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Pesquisa : D27.505.519.562.750.100 [Categoria DeCS]
Referências encontradas : 74 [refinar]
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  1 / 74 MEDLINE  
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[PMID]:28949138
[Au] Autor:Lynagh T; Romero-Rojo JL; Lund C; Pless SA
[Ad] Endereço:Center for Biopharmaceuticals, Department of Drug Design and Pharmacology, University of Copenhagen , Jagtvej 160, 2100 Copenhagen, Denmark.
[Ti] Título:Molecular Basis for Allosteric Inhibition of Acid-Sensing Ion Channel 1a by Ibuprofen.
[So] Source:J Med Chem;60(19):8192-8200, 2017 Oct 12.
[Is] ISSN:1520-4804
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:A growing body of evidence links certain aspects of nonsteroidal anti-inflammatory drug (NSAID) pharmacology with acid-sensing ion channels (ASICs), a small family of excitatory neurotransmitter receptors implicated in pain and neuroinflammation. The molecular basis of NSAID inhibition of ASICs has remained unknown, hindering the exploration of this line of therapy. Here, we characterized the mechanism of inhibition, explored the molecular determinants of sensitivity, and sought to establish informative structure-activity relationships, using electrophysiology, site-directed mutagenesis, and voltage-clamp fluorometry. Our results show that ibuprofen is an allosteric inhibitor of ASIC1a, which binds to a crucial site in the agonist transduction pathway and causes conformational changes that oppose channel activation. Ibuprofen inhibits several ASIC subtypes, but certain ibuprofen derivatives show some selectivity for ASIC1a over ASIC2a and vice versa. These results thus define the NSAID/ASIC interaction and pave the way for small-molecule drug design targeting pain and inflammation.
[Mh] Termos MeSH primário: Bloqueadores do Canal Iônico Sensível a Ácido/química
Bloqueadores do Canal Iônico Sensível a Ácido/farmacologia
Canais Iônicos Sensíveis a Ácido/química
Canais Iônicos Sensíveis a Ácido/efeitos dos fármacos
Anti-Inflamatórios não Esteroides/farmacologia
Ibuprofeno/farmacologia
[Mh] Termos MeSH secundário: Regulação Alostérica
Animais
Sítios de Ligação
Embrião de Galinha
Modelos Moleculares
Conformação Proteica
Ratos
Relação Estrutura-Atividade
Xenopus laevis
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Acid Sensing Ion Channel Blockers); 0 (Acid Sensing Ion Channels); 0 (Anti-Inflammatory Agents, Non-Steroidal); 0 (Asic1 protein, rat); WK2XYI10QM (Ibuprofen)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171030
[Lr] Data última revisão:
171030
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170927
[St] Status:MEDLINE
[do] DOI:10.1021/acs.jmedchem.7b01072


  2 / 74 MEDLINE  
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[PMID]:28237818
[Au] Autor:Mukhopadhyay M; Singh A; Sachchidanand S; Bera AK
[Ad] Endereço:Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences Building, Indian Institute of Technology Madras, Chennai 600036, India.
[Ti] Título:Quercetin inhibits acid-sensing ion channels through a putative binding site in the central vestibular region.
[So] Source:Neuroscience;348:264-272, 2017 Apr 21.
[Is] ISSN:1873-7544
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Acid-sensing ion channels (ASICs) are associated with many pathophysiological processes, such as neuronal death during ischemic stroke, epileptic seizure and nociception. However, there is a dearth of ASIC-specific therapeutic blockers. Here we report that quercetin, a plant flavonoid, which is known for its neuroprotective effect, reversibly inhibits homomeric rat ASIC1a, ASIC2a and ASIC3 with an IC of about 2µM. Also, quercetin prevents low pH-induced intracellular calcium rise and cell death in HEK-293 cells, which have endogenous expression of ASIC1a and 2a. The inhibitory effect of quercetin on ASICs is not due to membrane perturbation, as it did not have any effect on other channels, like NMDA receptor, GABA receptor and P2X4 receptor. Unlike quercetin, another flavonoid resveratrol had no effect on ASIC1a. Computational analysis revealed that quercetin binds to the channel in a cavity at the central vestibule, lined by several charged residues like Q276, R369, E373 and E416 in ASIC1a. Mutation of Arg369 to Ala or Glu416 to Gln abolished the inhibitory effect of quercetin on rat ASIC1a completely, while Glu373 to Gln showed reduced sensitivity. Our results raise the possibility of using quercetin for targeting ASICs in vivo.
