effects of 2-bromoterguride using amphetamine-induced locomotion (AIL). Its influence on spontaneous behavior was tested in the open field. Extrapyramidal side effect (EPS) liability was evaluated by catalepsy test. In a guanosine 5'-O-(3-[(35)S]thio)triphosphate ([(35)S]GTPγS) binding assay, 2-chloro-, 2-bromo-, and 2-iodoterguride produced intrinsic activities at human D2short (hD2S) receptors that were half as high as the intrinsic activity for terguride; aripiprazole lacked agonist activity. 2-Bromoterguride and aripiprazole activated D2S receptor-mediated inhibition of cAMP accumulation to the same extent; intrinsic activity was half as high as that of terguride. All compounds tested behaved as antagonists at human D2long/Gαo (hD2L/Gαo) receptors. Compared with aripiprazole, terguride and its derivatives displayed higher affinity at porcine 5-HT2A receptors and α2C-adrenoceptors and lower affinity at H1 receptors. 2-Bromoterguride inhibited AIL and did not induce catalepsy in rats. Because of its in vitro and in vivo properties, 2-bromoterguride may be a strong candidate for the treatment of schizophrenia with a lower risk to induce EPS.


Assuntos
Antipsicóticos/administração & dosagem , Antipsicóticos/metabolismo , Agonistas de Dopamina/metabolismo , Lisurida/análogos & derivados , Receptor 5-HT2A de Serotonina/metabolismo , Receptor 5-HT2C de Serotonina/metabolismo , Receptores de Dopamina D2/metabolismo , Animais , Células CHO , Vasos Coronários/efeitos dos fármacos , Vasos Coronários/metabolismo , Cricetinae , Cricetulus , Agonistas de Dopamina/química , Agonistas de Dopamina/farmacologia , Células HEK293 , Humanos , Lisurida/química , Lisurida/metabolismo , Lisurida/farmacologia , Masculino , Atividade Motora/efeitos dos fármacos , Atividade Motora/fisiologia , Técnicas de Cultura de Órgãos , Ligação Proteica/efeitos dos fármacos , Ligação Proteica/fisiologia , Ratos , Ratos Sprague-Dawley , Receptores de Dopamina D2/agonistas , Suínos
14.
Expert Opin Drug Metab Toxicol ; 9(7): 859-74, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23565891

RESUMO

INTRODUCTION: The development of pharmacogenetic-based clinical practice guidelines for the use of anti-Parkinson's disease drugs requires, as a pre-requisite, the identification and validation of genetic biomarkers. These biomarkers are then used as surrogate endpoints. This review analyzes potential genetic biomarkers which can be used to improve anti-Parkinson's disease therapy. AREAS COVERED: The authors present an overview of current knowledge of pharmacogenetic implications of anti-Parkinson's disease drugs, including genes coding for the corresponding drug-metabolizing enzymes and drug targets. The gene/drug pairings with the strongest potential for pharmacogenetic recommendations include: CYP2C19/benztropine, COMT/levodopa and entacapone, CYP2B6/selegiline, UGT1A/entacapone, DRD2/ropinirole, pramipexole and cabergoline, and DRD3/ropinirole and pramipexole. Evidence supporting the effect of substrates, inhibitor or inducers for drug specific metabolizing enzymes in anti-Parkinson's disease drug response includes CYP1A2 in the response to ropinirole and rasagiline, and CYP3A4 in the response to bromocriptine, lisuride, pergolide and cabergoline. The authors present and discuss the current information on gene variations according to the 1000 genomes catalog and other databases with regards to anti-Parkinson's disease drugs. They also review and discuss the clinical implications of these variations. EXPERT OPINION: The goal of pharmacogenomic testing for anti-Parkinson's disease drugs should be conservative and aimed at selecting determined drugs for determined patients. However, much additional research is still needed to obtain reliable pre-prescription tests.


