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Pesquisa : D12.776.543.750.720.600.860 [Categoria DeCS]
Referências encontradas : 616 [refinar]
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[PMID]:29305326
[Au] Autor:Fernandez MO; Bourguignon NS; Arocena P; Rosa M; Libertun C; Lux-Lantos V
[Ad] Endereço:Consejo Nacional de Investigaciones Cientificas y Técnicas, Instituto de Biología y Medicina Experimental, Vuelta de Obligado 2490, CABA, Argentina. Electronic address: mfernandez@dna.uba.ar.
[Ti] Título:Neonatal exposure to bisphenol A alters the hypothalamic-pituitary-thyroid axis in female rats.
[So] Source:Toxicol Lett;285:81-86, 2018 Mar 15.
[Is] ISSN:1879-3169
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Bisphenol A (BPA) is a component of polycarbonate plastics, epoxy resins and polystyrene found in many common products. Several reports revealed potent in vivo and in vitro effects. In this study we analyzed the effects of the exposure to BPA in the hypothalamic-pituitary-thyroid axis in female rats, both in vivo and in vitro. Female Sprague-Dawley rats were injected sc from postnatal day 1 (PND1) to PND10 with BPA: 500 µg 50 µl oil (B500), or 50 µg 50 µl (B50), or 5 µg 50 µl (B5). Controls were injected with 50 µl vehicle during the same period. Neonatal exposure to BPA did not modify TSH levels in PND13 females, but it increased them in adults in estrus. Serum T4 was lower in B5 and B500 with regards to Control, whereas no difference was seen in T3. No significant differences were observed in TRH, TSHß and TRH receptor expression between groups. TSH release from PPC obtained from adults in estrus was also higher in B50 with regard to Control. In vitro 24 h pre-treatment with BPA or E increased basal TSH as well as prolactin release. On the other hand, both BPA and E lowered the response to TRH. The results presented here show that the neonatal exposure to BPA alters the hypothalamic pituitary-thyroid axis in adult rats in estrus, possibly with effects on the pituitary and thyroid. They also show that BPA alters TSH release from rat PPC through direct actions on the pituitary.
[Mh] Termos MeSH primário: Compostos Benzidrílicos/toxicidade
Disruptores Endócrinos/toxicidade
Hipotálamo/efeitos dos fármacos
Fenóis/toxicidade
Hipófise/efeitos dos fármacos
Glândula Tireoide/efeitos dos fármacos
[Mh] Termos MeSH secundário: Envelhecimento/sangue
Envelhecimento/efeitos dos fármacos
Animais
Animais Recém-Nascidos
Células Cultivadas
Relação Dose-Resposta a Droga
Feminino
Hipotálamo/crescimento & desenvolvimento
Hipotálamo/metabolismo
Hipófise/crescimento & desenvolvimento
Hipófise/metabolismo
Ratos Sprague-Dawley
Receptores do Hormônio Liberador da Tireotropina/genética
Receptores do Hormônio Liberador da Tireotropina/metabolismo
Glândula Tireoide/crescimento & desenvolvimento
Glândula Tireoide/metabolismo
Tireotropina/sangue
Tireotropina/genética
Hormônio Liberador de Tireotropina/sangue
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Benzhydryl Compounds); 0 (Endocrine Disruptors); 0 (Phenols); 0 (Receptors, Thyrotropin-Releasing Hormone); 5Y5F15120W (Thyrotropin-Releasing Hormone); 9002-71-5 (Thyrotropin); MLT3645I99 (bisphenol A)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180219
[Lr] Data última revisão:
180219
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180107
[St] Status:MEDLINE


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[PMID]:28419241
[Au] Autor:García M; González de Buitrago J; Jiménez-Rosés M; Pardo L; Hinkle PM; Moreno JC
[Ad] Endereço:Thyroid Molecular Laboratory, Institute for Medical and Molecular Genetics, La Paz University Hospital, Autonomous University of Madrid, 28046 Madrid, Spain.
[Ti] Título:Central Hypothyroidism Due to a TRHR Mutation Causing Impaired Ligand Affinity and Transactivation of Gq.
[So] Source:J Clin Endocrinol Metab;102(7):2433-2442, 2017 Jul 01.