[Mh] Termos MeSH primário: Bloqueadores do Canal Iônico Sensível a Ácido/farmacologia
Canais Iônicos Sensíveis a Ácido/metabolismo
Neurônios/efeitos dos fármacos
Quercetina/farmacologia
[Mh] Termos MeSH secundário: Animais
Sítios de Ligação
Células CHO
Cálcio/metabolismo
Morte Celular/efeitos dos fármacos
Cricetulus
Células HEK293
Seres Humanos
Modelos Moleculares
Neurônios/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Acid Sensing Ion Channel Blockers); 0 (Acid Sensing Ion Channels); 9IKM0I5T1E (Quercetin); SY7Q814VUP (Calcium)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170926
[Lr] Data última revisão:
170926
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170227
[St] Status:MEDLINE


  3 / 74 MEDLINE  
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[PMID]:27431941
[Au] Autor:Dohke T; Iba K; Hanaka M; Kanaya K; Abe Y; Okazaki S; Yamashita T
[Ad] Endereço:Department of Orthopaedic Surgery, Sapporo Medical University School of Medicine, South 1, West 16, Chuo-ku, Sapporo, 060-8543, Japan.
[Ti] Título:Regional osteoporosis due to osteoclast activation as a trigger for the pain-like behaviors in tail-suspended mice.
[So] Source:J Orthop Res;35(6):1226-1236, 2017 Jun.
[Is] ISSN:1554-527X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Pathological conditions with refractory skeletal pain are often characterized by regional osteoporotic changes such as transient osteoporosis of the hip, regional migratory osteoporosis, or complex regional pain syndrome (CRPS). Our previous study demonstrated that the acidic microenvironment created by osteoclast activation under high bone turnover conditions induced pain-like behaviors in ovariectomized mice through the stimulation of acid-sensing nociceptors. The aim of the present study was to examine whether regional transient osteoporotic changes are related to pain-like behaviors in the hind limb using tail-suspended model mice. The hind limbs of tail-suspended mice were unloaded for 2 weeks, during which time the mice revealed significant regional osteoporotic changes in their hind limbs accompanied by osteoclast activation. In addition, these changes were significantly recovered by the resumption of weight bearing on the hind limbs for 4 weeks. Consistent with the pathological changes in the hind limbs, pain-like behaviors in the mice were induced by tail suspension and recovered by the resumption of weight bearing. Moreover, treatment with bisphosphonate significantly prevented the triggering of the regional osteoporosis and pain-like behaviors, and antagonists of the acid-sensing nociceptors, such as transient receptor potential channel vanilloid subfamily member 1 and acid-sensing ion channels, significantly improved the pain-like behaviors in the tail-suspended mice. We, therefore, believe that regional transient osteoporosis due to osteoclast activation might be a trigger for the pain-like behaviors in tail-suspended model mice. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:1226-1236, 2017.
[Mh] Termos MeSH primário: Osteoporose/complicações
Dor/etiologia
[Mh] Termos MeSH secundário: Bloqueadores do Canal Iônico Sensível a Ácido
Anilidas/farmacologia
Anilidas/uso terapêutico
Animais
Cinamatos/farmacologia
Cinamatos/uso terapêutico
Venenos de Cnidários/farmacologia
Venenos de Cnidários/uso terapêutico
Avaliação Pré-Clínica de Medicamentos
Membro Posterior/fisiologia
Elevação dos Membros Posteriores
Masculino
Camundongos Endogâmicos C57BL
Dor/tratamento farmacológico
Manejo da Dor
Canais de Cátion TRPV/antagonistas & inibidores
Suporte de Carga
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (APETx2 protein, Anthopleura elegantissima); 0 (Acid Sensing Ion Channel Blockers); 0 (Anilides); 0 (Cinnamates); 0 (Cnidarian Venoms); 0 (N-(3-methoxyphenyl)-4-chlorocinnamanilide); 0 (TRPV Cation Channels)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171002
[Lr] Data última revisão:
171002
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160720
[St] Status:MEDLINE
[do] DOI:10.1002/jor.23373


  4 / 74 MEDLINE  
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[PMID]:27377725
[Au] Autor:Ievglevskyi O; Isaev D; Netsyk O; Romanov A; Fedoriuk M; Maximyuk O; Isaeva E; Akaike N; Krishtal O
[Ad] Endereço:Department of Cellular Membranology, Bogomoletz Institute of Physiology, 01024 Kyiv, Ukraine.