Assuntos
Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/genética , Farmacogenética , Hidrocarboneto de Aril Hidroxilases/genética , Hidrocarboneto de Aril Hidroxilases/metabolismo , Benzotiazóis/uso terapêutico , Benzotropina/uso terapêutico , Bromocriptina/uso terapêutico , Cabergolina , Catecóis/uso terapêutico , Citocromo P-450 CYP1A2/metabolismo , Inibidores do Citocromo P-450 CYP1A2 , Citocromo P-450 CYP2B6 , Citocromo P-450 CYP2C19 , Citocromo P-450 CYP3A/genética , Citocromo P-450 CYP3A/metabolismo , Ergolinas/uso terapêutico , Marcadores Genéticos , Humanos , Indanos/uso terapêutico , Indóis/uso terapêutico , Levodopa/uso terapêutico , Lisurida/uso terapêutico , Nitrilos/uso terapêutico , Pergolida/uso terapêutico , Pramipexol , Receptores de Dopamina D2/genética , Receptores de Dopamina D2/metabolismo , Receptores de Dopamina D3/genética , Receptores de Dopamina D3/metabolismo , Reprodutibilidade dos Testes , Selegilina/uso terapêutico
15.
Psychopharmacology (Berl) ; 227(4): 727-39, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23407781

RESUMO

RATIONALE: The head-twitch response (HTR) is a rapid side-to-side rotational head movement that occurs in rats and mice after administration of serotonergic hallucinogens and other 5-HT2A agonists. The HTR is widely used as a behavioral assay for 5-HT2A activation and to probe for interactions between the 5-HT2A receptor and other transmitter systems. OBJECTIVE: High-speed video recordings were used to analyze the head movement that occurs during head twitches in C57BL/6J mice. Experiments were also conducted in C57BL/6J mice to determine whether a head-mounted magnet and a magnetometer coil could be used to detect the HTR induced by serotonergic hallucinations based on the dynamics of the response. RESULTS: Head movement during the HTR was highly rhythmic and occurred within a specific frequency range (mean head movement frequency of 90.3 Hz). Head twitches produced wave-like oscillations of magnetometer coil voltage that matched the frequency of head movement during the response. The magnetometer coil detected the HTR induced by the serotonergic hallucinogens 2,5-dimethoxy-4-iodoamphetamine (DOI; 0.25, 0.5, and 1.0 mg/kg, i.p.) and lysergic acid diethylamide (LSD; 0.05, 0.1, 0.2, and 0.4 mg/kg, i.p.) with extremely high sensitivity and specificity. Magnetometer coil recordings demonstrated that the non-hallucinogenic compounds (+)-amphetamine (2.5 and 5.0 mg/kg, i.p.) and lisuride (0.8, 1.6, and 3.2 mg/kg, i.p.) did not induce the HTR. CONCLUSIONS: These studies confirm that a magnetometer coil can be used to detect the HTR induced by hallucinogens. The use of magnetometer-based HTR detection provides a high-throughput, semi-automated assay for this behavior, and offers several advantages over traditional assessment methods.


Assuntos
Anfetaminas/farmacologia , Comportamento Animal/efeitos dos fármacos , Alucinógenos/farmacologia , Dietilamida do Ácido Lisérgico/farmacologia , Anfetamina/administração & dosagem , Anfetamina/farmacologia , Anfetaminas/administração & dosagem , Animais , Alucinógenos/administração & dosagem , Movimentos da Cabeça/efeitos dos fármacos , Ensaios de Triagem em Larga Escala/métodos , Lisurida/administração & dosagem , Lisurida/farmacologia , Dietilamida do Ácido Lisérgico/administração & dosagem , Magnetometria , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Sensibilidade e Especificidade , Gravação em Vídeo
16.
Eur Respir Rev ; 21(126): 321-7, 2012 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-23204120

RESUMO

It is well established that the endothelin, nitric oxide and prostacyclin pathways play an important role in the development of pulmonary arterial hypertension (PAH). Indeed, the therapeutic options currently available for the management of PAH all act on one of these mechanistic pathways. However, this is an exciting time for both clinicians and scientists, as increased understanding of the mechanisms involved in the pathogenesis and progression of PAH has resulted in the development of a number of novel therapeutic options. This article highlights how the introduction of new compounds such as macitentan, riociguat and selexipag, which act on the endothelin, nitric oxide and prostacyclin pathways, respectively, have the potential to further improve the prognosis for patients with PAH.