[Is] ISSN:1945-7197
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Context: Central congenital hypothyroidism (CCH) is an underdiagnosed disorder characterized by deficient production and bioactivity of thyroid-stimulating hormone (TSH) leading to low thyroid hormone synthesis. Thyrotropin-releasing hormone (TRH) receptor (TRHR) defects are rare recessive disorders usually associated with incidentally identified CCH and short stature in childhood. Objectives: Clinical and genetic characterization of a consanguineous family of Roma origin with central hypothyroidism and identification of underlying molecular mechanisms. Design: All family members were phenotyped with thyroid hormone profiles, pituitary magnetic resonance imaging, TRH tests, and dynamic tests for other pituitary hormones. Candidate TRH, TRHR, TSHB, and IGSF1 genes were screened for mutations. A mutant TRHR was characterized in vitro and by molecular modeling. Results: A homozygous missense mutation in TRHR (c.392T > C; p.I131T) was identified in an 8-year-old boy with moderate hypothyroidism (TSH: 2.61 mIU/L, Normal: 0.27 to 4.2; free thyroxine: 9.52 pmol/L, Normal: 10.9 to 25.7) who was overweight (body mass index: 20.4 kg/m2, p91) but had normal stature (122 cm; -0.58 standard deviation). His mother, two brothers, and grandmother were heterozygous for the mutation with isolated hyperthyrotropinemia (TSH: 4.3 to 8 mIU/L). The I131T mutation, in TRHR intracellular loop 2, decreases TRH affinity and increases the half-maximal effective concentration for signaling. Modeling of TRHR-Gq complexes predicts that the mutation disrupts the interaction between receptor and a hydrophobic pocket formed by Gq. Conclusions: A unique missense TRHR defect identified in a consanguineous family is associated with central hypothyroidism in homozygotes and hyperthyrotropinemia in heterozygotes, suggesting compensatory elevation of TSH with reduced biopotency. The I131T mutation decreases TRH binding and TRHR-Gq coupling and signaling.
[Mh] Termos MeSH primário: Hipotireoidismo Congênito/genética
Predisposição Genética para Doença
Receptores do Hormônio Liberador da Tireotropina/genética
Ativação Transcricional/genética
[Mh] Termos MeSH secundário: Criança
Simulação por Computador
Hipotireoidismo Congênito/diagnóstico
Subunidades alfa Gq-G11 de Proteínas de Ligação ao GTP/genética
Seres Humanos
Masculino
Mutação de Sentido Incorreto
Linhagem
Doenças Raras
Testes de Função Tireóidea
Tireotropina/metabolismo
[Pt] Tipo de publicação:CASE REPORTS; JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Receptors, Thyrotropin-Releasing Hormone); 9002-71-5 (Thyrotropin); EC 3.6.5.1 (GTP-Binding Protein alpha Subunits, Gq-G11)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171004
[Lr] Data última revisão:
171004
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170419
[St] Status:MEDLINE
[do] DOI:10.1210/jc.2016-3977


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[PMID]:28324000
[Au] Autor:Turgeon MO; Silander TL; Doycheva D; Liao XH; Rigden M; Ongaro L; Zhou X; Joustra SD; Wit JM; Wade MG; Heuer H; Refetoff S; Bernard DJ
[Ad] Endereço:Department of Anatomy and Cell Biology, McGill University, Montreal, Quebec, Canada.
[Ti] Título:TRH Action Is Impaired in Pituitaries of Male IGSF1-Deficient Mice.
[So] Source:Endocrinology;158(4):815-830, 2017 04 01.
[Is] ISSN:1945-7170
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Loss-of-function mutations in the X-linked immunoglobulin superfamily, member 1 (IGSF1) gene cause central hypothyroidism. IGSF1 is a transmembrane glycoprotein of unknown function expressed in thyrotropin (TSH)-producing thyrotrope cells of the anterior pituitary gland. The protein is cotranslationally cleaved, with only its C-terminal domain (CTD) being trafficked to the plasma membrane. Most intragenic IGSF1 mutations in humans map to the CTD. In this study, we used CRISPR-Cas9 to introduce a loss-of-function mutation into the IGSF1-CTD in mice. The modified allele encodes a truncated protein that fails to traffic to the plasma membrane. Under standard laboratory conditions, Igsf1-deficient males exhibit normal serum TSH levels as well as normal numbers of TSH-expressing thyrotropes. However, pituitary expression of the TSH subunit genes and TSH protein content are reduced, as is expression of the receptor for thyrotropin-releasing hormone (TRH). When challenged with exogenous TRH, Igsf1-deficient males release TSH, but to a significantly lesser extent than do their wild-type littermates. The mice show similarly attenuated TSH secretion when rendered profoundly hypothyroid with a low iodine diet supplemented with propylthiouracil. Collectively, these results indicate that impairments in pituitary TRH receptor expression and/or downstream signaling underlie central hypothyroidism in IGSF1 deficiency syndrome.
[Mh] Termos MeSH primário: Imunoglobulinas/genética
Proteínas de Membrana/genética
Hipófise/metabolismo
Receptores do Hormônio Liberador da Tireotropina/metabolismo
Hormônio Liberador de Tireotropina/metabolismo
Tireotropina/metabolismo
[Mh] Termos MeSH secundário: Animais
Imunoglobulinas/metabolismo
Masculino
Proteínas de Membrana/metabolismo
Camundongos
Camundongos Knockout
Receptores do Hormônio Liberador da Tireotropina/genética
Transdução de Sinais/fisiologia
Tireotropina/genética
Hormônio Liberador de Tireotropina/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Immunoglobulins); 0 (Membrane Proteins); 0 (Receptors, Thyrotropin-Releasing Hormone); 5Y5F15120W (Thyrotropin-Releasing Hormone); 9002-71-5 (Thyrotropin)
[Em] Mês de entrada:1704
[Cu] Atualização por classe:170719
[Lr] Data última revisão:
170719
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170322
[St] Status:MEDLINE
[do] DOI:10.1210/en.2016-1788


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[PMID]:27629718
[Au] Autor:Rosa JM; Morrie RD; Baertsch HC; Feller MB
[Ad] Endereço:Department of Molecular and Cell Biology and.
[Ti] Título:Contributions of Rod and Cone Pathways to Retinal Direction Selectivity Through Development.
[So] Source:J Neurosci;36(37):9683-95, 2016 Sep 14.
[Is] ISSN:1529-2401
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:UNLABELLED: Direction selectivity is a robust computation across a broad stimulus space that is mediated by activity of both rod and cone photoreceptors through the ON and OFF pathways. However, rods, S-cones, and M-cones activate the ON and OFF circuits via distinct pathways and the relative contribution of each to direction selectivity is unknown. Using a variety of stimulation paradigms, pharmacological agents, and knockout mice that lack rod transduction, we found that inputs from the ON pathway were critical for strong direction-selective (DS) tuning in the OFF pathway. For UV light stimulation, the ON pathway inputs to the OFF pathway originated with rod signaling, whereas for visible stimulation, the ON pathway inputs to the OFF pathway originated with both rod and M-cone signaling. Whole-cell voltage-clamp recordings revealed that blocking the ON pathway reduced directional tuning in the OFF pathway via a reduction in null-side inhibition, which is provided by OFF starburst amacrine cells (SACs). Consistent with this, our recordings from OFF SACs confirmed that signals originating in the ON pathway contribute to their excitation. Finally, we observed that, for UV stimulation, ON contributions to OFF DS tuning matured earlier than direct signaling via the OFF pathway. These data indicate that the retina uses multiple strategies for computing DS responses across different colors and stages of development. SIGNIFICANCE STATEMENT: The retina uses parallel pathways to encode different features of the visual scene. In some cases, these distinct pathways converge on circuits that mediate a distinct computation. For example, rod and cone pathways enable direction-selective (DS) ganglion cells to encode motion over a wide range of light intensities. Here, we show that although direction selectivity is robust across light intensities, motion discrimination for OFF signals is dependent upon ON signaling. At eye opening, ON directional tuning is mature, whereas OFF DS tuning is significantly reduced due to a delayed maturation of S-cone to OFF cone bipolar signaling. These results provide evidence that the retina uses multiple strategies for computing DS responses across different stimulus conditions.
[Mh] Termos MeSH primário: Orientação/fisiologia
Retina/citologia
Células Fotorreceptoras Retinianas Cones/fisiologia
Células Fotorreceptoras Retinianas Bastonetes/fisiologia
Vias Visuais/fisiologia
[Mh] Termos MeSH secundário: Potenciais de Ação
Animais
Opsinas dos Cones/metabolismo
Luz
Transdução de Sinal Luminoso/efeitos dos fármacos
Camundongos
Camundongos Endogâmicos C57BL
Camundongos Transgênicos
Estimulação Luminosa
Receptores de AMPA/genética
Receptores de AMPA/metabolismo
Receptores de Interleucina-2/genética
Receptores de Interleucina-2/metabolismo
Receptores do Hormônio Liberador da Tireotropina/genética
Receptores do Hormônio Liberador da Tireotropina/metabolismo
Células Ganglionares da Retina
Opsinas de Bastonetes/metabolismo
Potenciais Sinápticos/fisiologia
Raios Ultravioleta
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Cone Opsins); 0 (Receptors, AMPA); 0 (Receptors, Interleukin-2); 0 (Receptors, Thyrotropin-Releasing Hormone); 0 (Rod Opsins); 0 (glutamate receptor ionotropic, AMPA 2)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170822
[Lr] Data última revisão:
170822
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160916
[St] Status:MEDLINE
[do] DOI:10.1523/JNEUROSCI.3824-15.2016


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[PMID]:26854379
[Au] Autor:Meena CL; Thakur A; Nandekar PP; Sharma SS; Sangamwar AT; Jain R
[Ad] Endereço:Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research, Sector 67, S. A. S. Nagar, Punjab 160 062, India.
[Ti] Título:Synthesis and biology of ring-modified l-Histidine containing thyrotropin-releasing hormone (TRH) analogues.
[So] Source:Eur J Med Chem;111:72-83, 2016 Mar 23.
[Is] ISSN:1768-3254
[Cp] País de publicação:France
[La] Idioma:eng
[Ab] Resumo:Thyrotropin-releasing hormone (TRH) analogues bearing halogen groups (Cl, Br and I) at the C-2 and/or C-5 position, and the alkyl group (CH3, C2H5, C3H7, CH2C6H5) at the N-1 position of the imidazole ring of the central histidine residue were synthesized and evaluated for the receptor binding, calcium mobilization (FLIPR), and IP-1 assay at the HEK mTRHR1 and HEK mTRHR2 expressing cell lines. The most promising analogue 7k showed 925-fold selectivity for HEK mTRH-R2 receptor subtype in the IP-1 assay, 272-fold selectivity for HEK mTRH-R2 receptor subtype in the FLIPR assay, and 21-fold receptor binding specificity at HEK TRH-R2 receptor subtype. The peptide 7k was evaluated in vitro in a brain membrane competitive binding assay, and for stability analysis in the presence of TRH-DE, in vivo. The analogue 7k showed decrease in the sleeping time by more than 76% in a pentobarbital-induced sleeping assay, and showed comparatively less elevation in the TSH level in the blood, in vivo. The computational homology modeling of TRH-R1 and TRH-R2 and docking study with the most potent peptide 7k provide impetus to design CNS specific TRH analogues.
[Mh] Termos MeSH primário: Histidina/metabolismo
Hormônio Liberador de Tireotropina/análogos & derivados
Hormônio Liberador de Tireotropina/metabolismo
[Mh] Termos MeSH secundário: Células HEK293
Histidina/química
Seres Humanos
Modelos Moleculares
Conformação Molecular
Receptores do Hormônio Liberador da Tireotropina/química
Receptores do Hormônio Liberador da Tireotropina/metabolismo
Hormônio Liberador de Tireotropina/química
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Receptors, Thyrotropin-Releasing Hormone); 4QD397987E (Histidine); 5Y5F15120W (Thyrotropin-Releasing Hormone)
[Em] Mês de entrada:1611
[Cu] Atualização por classe:161230
[Lr] Data última revisão:
161230
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160209
[St] Status:MEDLINE


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[PMID]:26735259
[Au] Autor:Koulouri O; Nicholas AK; Schoenmakers E; Mokrosinski J; Lane F; Cole T; Kirk J; Farooqi IS; Chatterjee VK; Gurnell M; Schoenmakers N
[Ad] Endereço:Metabolic Research Laboratories (O.K., A.K.N., E.S., J.M., I.S.F., V.K.C., M.G., N.S.), Wellcome Trust-Medical Research Council Institute of Metabolic Science, University of Cambridge and National Institute for Health Research, Cambridge Biomedical Research Centre, Addenbrooke's Hospital, Cambridge
[Ti] Título:A Novel Thyrotropin-Releasing Hormone Receptor Missense Mutation (P81R) in Central Congenital Hypothyroidism.
[So] Source:J Clin Endocrinol Metab;101(3):847-51, 2016 Mar.
[Is] ISSN:1945-7197
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:CONTEXT: Isolated central congenital hypothyroidism (CCH) is rare and evades diagnosis on TSH-based congenital hypothyroidism (CH) screening programs in the United Kingdom. Accordingly, genetic ascertainment facilitates diagnosis and treatment of familial cases. Recognized causes include TSH ß subunit (TSHB) and Ig superfamily member 1 (IGSF1) mutations, with only two previous reports of biallelic, highly disruptive mutations in the TRH receptor (TRHR) gene. CASE DESCRIPTION: A female infant presenting with prolonged neonatal jaundice was found to have isolated CCH, with TSH of 2.2 mU/L (Reference range, 0.4-3.5) and free T4 of 7.9 pmol/L (0.61 ng/dL) (Reference range, 10.7-21.8 pmol/L). Because TSHB or IGSF1 mutations are usually associated with profound or X-linked CCH, TRHR was sequenced, and a homozygous mutation (p.P81R) was identified, substituting arginine for a highly conserved proline residue in transmembrane helix 2. Functional studies demonstrated normal cell membrane expression and localization of the mutant TRHR; however, its ability to bind radio-labelled TRH and signal via Gqα was markedly impaired, likely due to structural distortion of transmembrane helix 2. CONCLUSIONS: Two previously reported biallelic, highly disruptive (nonsense; R17*, in-frame deletion and single amino acid substitution; p.[S115-T117del; A118T]) TRHR mutations have been associated with CCH; however, we describe the first deleterious, missense TRHR defect associated with this phenotype. Importantly, the location of the mutated amino acid (proline 81) highlights the functional importance of the second transmembrane helix in mediating hormone binding and receptor activation. Future identification of other naturally occurring TRHR mutations will likely offer important insights into the molecular basis of ligand binding and activation of TRHR, which are still poorly understood.
[Mh] Termos MeSH primário: Hipotireoidismo Congênito/genética
Mutação de Sentido Incorreto
Receptores do Hormônio Liberador da Tireotropina/genética
[Mh] Termos MeSH secundário: Feminino
Células HEK293
Seres Humanos
Recém-Nascido
[Pt] Tipo de publicação:CASE REPORTS; JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Receptors, Thyrotropin-Releasing Hormone)
[Em] Mês de entrada:1608
[Cu] Atualização por classe:170922
[Lr] Data última revisão:
170922
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:160107
[St] Status:MEDLINE
[do] DOI:10.1210/jc.2015-3916


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[PMID]:26470810
[Au] Autor:Zhang L; Kolaj M; Renaud LP
[Ad] Endereço:Ottawa Hospital Research Institute, Neuroscience Program and University of Ottawa, Department of Medicine, K1Y 4E9 Ottawa, Canada.
[Ti] Título:Intracellular postsynaptic cannabinoid receptors link thyrotropin-releasing hormone receptors to TRPC-like channels in thalamic paraventricular nucleus neurons.
[So] Source:Neuroscience;311:81-91, 2015 Dec 17.
[Is] ISSN:1873-7544
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:In rat thalamic paraventricular nucleus of thalamus (PVT) neurons, activation of thyrotropin-releasing hormone (TRH) receptors enhances excitability via concurrent decrease in G protein-coupled inwardly-rectifying potassium (GIRK)-like and activation of transient receptor potential cation (TRPC)4/5-like cationic conductances. An exploration of intracellular signaling pathways revealed the TRH-induced current to be insensitive to phosphatidylinositol-specific phospholipase C (PI-PLC) inhibitors, but reduced by D609, an inhibitor of phosphatidylcholine-specific PLC (PC-PLC). A corresponding change in the I-V relationship implied suppression of the cationic component of the TRH-induced current. Diacylglycerol (DAG) is a product of the hydrolysis of PC. Studies focused on the isolated cationic component of the TRH-induced response revealed a reduction by RHC80267, an inhibitor of DAG lipase, the enzyme involved in the hydrolysis of DAG to the endocannabinoid 2-arachidonoylglycerol (2-AG). Further investigation revealed enhancement of the cationic component in the presence of either JZL184 or WWL70, inhibitors of enzymes involved in the hydrolysis of 2-AG. A decrease in the TRH-induced response was noted in the presence of rimonabant or SR144528, membrane permeable CB1 and CB2 receptor antagonists, respectively. A decrease in the TRH-induced current by intracellular, but not by bath application of the membrane impermeable peptide hemopressin, selective for CB1 receptors, suggests a postsynaptic intracellular localization of these receptors. The TRH-induced current was increased in the presence of arachidonyl-2'-chloroethylamide (ACEA) or JWH133, CB1 and CB2 receptor agonists, respectively. The PI3-kinase inhibitor LY294002, known to inhibit TRPC translocation, decreased the response to TRH. In addition, a TRH-induced enhancement of the low-threshold spike was prevented by both rimonabant, and SR144528. TRH had no influence on excitatory or inhibitory miniature postsynaptic currents, suggesting presynaptic CB receptors are not involved in this situation. Collectively, the data imply that activation of TRH receptors in these midline thalamic neurons engages novel signaling pathways that include postsynaptic intracellular CB1 and CB2 receptors in the activation of TRPC4/5-like channels.
[Mh] Termos MeSH primário: Neurônios/fisiologia
Núcleo Hipotalâmico Paraventricular/fisiologia
Receptor CB1 de Canabinoide/metabolismo
Receptor CB2 de Canabinoide/metabolismo
Receptores do Hormônio Liberador da Tireotropina/metabolismo
Canais de Cátion TRPC/metabolismo
[Mh] Termos MeSH secundário: Animais
Espaço Intracelular/efeitos dos fármacos
Espaço Intracelular/metabolismo
Potenciais da Membrana/efeitos dos fármacos
Potenciais da Membrana/fisiologia
Neurônios/efeitos dos fármacos
Neurotransmissores/farmacologia
Núcleo Hipotalâmico Paraventricular/efeitos dos fármacos
Técnicas de Patch-Clamp
Ratos Wistar
Transdução de Sinais/efeitos dos fármacos
Sinapses/efeitos dos fármacos
Sinapses/metabolismo
Hormônio Liberador de Tireotropina/administração & dosagem
Hormônio Liberador de Tireotropina/metabolismo
Técnicas de Cultura de Tecidos
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Cnr1 protein, rat); 0 (Cnr2 protein, rat); 0 (Neurotransmitter Agents); 0 (Receptor, Cannabinoid, CB1); 0 (Receptor, Cannabinoid, CB2); 0 (Receptors, Thyrotropin-Releasing Hormone); 0 (TRPC Cation Channels); 5Y5F15120W (Thyrotropin-Releasing Hormone)
[Em] Mês de entrada:1609
[Cu] Atualização por classe:151128
[Lr] Data última revisão:
151128
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:151017
[St] Status:MEDLINE


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[PMID]:26216015
[Au] Autor:Meena CL; Thakur A; Nandekar PP; Sangamwar AT; Sharma SS; Jain R
[Ad] Endereço:Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research, Sector 67, S.A.S. Nagar, Punjab 160062, India.
[Ti] Título:Synthesis of CNS active thyrotropin-releasing hormone (TRH)-like peptides: Biological evaluation and effect on cognitive impairment induced by cerebral ischemia in mice.
[So] Source:Bioorg Med Chem;23(17):5641-53, 2015 Sep 01.
[Is] ISSN:1464-3391
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Thyrotropin-releasing hormone (TRH)-like peptides were synthesized by replacing critical histidine and pGlu residues in the native peptide. The peptides were evaluated in vitro for receptor binding activity assay and in the cell functional assay; the peptides exhibit selective basal signaling agonist behavior toward TRH-R2. For example, peptides 8a, 8b, 8c, 8 f, 8 h, 8 l and 12 d activated TRH-R2 with potency (EC50) of 0.53 µM, 0.048 µM, 0.05 µM, 0.006 µM, 0.31 µM, 0.034 µM and 0.004 µM, respectively. In contrast for signaling activation of TRH-R1, the same peptide required higher concentration of 19.35 µM, 3.98 µM, 2.54 µM, 0.287 µM, 11.28 µM, 0.986 µM and 0.944 µM, respectively. The results showed that peptides were 36.5, 82.9, 50.8, 47.8, 36.3, 32.6 and 235-fold selective to TRH-R2 receptor subtype. The peptides were investigated for CNS activity at 10 µmol/kg in pentobarbital-induced sleep assay study. Peptides 8c (16.5 ± 1.4 min) and 8l (16.5 ± 2.1 min) displayed excellent CNS activity. In an in vivo study, peptide 8c did not cause significant change in the rat plasma TSH levels. The peptide 8c was further investigated for neuroprotective potential, and significantly reduced infracts volume and neurological score in the focal cerebral ischemia model in mice. Peptide 8c also significantly lowered MDA levels, indicating reduction of oxidative and enhanced percentage cell survival in CA1 region, when compared to ischemic brain.
[Mh] Termos MeSH primário: Transtornos Cognitivos/genética
Peptídeos/metabolismo
Receptores do Hormônio Liberador da Tireotropina/química
Hormônio Liberador de Tireotropina/síntese química
[Mh] Termos MeSH secundário: Animais
Isquemia Encefálica
Camundongos
Estrutura Molecular
Ratos
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Peptides); 0 (Receptors, Thyrotropin-Releasing Hormone); 5Y5F15120W (Thyrotropin-Releasing Hormone)
[Em] Mês de entrada:1606
[Cu] Atualização por classe:150831
[Lr] Data última revisão:
150831
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150729
[St] Status:MEDLINE


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[PMID]:26142830
[Au] Autor:Ijiro T; Nakamura K; Ogata M; Inada H; Kiguchi S; Maruyama K; Nabekura J; Kobayashi M; Ishibashi H
[Ad] Endereço:Pharmacology Research Laboratory R&D, Kissei Pharmaceutical Co., Ltd., 4365-1, Kashiwabara, Hotaka, Azumino Nagano 399-8304, Japan. Electronic address: tomoyuki_ijiro@pharm.kissei.co.jp.
[Ti] Título:Effect of rovatirelin, a novel thyrotropin-releasing hormone analog, on the central noradrenergic system.
[So] Source:Eur J Pharmacol;761:413-22, 2015 Aug 15.
[Is] ISSN:1879-0712
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Rovatirelin ([1-[-[(4S,5S)-(5-methyl-2-oxo oxazolidin-4-yl) carbonyl]-3-(thiazol-4-yl)-l-alanyl]-(2R)-2-methylpyrrolidine) is a novel synthetic agent that mimics the actions of thyrotropin-releasing hormone (TRH). The aim of this study was to investigate the electrophysiological and pharmacological effects of rovatirelin on the central noradrenergic system and to compare the results with those of another TRH mimetic agent, taltirelin, which is approved for the treatment of spinocerebellar degeneration (SCD) in Japan. Rovatirelin binds to the human TRH receptor with higher affinity (Ki=702nM) than taltirelin (Ki=3877nM). Rovatirelin increased the spontaneous firing of action potentials in the acutely isolated noradrenergic neurons of rat locus coeruleus (LC). The facilitatory action of rovatirelin on the firing rate in the LC neurons was inhibited by the TRH receptor antagonist, chlordiazepoxide. Reduction of the extracellular pH increased the spontaneous firing of LC neurons and rovatirelin failed to increase the firing frequency further, indicating an involvement of acid-sensitive K+ channels in the rovatirelin action. In in vivo studies, oral administration of rovatirelin increased both c-Fos expression in the LC and extracellular levels of noradrenaline (NA) in the medial prefrontal cortex (mPFC) of rats. Furthermore, rovatirelin increased locomotor activity. The increase in NA level and locomotor activity by rovatirelin was more potent and longer acting than those by taltirelin. These results indicate that rovatirelin exerts a central nervous system (CNS)-mediated action through the central noradrenergic system, which is more potent than taltirelin. Thus, rovatirelin may have an orally effective therapeutic potential in patients with SCD.
[Mh] Termos MeSH primário: Neurônios Adrenérgicos/efeitos dos fármacos
Locus Cerúleo/efeitos dos fármacos
Oxazolidinonas/farmacologia
Córtex Pré-Frontal/efeitos dos fármacos
Pirrolidinas/farmacologia
Hormônio Liberador de Tireotropina/farmacologia
[Mh] Termos MeSH secundário: Potenciais de Ação
Administração Oral
Neurônios Adrenérgicos/metabolismo
Animais
Relação Dose-Resposta a Droga
Ligantes
Locus Cerúleo/citologia
Locus Cerúleo/metabolismo
Masculino
Microdiálise
Atividade Motora/efeitos dos fármacos
Norepinefrina/metabolismo
Oxazolidinonas/administração & dosagem
Oxazolidinonas/metabolismo
Córtex Pré-Frontal/citologia
Córtex Pré-Frontal/metabolismo
Ligação Proteica
Proteínas Proto-Oncogênicas c-fos/metabolismo
Pirrolidinas/administração & dosagem
Pirrolidinas/metabolismo
Ensaio Radioligante
Ratos Sprague-Dawley
Ratos Wistar
Receptores do Hormônio Liberador da Tireotropina/agonistas
Receptores do Hormônio Liberador da Tireotropina/metabolismo
Hormônio Liberador de Tireotropina/administração & dosagem
Hormônio Liberador de Tireotropina/análogos & derivados
Hormônio Liberador de Tireotropina/metabolismo
Fatores de Tempo
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Ligands); 0 (Oxazolidinones); 0 (Proto-Oncogene Proteins c-fos); 0 (Pyrrolidines); 0 (Receptors, Thyrotropin-Releasing Hormone); 0 (rovatirelin); 103300-74-9 (TA 0910); 5Y5F15120W (Thyrotropin-Releasing Hormone); X4W3ENH1CV (Norepinephrine)
[Em] Mês de entrada:1605
[Cu] Atualização por classe:150810
[Lr] Data última revisão:
150810
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150706
[St] Status:MEDLINE


  10 / 616 MEDLINE  
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[PMID]:26107116
[Au] Autor:Choi J; Kim JE; Kim TK; Park JY; Lee JE; Kim H; Lee EH; Han PL
[Ad] Endereço:Departments of Brain and Cognitive Sciences, Ewha Womans University, Seoul, Republic of Korea.
[Ti] Título:TRH and TRH receptor system in the basolateral amygdala mediate stress-induced depression-like behaviors.
[So] Source:Neuropharmacology;97:346-56, 2015 Oct.
[Is] ISSN:1873-7064
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Chronic stress is a potent risk factor for depression, but the mechanism by which stress causes depression is not fully understood. To investigate the molecular mechanism underlying stress-induced depression, C57BL/6 inbred mice were treated with repeated restraint to induce lasting depressive behavioral changes. Behavioral states of individual animals were evaluated using the forced swim test, which measures psychomotor withdrawals, and the U-field test, which measures sociability. From these behavioral analyses, individual mice that showed depression-like behaviors in both psychomotor withdrawal and sociability tests, and individuals that showed a resiliency to stress-induced depression in both tests were selected. Among the neuropeptides expressed in the amygdala, thyrotropin-releasing hormone (TRH) was identified as being persistently up-regulated in the basolateral amygdala (BLA) in individuals exhibiting severe depressive behaviors in the two behavior tests, but not in individuals displaying a stress resiliency. Activation of TRH receptors by local injection of TRH in the BLA in normal mice produced depressive behaviors, mimicking chronic stress effects, whereas siRNA-mediated suppression of either TRH or TRHR1 in the BLA completely blocked stress-induced depressive symptoms. The TRHR1 agonist, taltirelin, injection in the BLA increased the level of p-ERK, which mimicked the increased p-ERK level in the BLA that was induced by treatment with repeated stress. Stereotaxic injection of U0126, a potent inhibitor of the ERK pathway, within the BLA blocked stress-induced behavioral depression. These results suggest that repeated stress produces lasting depression-like behaviors via the up-regulation of TRH and TRH receptors in the BLA.
[Mh] Termos MeSH primário: Complexo Nuclear Basolateral da Amígdala/metabolismo
Transtorno Depressivo/fisiopatologia
Receptores do Hormônio Liberador da Tireotropina/metabolismo
Estresse Psicológico/fisiopatologia
Hormônio Liberador de Tireotropina/metabolismo
[Mh] Termos MeSH secundário: Animais
Complexo Nuclear Basolateral da Amígdala/efeitos dos fármacos
Complexo Nuclear Basolateral da Amígdala/patologia
Butadienos/farmacologia
Doença Crônica
Transtorno Depressivo/induzido quimicamente
Transtorno Depressivo/tratamento farmacológico
Transtorno Depressivo/etiologia
Transtorno Depressivo/patologia
Modelos Animais de Doenças
Inibidores Enzimáticos/farmacologia
MAP Quinases Reguladas por Sinal Extracelular/antagonistas & inibidores
MAP Quinases Reguladas por Sinal Extracelular/metabolismo
Masculino
Camundongos Endogâmicos C57BL
Nitrilos/farmacologia
Psicotrópicos/farmacologia
RNA Interferente Pequeno
Receptores do Hormônio Liberador da Tireotropina/genética
Restrição Física
Estresse Psicológico/complicações
Estresse Psicológico/patologia
Hormônio Liberador de Tireotropina/agonistas
Hormônio Liberador de Tireotropina/análogos & derivados
Hormônio Liberador de Tireotropina/genética
Hormônio Liberador de Tireotropina/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Butadienes); 0 (Enzyme Inhibitors); 0 (Nitriles); 0 (Psychotropic Drugs); 0 (RNA, Small Interfering); 0 (Receptors, Thyrotropin-Releasing Hormone); 0 (U 0126); 103300-74-9 (TA 0910); 5Y5F15120W (Thyrotropin-Releasing Hormone); EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases)
[Em] Mês de entrada:1605
[Cu] Atualização por classe:150814
[Lr] Data última revisão:
150814
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150625
[St] Status:MEDLINE



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