[Ti] Título:Acid-sensing ion channels regulate spontaneous inhibitory activity in the hippocampus: possible implications for epilepsy.
[So] Source:Philos Trans R Soc Lond B Biol Sci;371(1700), 2016 Aug 05.
[Is] ISSN:1471-2970
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Acid-sensing ion channels (ASICs) play an important role in numerous functions in the central and peripheral nervous systems ranging from memory and emotions to pain. The data correspond to a recent notion that each neuron and many glial cells of the mammalian brain express at least one member of the ASIC family. However, the mechanisms underlying the involvement of ASICs in neuronal activity are poorly understood. However, there are two exceptions, namely, the straightforward role of ASICs in proton-based synaptic transmission in certain brain areas and the role of the Ca(2+)-permeable ASIC1a subtype in ischaemic cell death. Using a novel orthosteric ASIC antagonist, we have found that ASICs specifically control the frequency of spontaneous inhibitory synaptic activity in the hippocampus. Inhibition of ASICs leads to a strong increase in the frequency of spontaneous inhibitory postsynaptic currents. This effect is presynaptic because it is fully reproducible in single synaptic boutons attached to isolated hippocampal neurons. In concert with this observation, inhibition of the ASIC current diminishes epileptic discharges in a low Mg(2+) model of epilepsy in hippocampal slices and significantly reduces kainate-induced discharges in the hippocampus in vivo Our results reveal a significant novel role for ASICs.This article is part of the themed issue 'Evolution brings Ca(2+) and ATP together to control life and death'.
[Mh] Termos MeSH primário: Bloqueadores do Canal Iônico Sensível a Ácido/farmacologia
Canais Iônicos Sensíveis a Ácido/genética
Epilepsia/fisiopatologia
Hipocampo/efeitos dos fármacos
[Mh] Termos MeSH secundário: Canais Iônicos Sensíveis a Ácido/metabolismo
Animais
Hipocampo/metabolismo
Rede Nervosa/metabolismo
Ratos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Acid Sensing Ion Channel Blockers); 0 (Acid Sensing Ion Channels)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171023
[Lr] Data última revisão:
171023
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160706
[St] Status:MEDLINE


  5 / 74 MEDLINE  
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[PMID]:27259686
[Au] Autor:Hagiwara T; Yoshida S
[Ad] Endereço:Department of Life Science, School of Science and Engineering, Kindai University, Higashi-Osaka, Osaka, Japan. Electronic address: hagi@life.kindai.ac.jp.
[Ti] Título:Contribution of concentration-sensitive sodium channels to the absorption of alveolar fluid in mice.
[So] Source:Respir Physiol Neurobiol;231:45-54, 2016 Sep.
[Is] ISSN:1878-1519
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:The concentration-sensitive sodium channel (Nac) is activated by an increase in the extracellular sodium concentration. Although the expression of Nac in alveolar type II epithelial cells (AEC II) has been reported previously, the physiological role of Nac in the lung has not been established. We characterized Nac expression and examined amiloride-insensitive sodium transport mediated by Nac in mouse lung. Immunofluorescence studies revealed that Nac did not colocalize with either aquaporin 5 or cystic fibrosis transmembrane conductance regulator, but partially colocalized with the epithelial sodium channel γ-subunit. Immunoelectron microscopy studies showed that Nac localized at the basolateral membrane of pulmonary microvascular endothelial cells (PMVECs). Nac mRNA and protein were expressed in PMVECs isolated from the lungs of mice. Image analysis indicated that sodium influx into the alveolar wall was dependent on increases in extracellular sodium concentration. We conclude that Nac expressed in PMVECs and AEC II contributes to the reabsorption of sodium via an amiloride-insensitive pathway during alveolar fluid clearance.
[Mh] Termos MeSH primário: Líquidos Corporais/metabolismo
Alvéolos Pulmonares/metabolismo
Canais de Sódio/metabolismo
[Mh] Termos MeSH secundário: Bloqueadores do Canal Iônico Sensível a Ácido/farmacologia
Adsorção/efeitos dos fármacos
Adsorção/fisiologia
Amilorida/farmacologia
Animais
Líquidos Corporais/efeitos dos fármacos
Células Endoteliais/citologia
Células Endoteliais/metabolismo
Espaço Extracelular/efeitos dos fármacos
Espaço Extracelular/metabolismo
Imunofluorescência
Regulação da Expressão Gênica no Desenvolvimento
Hibridização In Situ
Masculino
Camundongos Endogâmicos ICR
Microscopia Imunoeletrônica
Microvasos/citologia
Microvasos/metabolismo
Alvéolos Pulmonares/irrigação sanguínea
Alvéolos Pulmonares/citologia
Alvéolos Pulmonares/crescimento & desenvolvimento
RNA Mensageiro/metabolismo
Reação em Cadeia da Polimerase em Tempo Real
Sódio/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Acid Sensing Ion Channel Blockers); 0 (RNA, Messenger); 0 (Sodium Channels); 7DZO8EB0Z3 (Amiloride); 9NEZ333N27 (Sodium)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170918
[Lr] Data última revisão:
170918
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160605
[St] Status:MEDLINE


  6 / 74 MEDLINE  
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[PMID]:27173673
[Au] Autor:Ergonul Z; Yang L; Palmer LG
[Ad] Endereço:Department of Physiology and Biophysics, Weill Cornell Medical College, New York, New York Department of Pediatrics, NewYork-Presbyterian/Weill Cornell Medical Center, New York, New York.
[Ti] Título:Properties of acid-induced currents in mouse dorsal root ganglia neurons.
[So] Source:Physiol Rep;4(9), 2016 May.
[Is] ISSN:2051-817X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Acid-sensing ion channels (ASICs) are cation channels that are activated by protons (H(+)). They are expressed in neurons throughout the nervous system and may play important roles in several neurologic disorders including inflammation, cerebral ischemia, seizures, neurodegeneration, anxiety, depression, and migraine. ASICs generally produce transient currents that desensitize in response to a decrease in extracellular pH Under certain conditions, the inactivation of ASICs can be incomplete and allow them to produce sustained currents. Here, we characterize the properties of both transient and sustained acid-induced currents in cultured mouse dorsal root ganglia (DRG) neurons. At pH levels between 7.3 and 7.1 they include "window currents" through ASICs. With stronger acid signals sustained currents are maintained in the absence of extracellular Na(+) or the presence of the ASIC blockers amiloride and Psalmotoxin-1(PcTx1). These sustained responses may have several different origins in these cells, including acid-induced stimulation of inward Cl(-) currents, block of outward K(+) currents, and augmentation of inward H(+) currents, properties that distinguish these novel sustained currents from the well-characterized transient currents.
[Mh] Termos MeSH primário: Bloqueadores do Canal Iônico Sensível a Ácido/farmacologia
Canais Iônicos Sensíveis a Ácido/fisiologia
Gânglios Espinais/fisiologia
Neurônios/fisiologia
[Mh] Termos MeSH secundário: Amilorida/farmacologia
Animais
Células Cultivadas
Gânglios Espinais/efeitos dos fármacos
Camundongos
Neurônios/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Acid Sensing Ion Channel Blockers); 0 (Acid Sensing Ion Channels); 7DZO8EB0Z3 (Amiloride)
[Em] Mês de entrada:1609
[Cu] Atualização por classe:170324
[Lr] Data última revisão:
170324
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160514
[St] Status:MEDLINE


  7 / 74 MEDLINE  
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[PMID]:26920689
[Au] Autor:Radu BM; Banciu A; Banciu DD; Radu M
[Ad] Endereço:Department of Neurological and Movement Sciences, Section of Anatomy and Histology, University of Verona, Verona, Italy; Department of Anatomy, Animal Physiology and Biophysics, Faculty of Biology, University of Bucharest, Bucharest, Romania.
[Ti] Título:Acid-Sensing Ion Channels as Potential Pharmacological Targets in Peripheral and Central Nervous System Diseases.
[So] Source:Adv Protein Chem Struct Biol;103:137-67, 2016.
[Is] ISSN:1876-1623
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Acid-sensing ion channels (ASICs) are widely expressed in the body and represent good sensors for detecting protons. The pH drop in the nervous system is equivalent to ischemia and acidosis, and ASICs are very good detectors in discriminating slight changes in acidity. ASICs are important pharmacological targets being involved in a variety of pathophysiological processes affecting both the peripheral nervous system (e.g., peripheral pain, diabetic neuropathy) and the central nervous system (e.g., stroke, epilepsy, migraine, anxiety, fear, depression, neurodegenerative diseases, etc.). This review discusses the role played by ASICs in different pathologies and the pharmacological agents acting on ASICs that might represent promising drugs. As the majority of above-mentioned pathologies involve not only neuronal dysfunctions but also microvascular alterations, in the next future, ASICs may be also considered as potential pharmacological targets at the vasculature level. Perspectives and limitations in the use of ASICs antagonists and modulators as pharmaceutical agents are also discussed.
[Mh] Termos MeSH primário: Canais Iônicos Sensíveis a Ácido/genética
Doenças do Sistema Nervoso Central/tratamento farmacológico
Neurônios/efeitos dos fármacos
Doenças do Sistema Nervoso Periférico/tratamento farmacológico
[Mh] Termos MeSH secundário: Bloqueadores do Canal Iônico Sensível a Ácido/uso terapêutico
Canais Iônicos Sensíveis a Ácido/efeitos dos fármacos
Doenças do Sistema Nervoso Central/classificação
Doenças do Sistema Nervoso Central/genética
Seres Humanos
Terapia de Alvo Molecular
Neurônios/patologia
Doenças do Sistema Nervoso Periférico/classificação
Doenças do Sistema Nervoso Periférico/genética
Agonistas de Canais de Sódio/uso terapêutico
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T; REVIEW
[Nm] Nome de substância:
0 (Acid Sensing Ion Channel Blockers); 0 (Acid Sensing Ion Channels); 0 (Sodium Channel Agonists)
[Em] Mês de entrada:1608
[Cu] Atualização por classe:160227
[Lr] Data última revisão:
160227
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160228
[St] Status:MEDLINE


  8 / 74 MEDLINE  
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[PMID]:26724742
[Au] Autor:Nishioka R; Sugimoto K; Aono H; Mise A; Choudhury ME; Miyanishi K; Islam A; Fujita T; Takeda H; Takahashi H; Yano H; Tanaka J
[Ad] Endereço:Department of Molecular and Cellular Physiology, Graduate School of Medicine, Ehime University, Japan.
[Ti] Título:Treadmill exercise ameliorates ischemia-induced brain edema while suppressing Na⁺/H⁺ exchanger 1 expression.
[So] Source:Exp Neurol;277:150-161, 2016 Mar.
[Is] ISSN:1090-2430
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Exercise may be one of the most effective and sound therapies for stroke; however, the mechanisms underlying the curative effects remain unclear. In this study, the effects of forced treadmill exercise with electric shock on ischemic brain edema were investigated. Wistar rats were subjected to transient (90 min) middle cerebral artery occlusion (tMCAO). Eighty nine rats with substantially large ischemic lesions were evaluated using magnetic resonance imaging (MRI) and were randomly assigned to exercise and non-exercise groups. The rats were forced to run at 4-6m/s for 10 min/day on days 2, 3 and 4. Brain edema was measured on day 5 by MRI, histochemical staining of brain sections and tissue water content determination (n=7, each experiment). Motor function in some rats was examined on day 30 (n=6). Exercise reduced brain edema (P<0.05-0.001, varied by the methods) and ameliorated motor function (P<0.05). The anti-glucocorticoid mifepristone or the anti-mineralocorticoid spironolactone abolished these effects, but orally administered corticosterone mimicked the ameliorating effects of exercise. Exercise prevented the ischemia-induced expression of mRNA encoding aquaporin 4 (AQP4) and Na(+)/H(+) exchangers (NHEs) (n=5 or 7, P<0.01). Microglia and NG2 glia expressed NHE1 in the peri-ischemic region of rat brains and also in mixed glial cultures. Corticosterone at ~10nM reduced NHE1 and AQP4 expression in mixed glial and pure microglial cultures. Dexamethasone and aldosterone at 10nM did not significantly alter NHE1 and AQP4 expression. Exposure to a NHE inhibitor caused shrinkage of microglial cells. These results suggest that the stressful short-period and slow-paced treadmill exercise suppressed NHE1 and AQP4 expression resulting in the amelioration of brain edema at least partly via the moderate increase in plasma corticosterone levels.
[Mh] Termos MeSH primário: Edema Encefálico/etiologia
Edema Encefálico/reabilitação
Terapia por Exercício/métodos
Regulação da Expressão Gênica/fisiologia
Infarto da Artéria Cerebral Média/complicações
Trocadores de Sódio-Hidrogênio/metabolismo
[Mh] Termos MeSH secundário: Bloqueadores do Canal Iônico Sensível a Ácido/farmacologia
Animais
Aquaporina 4/metabolismo
Células Cultivadas
Corticosterona/metabolismo
Corticosterona/uso terapêutico
Citocinas/genética
Citocinas/metabolismo
Modelos Animais de Doenças
Lateralidade Funcional
Regulação da Expressão Gênica/efeitos dos fármacos
Masculino
Mifepristona/uso terapêutico
Antagonistas de Receptores de Mineralocorticoides/farmacologia
Proteínas do Tecido Nervoso/genética
Proteínas do Tecido Nervoso/metabolismo
Neuroglia/efeitos dos fármacos
Ratos
Ratos Wistar
Trocadores de Sódio-Hidrogênio/genética
Espironolactona/uso terapêutico
Fatores de Tempo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Acid Sensing Ion Channel Blockers); 0 (Aqp4 protein, rat); 0 (Aquaporin 4); 0 (Cytokines); 0 (Mineralocorticoid Receptor Antagonists); 0 (Nerve Tissue Proteins); 0 (Sodium-Hydrogen Exchangers); 0 (growth factor-activatable Na-H exchanger NHE-1); 27O7W4T232 (Spironolactone); 320T6RNW1F (Mifepristone); W980KJ009P (Corticosterone)
[Em] Mês de entrada:1606
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160103
[St] Status:MEDLINE


  9 / 74 MEDLINE  
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[PMID]:26686983
[Au] Autor:Osmakov DI; Koshelev SG; Andreev YA; Dyachenko IA; Bondarenko DA; Murashev AN; Grishin EV; Kozlov SA
[Ad] Endereço:Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, ul. Miklukho-Maklaya 16/10, 117997 Moscow, Russia. Electronic address: osmadim@gmail.com.
[Ti] Título:Conversed mutagenesis of an inactive peptide to ASIC3 inhibitor for active sites determination.
[So] Source:Toxicon;116:11-6, 2016 Jun 15.
[Is] ISSN:1879-3150
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Peptide Ugr9-1 from the venom of sea anemone Urticina grebelnyi selectively inhibits the ASIC3 channel and significantly reverses inflammatory and acid-induced pain in vivo. A close homolog peptide Ugr 9-2 does not have these features. To find the pharmacophore residues and explore structure-activity relationships of Ugr 9-1, we performed site-directed mutagenesis of Ugr 9-2 and replaced several positions by the corresponding residues from Ugr 9-1. Mutant peptides Ugr 9-2 T9F and Ugr 9-2 Y12H were able to inhibit currents of the ASIC3 channels 2.2 times and 1.3 times weaker than Ugr 9-1, respectively. Detailed analysis of the spatial models of Ugr 9-1, Ugr 9-2 and both mutant peptides revealed the presence of the basic-aromatic clusters on opposite sides of the molecule, each of which is responsible for the activity. Additionally, Ugr9-1 mutant with truncated N- and C-termini retained similar with the Ugr9-1 action in vitro and was equally potent in vivo model of thermal hypersensitivity. All together, these results are important for studying the structure-activity relationships of ligand-receptor interaction and for the future development of peptide drugs from animal toxins.
[Mh] Termos MeSH primário: Bloqueadores do Canal Iônico Sensível a Ácido/química
Canais Iônicos Sensíveis a Ácido/química
Venenos de Cnidários/química
[Mh] Termos MeSH secundário: Animais
Domínio Catalítico
Seres Humanos
Modelos Moleculares
Mutagênese Sítio-Dirigida
Estrutura Terciária de Proteína
Análise de Sequência de Proteína
Relação Estrutura-Atividade
Xenopus laevis
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Acid Sensing Ion Channel Blockers); 0 (Acid Sensing Ion Channels); 0 (Cnidarian Venoms)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170629
[Lr] Data última revisão:
170629
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:151222
[St] Status:MEDLINE


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[PMID]:26663905
[Au] Autor:Munro G; Christensen JK; Erichsen HK; Dyhring T; Demnitz J; Dam E; Ahring PK
[Ad] Endereço:NeuroSearch A/S, Ballerup, Denmark.
[Ti] Título:NS383 Selectively Inhibits Acid-Sensing Ion Channels Containing 1a and 3 Subunits to Reverse Inflammatory and Neuropathic Hyperalgesia in Rats.
[So] Source:CNS Neurosci Ther;22(2):135-45, 2016 Feb.
[Is] ISSN:1755-5949
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:AIMS: Here, we investigate the pharmacology of NS383, a novel small molecule inhibitor of acid-sensing ion channels (ASICs). METHODS: ASIC inhibition by NS383 was characterized in patch-clamp electrophysiological studies. Analgesic properties were evaluated in four rat behavioral models of pain. RESULTS: NS383 inhibited H(+)-activated currents recorded from rat homomeric ASIC1a, ASIC3, and heteromeric ASIC1a+3 with IC50 values ranging from 0.61 to 2.2 µM. However, NS383 was completely inactive at homomeric ASIC2a. Heteromeric receptors containing AISC2a, such as ASIC1a+2a and ASIC2a+3, were only partially inhibited, presumably as a result of stoichiometry-dependent binding. NS383 (10-60 mg/kg, i.p.), amiloride (50-200 mg/kg, i.p.), acetaminophen (100-400 mg/kg, i.p.), and morphine (3-10 mg/kg, i.p.) all dose-dependently attenuated nocifensive behaviors in the rat formalin test, reversed pathological inflammatory hyperalgesia in complete Freund's adjuvant-inflamed rats, and reversed mechanical hypersensitivity in the chronic constriction injury model of neuropathic pain. However, in contrast to acetaminophen and morphine, motor function was unaffected by NS383 at doses at least 8-fold greater than those that were effective in pain models, whilst analgesic doses of amiloride were deemed to be toxic. CONCLUSIONS: NS383 is a potent and uniquely selective inhibitor of rat ASICs containing 1a and/or 3 subunits. It is well tolerated and capable of reversing pathological painlike behaviors, presumably via peripheral actions, but possibly also via actions within central pain circuits.
[Mh] Termos MeSH primário: Bloqueadores do Canal Iônico Sensível a Ácido/uso terapêutico
Canais Iônicos Sensíveis a Ácido
Compostos Heterocíclicos com 3 Anéis/química
Compostos Heterocíclicos com 3 Anéis/uso terapêutico
Hiperalgesia/tratamento farmacológico
Neuralgia/tratamento farmacológico
Oximas/química
Oximas/uso terapêutico
[Mh] Termos MeSH secundário: Bloqueadores do Canal Iônico Sensível a Ácido/química
Bloqueadores do Canal Iônico Sensível a Ácido/farmacologia
Canais Iônicos Sensíveis a Ácido/fisiologia
Analgésicos/química
Analgésicos/farmacologia
Analgésicos/uso terapêutico
Animais
Células CHO
Cricetinae
Cricetulus
Relação Dose-Resposta a Droga
Compostos Heterocíclicos com 3 Anéis/farmacologia
Hiperalgesia/fisiopatologia
Masculino
Neuralgia/fisiopatologia
Oximas/farmacologia
Medição da Dor/efeitos dos fármacos
Medição da Dor/métodos
Subunidades Proteicas/antagonistas & inibidores
Subunidades Proteicas/fisiologia
Ratos
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Accn3 protein, rat); 0 (Acid Sensing Ion Channel Blockers); 0 (Acid Sensing Ion Channels); 0 (Analgesics); 0 (Asic1 protein, rat); 0 (Heterocyclic Compounds, 3-Ring); 0 (NS383 compound); 0 (Oximes); 0 (Protein Subunits)
[Em] Mês de entrada:1610
[Cu] Atualização por classe:161230
[Lr] Data última revisão:
161230
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:151215
[St] Status:MEDLINE
[do] DOI:10.1111/cns.12487



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