Assuntos
Hipertensão Pulmonar/tratamento farmacológico , Hipertensão Pulmonar/metabolismo , Acetamidas/uso terapêutico , Animais , Anti-Hipertensivos/uso terapêutico , Benzamidas/uso terapêutico , Ensaios Clínicos como Assunto , Drogas em Investigação , Antagonistas do Receptor de Endotelina A , Antagonistas do Receptor de Endotelina B , Endotelina-1/metabolismo , Epoprostenol/análogos & derivados , Epoprostenol/metabolismo , Epoprostenol/uso terapêutico , Guanilato Ciclase/antagonistas & inibidores , Humanos , Mesilato de Imatinib , Lisurida/análogos & derivados , Lisurida/uso terapêutico , Óxido Nítrico/metabolismo , Inibidores da Fosfodiesterase 5/uso terapêutico , Piperazinas/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Pirazinas/uso terapêutico , Pirazóis/uso terapêutico , Pirimidinas/uso terapêutico , Antagonistas da Serotonina/uso terapêutico , Sulfonamidas/uso terapêutico
17.
Cerebellum ; 11(4): 1051-6, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-22477456

RESUMO

Periodic leg movements (PLMs) are a common sleep disorder in spinocerebellar ataxia type 2 (SCA2) being associated to higher disease severity and altered sleep patterns. To assess the efficacy and safety of lisuride for the treatment of PLMs in SCA2 patients, an open-label clinical trial was conducted in 12 SCA2 patients suffering from PLMs associated to other subjective sleep complaints. All subjects received 0.1 mg of oral lisuride daily for 4 weeks. Primary outcome measure was the change of PLMs index. Changes in the subjective sleep quality, other polysomnographical sleep parameters, Scale for the Assessment and Rating of Ataxia score, and saccadic velocity were assessed as secondary outcome parameters. Safety assessments included hemoglobin, hematocrit, cholesterol, creatinine, and TGP. A significant decrease in both the PLMs index and R stage latency were observed during the treatment, associated to subjective improvement of frequent awakenings, early insomnia, restless leg syndrome, and nocturnal limb paresthesias in most cases. Ataxia score and saccadic pathology were unchanged. No significantly adverse events were observed. Our study suggests the efficacy of dopamine agonist therapy in the treatment of PLMs in SCA2, improving various subjective sleep complaints. These findings serve to promote the adequate management of sleep-related disorders in SCA2, which could improve the life quality of the patients.


Assuntos
Agonistas de Dopamina/uso terapêutico , Perna (Membro)/fisiopatologia , Lisurida/uso terapêutico , Síndrome das Pernas Inquietas/tratamento farmacológico , Ataxias Espinocerebelares/tratamento farmacológico , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Polissonografia/métodos , Síndrome das Pernas Inquietas/etiologia , Sono/fisiologia , Ataxias Espinocerebelares/complicações
18.
J Pharmacol Exp Ther ; 340(2): 369-76, 2012 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-22049464

RESUMO

Serotonin (5-hydroxytryptamine; 5-HT) is involved in heart valve tissue fibrosis, pulmonary arterial fibrosis, and pulmonary hypertension. We aimed at characterizing the antiserotonergic properties of the ergot alkaloid derivative terguride [1,1-diethyl-3-(6-methyl-8α-ergolinyl)urea] by using functional receptor assays and valvular interstitial cell culture. Terguride showed no vasoconstrictor effect in porcine coronary arteries (5-HT(2A) receptor bioassay) and no relaxant effect in porcine pulmonary arteries (5-HT(2B) receptor bioassay). Terguride behaved as a potent antagonist at 5-HT(2A) receptors (noncompetitive antagonist parameter pD'2 9.43) and 5-HT(2B) receptors (apparent pA2 8.87). Metabolites of terguride (N″-monodeethylterguride and 6-norterguride) lacked agonism at both sites. N″-monodeethylterguride and 6-norterguride were surmountable antagonists at 5-HT(2A) receptors (pA2 7.82 and 7.85, respectively) and 5-HT(2B) receptors (pA2 7.30 and 7.11, respectively). Kinetic studies on the effects of terguride in pulmonary arteries showed that the rate to reach drug-receptor equilibrium for terguride was fast. Washout experiments showed that terguride easily disappeared from the receptor biophase. Pretreatment with terguride inhibited 5-HT-induced amplification of ADP-stimulated human platelet aggregation (IC50 16 nM). In porcine valvular interstitial cells, 5-HT-induced activation of extracellular signal-regulated kinase (ERK) 1/2, an initiator of cellular proliferation and activity, was blocked by terguride as shown by Western blotting. In these cells, the stimulatory effect of 5-HT on [³H]proline incorporation (index of extracellular matrix collagen) was blocked by terguride. Because of the inhibition of both 5-HT(2A) and 5-HT(2B) receptors, platelet aggregation, and cellular proliferation and activity (ERK1/2 phosphorylation and collagen production) terguride may have therapeutic potential in the treatment of fibrotic disorders.


Assuntos
Vasos Sanguíneos/efeitos dos fármacos , Valvas Cardíacas/citologia , Lisurida/análogos & derivados , Agregação Plaquetária/efeitos dos fármacos , Antagonistas do Receptor 5-HT2 de Serotonina/farmacologia , Ácido 15-Hidroxi-11 alfa,9 alfa-(epoximetano)prosta-5,13-dienoico/farmacologia , Difosfato de Adenosina/farmacologia , Animais , Valva Aórtica/citologia , Vasos Sanguíneos/fisiologia , Células Cultivadas , Colágeno/biossíntese , Vasos Coronários/efeitos dos fármacos , Vasos Coronários/fisiologia , Relação Dose-Resposta a Droga , Humanos , Técnicas In Vitro , Concentração Inibidora 50 , Ketanserina/farmacologia , Cinética , Lisurida/metabolismo , Lisurida/farmacologia , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Valva Mitral/citologia , Fosforilação/efeitos dos fármacos , Artéria Pulmonar/efeitos dos fármacos , Artéria Pulmonar/fisiologia , Serotonina/farmacologia , Antagonistas do Receptor 5-HT2 de Serotonina/metabolismo , Sus scrofa , Vasoconstrição/efeitos dos fármacos , Vasoconstrição/fisiologia , Vasodilatação/efeitos dos fármacos , Vasodilatação/fisiologia
19.
J Gynecol Obstet Biol Reprod (Paris) ; 41(2): 167-73, 2012 Apr.
Artigo em Francês | MEDLINE | ID: mdl-22000685

RESUMO

OBJECTIVES: To provide an overview of ergot derivatives prescription for lactation inhibition in France, either label (bromocriptine 2.5mg and lisuride 0.2mg) or off-label prescription (dihydroergocryptine and cabergoline). PATIENTS AND METHODS: Analysis based on a questionnaire sent to all 618 French maternity wards in 2009, and prescription modalities from social security reimbursement data in the Rhône-Alpes region. RESULTS: The mean response rate to the questionnaire was 43% and main characteristics of respondents in this sample were very close to those found at the national level. The use of bromocriptine (89%) was the most frequently proposed. Dihydroergocryptine and cabergoline were mentioned as first or second alternatives in 39 and 24% of cases, respectively. Lisuride, homeopathy and phytotherapy were very rarely mentioned. The analysis of social security reimbursement data in the Rhône-Alpes region between 2008 and 2009 evidenced an increase in the rate of dihydroergocryptine prescriptions (from 37 to 46%), which were more frequent in women also treated with cardiovascular or psychotropic drugs, while that of bromocriptine decreased. CONCLUSION: This study shows that, in France, the main alternative to bromocriptine for lactation inhibition is the off-label use of dihydroergocryptine followed by cabergoline, which seems to be safer.


Assuntos
Alcaloides de Claviceps/administração & dosagem , Lactação/efeitos dos fármacos , Padrões de Prática Médica/estatística & dados numéricos , Bromocriptina/administração & dosagem , Cabergolina , Di-Hidroergocriptina/administração & dosagem , Agonistas de Dopamina/administração & dosagem , Ergolinas/administração & dosagem , Feminino , França , Humanos , Lisurida/administração & dosagem , Prolactina/antagonistas & inibidores , Prolactina/metabolismo , Inquéritos e Questionários
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA