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[PMID]:28615047
[Au] Autor:Nagasaka Y; Wepler M; Thoonen R; Sips PY; Allen K; Graw JA; Yao V; Burns SM; Muenster S; Brouckaert P; Miller K; Solt K; Buys ES; Ichinose F; Zapol WM
[Ad] Endereço:Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
[Ti] Título:Sensitivity to Sevoflurane anesthesia is decreased in mice with a congenital deletion of Guanylyl Cyclase-1 alpha.
[So] Source:BMC Anesthesiol;17(1):76, 2017 Jun 14.
[Is] ISSN:1471-2253
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Volatile anesthetics increase levels of the neurotransmitter nitric oxide (NO) and the secondary messenger molecule cyclic guanosine monophosphate (cGMP) in the brain. NO activates the enzyme guanylyl cyclase (GC) to produce cGMP. We hypothesized that the NO-GC-cGMP pathway contributes to anesthesia-induced unconsciousness. METHODS: Sevoflurane-induced loss and return of righting reflex (LORR and RORR, respectively) were studied in wild-type mice (WT) and in mice congenitally deficient in the GC-1α subunit (GC-1 mice). Spatial distributions of GC-1α and the GC-2α subunit in the brain were visualized by in situ hybridization. Brain cGMP levels were measured in WT and GC-1 mice after inhaling oxygen with or without 1.2% sevoflurane for 20 min. RESULTS: Higher concentrations of sevoflurane were required to induce LORR in GC-1 mice than in WT mice (1.5 ± 0.1 vs. 1.1 ± 0.2%, respectively, n = 14 and 14, P < 0.0001). Similarly, RORR occurred at higher concentrations of sevoflurane in GC-1 mice than in WT mice (1.0 ± 0.1 vs. 0.8 ± 0.1%, respectively, n = 14 and 14, P < 0.0001). Abundant GC-1α and GC-2α mRNA expression was detected in the cerebral cortex, medial habenula, hippocampus, and cerebellum. Inhaling 1.2% sevoflurane for 20 min increased cGMP levels in the brains of WT mice from 2.6 ± 2.0 to 5.5 ± 3.7 pmol/mg protein (n = 13 and 10, respectively, P = 0.0355) but not in GC-1 mice. CONCLUSION: Congenital deficiency of GC-1α abolished the ability of sevoflurane anesthesia to increase cGMP levels in the whole brain, and increased the concentration of sevoflurane required to induce LORR. Impaired NO-cGMP signaling raises the threshold for producing sevoflurane-induced unconsciousness in mice.
[Mh] Termos MeSH primário: Anestésicos Inalatórios/farmacologia
Guanilato Ciclase/genética
Éteres Metílicos/farmacologia
[Mh] Termos MeSH secundário: Animais
Encéfalo/metabolismo
Guanosina Monofosfato/metabolismo
Camundongos Knockout
Reflexo de Endireitamento/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Anesthetics, Inhalation); 0 (Methyl Ethers); 38LVP0K73A (sevoflurane); 85-32-5 (Guanosine Monophosphate); EC 4.6.1.2 (Guanylate Cyclase)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171107
[Lr] Data última revisão:
171107
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170616
[St] Status:MEDLINE
[do] DOI:10.1186/s12871-017-0368-5


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[PMID]:28504671
[Au] Autor:Fletcher EV; Simon CM; Pagiazitis JG; Chalif JI; Vukojicic A; Drobac E; Wang X; Mentis GZ
[Ad] Endereço:Center for Motor Neuron Biology and Disease, Columbia University, New York, New York, USA.
[Ti] Título:Reduced sensory synaptic excitation impairs motor neuron function via Kv2.1 in spinal muscular atrophy.
[So] Source:Nat Neurosci;20(7):905-916, 2017 Jul.
[Is] ISSN:1546-1726
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Behavioral deficits in neurodegenerative diseases are often attributed to the selective dysfunction of vulnerable neurons via cell-autonomous mechanisms. Although vulnerable neurons are embedded in neuronal circuits, the contributions of their synaptic partners to disease process are largely unknown. Here we show that, in a mouse model of spinal muscular atrophy (SMA), a reduction in proprioceptive synaptic drive leads to motor neuron dysfunction and motor behavior impairments. In SMA mice or after the blockade of proprioceptive synaptic transmission, we observed a decrease in the motor neuron firing that could be explained by the reduction in the expression of the potassium channel Kv2.1 at the surface of motor neurons. Chronically increasing neuronal activity pharmacologically in vivo led to a normalization of Kv2.1 expression and an improvement in motor function. Our results demonstrate a key role of excitatory synaptic drive in shaping the function of motor neurons during development and the contribution of its disruption to a neurodegenerative disease.
[Mh] Termos MeSH primário: Neurônios Motores/fisiologia
Atrofia Muscular Espinal/fisiopatologia
Propriocepção/fisiologia
Canais de Potássio Shab/fisiologia
Sinapses/fisiologia
[Mh] Termos MeSH secundário: Potenciais de Ação/fisiologia
Animais
Sobrevivência Celular/fisiologia
Modelos Animais de Doenças
Ácido Caínico/farmacologia
Metaloendopeptidases/farmacologia
Camundongos
Camundongos Transgênicos
Neurônios Motores/efeitos dos fármacos
Neurônios Motores/metabolismo
Junção Neuromuscular/fisiologia
Reflexo de Endireitamento/fisiologia
Canais de Potássio Shab/biossíntese
Proteína 1 de Sobrevivência do Neurônio Motor/genética
Proteína 2 de Sobrevivência do Neurônio Motor/genética
Sinapses/efeitos dos fármacos
Toxina Tetânica/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (SMN2 protein, human); 0 (Shab Potassium Channels); 0 (Smn1 protein, mouse); 0 (Survival of Motor Neuron 1 Protein); 0 (Survival of Motor Neuron 2 Protein); 0 (Tetanus Toxin); EC 3.4.24.- (Metalloendopeptidases); EC 3.4.24.- (zinc-endopeptidase, tetanus neurotoxin); SIV03811UC (Kainic Acid)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:171115
[Lr] Data última revisão:
171115
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170516
[St] Status:MEDLINE
[do] DOI:10.1038/nn.4561


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[PMID]:28000031
[Au] Autor:Müller CP; Kalinichenko LS; Tiesel J; Witt M; Stöckl T; Sprenger E; Fuchser J; Beckmann J; Praetner M; Huber SE; Amato D; Mühle C; Büttner C; Ekici AB; Smaga I; Pomierny-Chamiolo L; Pomierny B; Filip M; Eulenburg V; Gulbins E; Lourdusamy A; Reichel M; Kornhuber J
[Ad] Endereço:Department of Psychiatry and Psychotherapy, University Clinic, Friedrich-Alexander-University of Erlangen-Nuremberg, Schwabachanlage 6, 91054, Erlangen, Germany. Christian.Mueller@uk-erlangen.de.
[Ti] Título:Paradoxical antidepressant effects of alcohol are related to acid sphingomyelinase and its control of sphingolipid homeostasis.
[So] Source:Acta Neuropathol;133(3):463-483, 2017 Mar.
[Is] ISSN:1432-0533
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:Alcohol is a widely consumed drug that can lead to addiction and severe brain damage. However, alcohol is also used as self-medication for psychiatric problems, such as depression, frequently resulting in depression-alcoholism comorbidity. Here, we identify the first molecular mechanism for alcohol use with the goal to self-medicate and ameliorate the behavioral symptoms of a genetically induced innate depression. An induced over-expression of acid sphingomyelinase (ASM), as was observed in depressed patients, enhanced the consumption of alcohol in a mouse model of depression. ASM hyperactivity facilitates the establishment of the conditioned behavioral effects of alcohol, and thus drug memories. Opposite effects on drinking and alcohol reward learning were observed in animals with reduced ASM function. Importantly, free-choice alcohol drinking-but not forced alcohol exposure-reduces depression-like behavior selectively in depressed animals through the normalization of brain ASM activity. No such effects were observed in normal mice. ASM hyperactivity caused sphingolipid and subsequent monoamine transmitter hypo-activity in the brain. Free-choice alcohol drinking restores nucleus accumbens sphingolipid- and monoamine homeostasis selectively in depressed mice. A gene expression analysis suggested strong control of ASM on the expression of genes related to the regulation of pH, ion transmembrane transport, behavioral fear response, neuroprotection and neuropeptide signaling pathways. These findings suggest that the paradoxical antidepressant effects of alcohol in depressed organisms are mediated by ASM and its control of sphingolipid homeostasis. Both emerge as a new treatment target specifically for depression-induced alcoholism.
[Mh] Termos MeSH primário: Antidepressivos/uso terapêutico
Depressão/tratamento farmacológico
Etanol/uso terapêutico
Homeostase/genética
Esfingolipídeos/metabolismo
Esfingomielina Fosfodiesterase/metabolismo
[Mh] Termos MeSH secundário: Animais
Comportamento de Escolha/efeitos dos fármacos
Condicionamento Operante/efeitos dos fármacos
Depressão/genética
Etanol/sangue
Preferências Alimentares/efeitos dos fármacos
Regulação da Expressão Gênica/efeitos dos fármacos
Regulação da Expressão Gênica/genética
Seres Humanos
Camundongos
Camundongos Endogâmicos C57BL
Camundongos Transgênicos
Reflexo de Endireitamento/efeitos dos fármacos
Reflexo de Endireitamento/genética
Transdução de Sinais/efeitos dos fármacos
Transdução de Sinais/genética
Esfingomielina Fosfodiesterase/genética
Superóxido Dismutase/genética
Superóxido Dismutase/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antidepressive Agents); 0 (Sphingolipids); 3K9958V90M (Ethanol); EC 1.15.1.1 (Superoxide Dismutase); EC 3.1.4.12 (ASMase, mouse); EC 3.1.4.12 (Sphingomyelin Phosphodiesterase)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170920
[Lr] Data última revisão:
170920
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161222
[St] Status:MEDLINE
[do] DOI:10.1007/s00401-016-1658-6


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[PMID]:27743929
[Au] Autor:De Bellis M; Carbonara R; Roussel J; Farinato A; Massari A; Pierno S; Muraglia M; Corbo F; Franchini C; Carratù MR; De Luca A; Conte Camerino D; Desaphy JF
[Ad] Endereço:Section of Pharmacology, Department of Pharmacy and Drug Sciences, University of Bari Aldo Moro, 70125, Bari, Italy.
[Ti] Título:Increased sodium channel use-dependent inhibition by a new potent analogue of tocainide greatly enhances in vivo antimyotonic activity.
[So] Source:Neuropharmacology;113(Pt A):206-216, 2017 Feb.
[Is] ISSN:1873-7064
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Although the sodium channel blocker, mexiletine, is the first choice drug in myotonia, some myotonic patients remain unsatisfied due to contraindications, lack of tolerability, or incomplete response. More therapeutic options are thus needed for myotonic patients, which require clinical trials based on solid preclinical data. In previous structure-activity relationship studies, we identified two newly-synthesized derivatives of tocainide, To040 and To042, with greatly enhanced potency and use-dependent behavior in inhibiting sodium currents in frog skeletal muscle fibers. The current study was performed to verify their potential as antimyotonic agents. Patch-clamp experiments show that both compounds, especially To042, are greatly more potent and use-dependent blockers of human skeletal muscle hNav1.4 channels compared to tocainide and mexiletine. Reduced effects on F1586C hNav1.4 mutant suggest that the compounds bind to the local anesthetic receptor, but that the increased hindrance and lipophilia of the N-substituent may further strengthen drug-receptor interaction and use-dependence. Compared to mexiletine, To042 was 120 times more potent to block hNav1.4 channels in a myotonia-like cellular condition and 100 times more potent to improve muscle stiffness in vivo in a previously-validated rat model of myotonia. To explore toxicological profile, To042 was tested on hERG potassium currents, motor coordination using rotarod, and C2C12 cell line for cytotoxicity. All these experiments suggest a satisfactory therapeutic index for To042. This study shows that, owing to a huge use-dependent block of sodium channels, To042 is a promising candidate drug for myotonia and possibly other membrane excitability disorders, warranting further preclinical and human studies.
[Mh] Termos MeSH primário: Miotonia/prevenção & controle
Canal de Sódio Disparado por Voltagem NAV1.4/fisiologia
Tocainide/farmacologia
Bloqueadores do Canal de Sódio Disparado por Voltagem/farmacologia
[Mh] Termos MeSH secundário: Animais
Relação Dose-Resposta a Droga
Canais de Potássio Éter-A-Go-Go/fisiologia
Seres Humanos
Masculino
Mexiletina/farmacologia
Músculo Esquelético/efeitos dos fármacos
Músculo Esquelético/fisiologia
Miotonia/fisiopatologia
Ratos
Ratos Wistar
Reflexo de Endireitamento/efeitos dos fármacos
Teste de Desempenho do Rota-Rod
Tocainide/efeitos adversos
Tocainide/análogos & derivados
Tocainide/uso terapêutico
Bloqueadores do Canal de Sódio Disparado por Voltagem/efeitos adversos
Bloqueadores do Canal de Sódio Disparado por Voltagem/uso terapêutico
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Ether-A-Go-Go Potassium Channels); 0 (NAV1.4 Voltage-Gated Sodium Channel); 0 (SCN4A protein, human); 0 (Voltage-Gated Sodium Channel Blockers); 1U511HHV4Z (Mexiletine); 27DXO59SAN (Tocainide)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170922
[Lr] Data última revisão:
170922
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161105
[St] Status:MEDLINE


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[PMID]:27009683
[Au] Autor:Usui N; Co M; Harper M; Rieger MA; Dougherty JD; Konopka G
[Ad] Endereço:Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, Texas.
[Ti] Título:Sumoylation of FOXP2 Regulates Motor Function and Vocal Communication Through Purkinje Cell Development.
[So] Source:Biol Psychiatry;81(3):220-230, 2017 Feb 01.
[Is] ISSN:1873-2402
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Mutations in the gene encoding the transcription factor forkhead box P2 (FOXP2) result in brain developmental abnormalities, including reduced gray matter in both human patients and rodent models and speech and language deficits. However, neither the region-specific function of FOXP2 in the brain, in particular the cerebellum, nor the effects of any posttranslational modifications of FOXP2 in the brain and disorders have been explored. METHODS: We characterized sumoylation of FOXP2 biochemically and analyzed the region-specific function and sumoylation of FOXP2 in the developing mouse cerebellum. Using in utero electroporation to manipulate the sumoylation state of FOXP2 as well as Foxp2 expression levels in Purkinje cells of the cerebellum in vivo, we reduced Foxp2 expression approximately 40% in the mouse cerebellum. Such a reduction approximates the haploinsufficiency observed in human patients who demonstrate speech and language impairments. RESULTS: We identified sumoylation of FOXP2 at K674 (K673 in mice) in the cerebellum of neonates. In vitro co-immunoprecipitation and in vivo colocalization experiments suggest that PIAS3 acts as the small ubiquitin-like modifier E3 ligase for FOXP2 sumoylation. This sumoylation modifies transcriptional regulation by FOXP2. We demonstrated that FOXP2 sumoylation is required for regulation of cerebellar motor function and vocal communication, likely through dendritic outgrowth and arborization of Purkinje cells in the mouse cerebellum. CONCLUSIONS: Sumoylation of FOXP2 in neonatal mouse cerebellum regulates Purkinje cell development and motor functions and vocal communication, demonstrating evidence for sumoylation in regulating mammalian behaviors.
[Mh] Termos MeSH primário: Cerebelo/crescimento & desenvolvimento
Fatores de Transcrição Forkhead/metabolismo
Movimento
Células de Purkinje/metabolismo
Proteínas Repressoras/metabolismo
Sumoilação
Vocalização Animal/fisiologia
[Mh] Termos MeSH secundário: Animais
Diferenciação Celular
Cerebelo/metabolismo
Dendritos/fisiologia
Camundongos
Camundongos Endogâmicos C57BL
Reflexo de Endireitamento
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Forkhead Transcription Factors); 0 (Foxp2 protein, mouse); 0 (Repressor Proteins)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170809
[Lr] Data última revisão:
170809
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160325
[St] Status:MEDLINE


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[PMID]:27783647
[Au] Autor:Koyama Y; Andoh T; Kamiya Y; Miyazaki T; Maruyama K; Kariya T; Goto T
[Ad] Endereço:Department of Anesthesiology and Critical Care Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
[Ti] Título:Bumetanide, an Inhibitor of NKCC1 (Na-K-2Cl Cotransporter Isoform 1), Enhances Propofol-Induced Loss of Righting Reflex but Not Its Immobilizing Actions in Neonatal Rats.
[So] Source:PLoS One;11(10):e0164125, 2016.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Gamma-aminobutyric acid (GABA) has been shown to induce excitation on immature neurons due to increased expression of Na+-K+-2Cl- co-transporter isoform 1 (NKCC1), and the transition of GABAergic signaling from excitatory to inhibitory occurs before birth in the rat spinal cord and spreads rostrally according to the developmental changes in cation-chloride co-transporter expression. We previously showed that midazolam activates the hippocampal CA3 area and induces less sedation in neonatal rats compared with adolescent rats in an NKCC1-dependent manner. In the present study, we tested the hypothesis that propofol-induced loss of righting reflex (LORR) but not immobilizing actions are modulated by NKCC1-dependent mechanisms and reduced in neonatal rats compared with adolescent rats. We estimated neuronal activity in the cortex, hippocampus and thalamus after propofol administration with or without bumetanide, an NKCC1 inhibitor, by immunostaining of phosphorylated cyclic adenosine monophosphate-response element binding protein (pCREB). We studied effects of bumetanide on propofol-induced LORR and immobilizing actions in postnatal day 7 and 28 (P7 and P28) rats. The pCREB expression in the cortex (P = 0.001) and hippocampus (P = 0.01) was significantly greater in the rats receiving propofol only than in the rats receiving propofol plus bumetanide at P 7. Propofol-induced LORR or immobilizing effects did not differ significantly between P7 and P28. Bumetanide significantly enhanced propofol-induced LORR (P = 0.031) but not immobilization in P7 rats. These results are partially consistent with our hypothesis. They suggest that propofol may activate the rostral but not caudal central nervous system dependently on NKCC1, and these differential actions may underlie the different properties of sedative and immobilizing actions observed in neonatal rats.
[Mh] Termos MeSH primário: Bumetanida/farmacologia
Propofol/farmacologia
Reflexo de Endireitamento/efeitos dos fármacos
Membro 2 da Família 12 de Carreador de Soluto/química
[Mh] Termos MeSH secundário: Animais
Animais Recém-Nascidos
Comportamento Animal/efeitos dos fármacos
Proteína de Ligação a CREB/metabolismo
Córtex Cerebral/efeitos dos fármacos
Córtex Cerebral/metabolismo
Córtex Cerebral/patologia
Hipocampo/efeitos dos fármacos
Hipocampo/metabolismo
Hipocampo/patologia
Ratos
Ratos Sprague-Dawley
Membro 2 da Família 12 de Carreador de Soluto/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Slc12a2 protein, rat); 0 (Solute Carrier Family 12, Member 2); 0Y2S3XUQ5H (Bumetanide); EC 2.3.1.48 (CREB-Binding Protein); EC 2.3.1.48 (Crebbp protein, rat); YI7VU623SF (Propofol)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170614
[Lr] Data última revisão:
170614
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161027
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0164125


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[PMID]:27764701
[Au] Autor:Ait-Bali Y; Ba-M'hamed S; Bennis M
[Ad] Endereço:Laboratoire de Pharmacologie, Neurobiologie et Comportement (URAC 37) Cadi Ayyad University, Marrakech, Morocco.
[Ti] Título:Prenatal Paraquat exposure induces neurobehavioral and cognitive changes in mice offspring.
[So] Source:Environ Toxicol Pharmacol;48:53-62, 2016 Dec.
[Is] ISSN:1872-7077
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:In the present work, we investigated developmental toxicity of Paraquat (PQ), from the 1st or 6th day of mating and throughout the gestation period. We have examined several parameters, including toxicity indices, reproductive performance, sensorimotor development, as well as anxiety and cognitive performance of the offspring. Our results showed that exposure to 20mg/kg of Paraquat during the first days of pregnancy completely prevents pregnancy in treated mice, but from the 6th day of pregnancy, an alteration in fertility and reproductive parameters was observed. In offspring, the PQ was responsible for an overall delay of innate reflexes and a deficit in motor development. All exposed animals showed a decrease in the level of locomotor activity, increased levels of anxiety-like behavior and pronounced cognitive impairment in adulthood. These results demonstrated that Paraquat led to the onset of many behavioral changes that stem from the impairment of neuronal developmental processes in prenatally exposed mice.
[Mh] Termos MeSH primário: Comportamento Animal/efeitos dos fármacos
Cognição/efeitos dos fármacos
Herbicidas/toxicidade
Síndromes Neurotóxicas/etiologia
Paraquat/toxicidade
Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente
[Mh] Termos MeSH secundário: Animais
Aprendizagem da Esquiva/efeitos dos fármacos
Encéfalo/efeitos dos fármacos
Encéfalo/embriologia
Encéfalo/patologia
Feminino
Masculino
Aprendizagem em Labirinto/efeitos dos fármacos
Camundongos
Síndromes Neurotóxicas/embriologia
Síndromes Neurotóxicas/patologia
Síndromes Neurotóxicas/fisiopatologia
Gravidez
Efeitos Tardios da Exposição Pré-Natal/patologia
Efeitos Tardios da Exposição Pré-Natal/fisiopatologia
Reflexo de Endireitamento/efeitos dos fármacos
Teste de Desempenho do Rota-Rod
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Herbicides); PLG39H7695 (Paraquat)
[Em] Mês de entrada:1702
[Cu] Atualização por classe:170916
[Lr] Data última revisão:
170916
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161021
[St] Status:MEDLINE


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[PMID]:27648836
[Au] Autor:Chisholm JM; Pang DS
[Ad] Endereço:Department of Veterinary Clinical and Diagnostic Sciences, University of Calgary, Alberta, Canada, s.
[Ti] Título:Assessment of Carbon Dioxide, Carbon Dioxide/Oxygen, Isoflurane and Pentobarbital Killing Methods in Adult Female Sprague-Dawley Rats.
[So] Source:PLoS One;11(9):e0162639, 2016.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Exposure to carbon dioxide (CO2) gas as a killing method is aversive and exposure to high concentrations is likely to be painful. Bradycardia during exposure to CO2 is associated with nociception and pain. However, it is unclear if bradycardia occurs before loss of consciousness as definitions of loss of consciousness vary in the literature. The objectives of this study were to explore the relationship between recumbency, loss of righting reflex (LORR) and a quiescent electromyograph as measures of loss of consciousness, and identify the onset of bradycardia in relation to these measures. Our primary hypothesis was that CO2 exposure would result in bradycardia, which would precede LORR. METHODS: Thirty-two adult, female Sprague-Dawley rats were instrumented with a telemetry device and randomly assigned to one of four killing methods (concentrations of 100% CO2, CO2 (70%)/O2 (30%), isoflurane (5%) and intraperitoneal pentobarbital (200 mg/kg). Time to achieve recumbency, LORR, quiescent electromyograph, isoelectric electrocorticograph, heart rate and apnea were recorded. RESULTS: The general order of progression was recumbency, LORR, quiescent electromyograph, isoelectric electrocorticograph and apnea. Recumbency preceded LORR in the majority of animals (CO2; 7/8, CO2/O2; 8/8, isoflurane; 5/8, pentobarbital; 4/8). Bradycardia occurred before recumbency in the CO2 (p = 0.0002) and CO2/O2 (p = 0.005) groups, with a 50% reduction in heart rate compared to baseline. The slowest (time to apnea) and least consistent killing methods were CO2/O2 (1180 ± 658.1s) and pentobarbital (875 [239 to 4680]s). CONCLUSION: Bradycardia, and consequently nociception and pain, occurs before loss of consciousness during CO2 exposure. Pentobarbital displayed an unexpected lack of consistency, questioning its classification as an acceptable euthanasia method in rats.
[Mh] Termos MeSH primário: Dióxido de Carbono/administração & dosagem
Isoflurano/administração & dosagem
Oxigênio/administração & dosagem
Pentobarbital/administração & dosagem
[Mh] Termos MeSH secundário: Adjuvantes Anestésicos/administração & dosagem
Animais
Apneia/fisiopatologia
Bradicardia/fisiopatologia
Dióxido de Carbono/metabolismo
Eletrocardiografia
Eletrocorticografia
Eletromiografia
Feminino
Frequência Cardíaca/efeitos dos fármacos
Frequência Cardíaca/fisiologia
Oxigênio/metabolismo
Distribuição Aleatória
Ratos Sprague-Dawley
Reflexo de Endireitamento/efeitos dos fármacos
Reflexo de Endireitamento/fisiologia
Fatores de Tempo
Inconsciência/fisiopatologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Adjuvants, Anesthesia); 142M471B3J (Carbon Dioxide); CYS9AKD70P (Isoflurane); I4744080IR (Pentobarbital); S88TT14065 (Oxygen)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170816
[Lr] Data última revisão:
170816
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160921
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0162639


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[PMID]:27639989
[Au] Autor:Vincenzi F; Ravani A; Pasquini S; Merighi S; Gessi S; Romagnoli R; Baraldi PG; Borea PA; Varani K
[Ad] Endereço:Department of Medical Sciences, Pharmacology Section, University of Ferrara, Via Fossato di Mortara 17/19, 44121 Ferrara, Italy.
[Ti] Título:Positive allosteric modulation of A adenosine receptors as a novel and promising therapeutic strategy for anxiety.
[So] Source:Neuropharmacology;111:283-292, 2016 Dec.
[Is] ISSN:1873-7064
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Activation of A adenosine receptors (ARs) has been associated with anxiolytic-like effects in different behavioral tests, but development of A AR agonists for therapeutic use has been hampered, most likely due to the presence of side effects. With the aim to identify a safer approach for the treatment of anxiety, we investigated, in mice, the anxiolytic-like properties of a novel A AR positive allosteric modulator, TRR469. Acute administration of TRR469 (0.3-3 mg/kg) resulted in robust anxiolytic-like effects in the elevated plus maze, the dark/light box, the open field and the marble burying tests. The magnitude of the anxiolytic action of TRR469 was comparable to that obtained with benzodiazepine diazepam (1 mg/kg). The use of the A AR antagonist DPCPX (3 mg/kg) suggested that the effects of TRR469 were mediated by this receptor subtype. In contrast to diazepam, the novel positive allosteric modulator did not potentiate the sedative effect of ethanol (3.5 g/kg) evaluated by the loss of righting reflex. While diazepam produced motor coordination impairment in the rotarod test, this effect being enhanced by the presence of ethanol (1.5 g/kg), TRR469 did not elicit locomotor disturbances either when administered alone or in the presence of ethanol. In vitro, TRR469 was able to increase the number of A AR recognizable by the agonist radioligand [ H]-CCPA in mouse brain regions involved in emotional processes. TRR469 markedly increased the affinity of the agonist CCPA, suggesting the capability, in vivo, to increase the affinity of endogenous adenosine. Taken together, these findings indicate that the positive allosteric modulation of A AR may represent a promising approach for the treatment of anxiety-related disorders.
[Mh] Termos MeSH primário: Agonistas do Receptor A1 de Adenosina/administração & dosagem
Ansiolíticos/administração & dosagem
Transtornos de Ansiedade/tratamento farmacológico
Piperazinas/administração & dosagem
Receptor A1 de Adenosina/metabolismo
Tiofenos/administração & dosagem
[Mh] Termos MeSH secundário: Adenosina/administração & dosagem
Adenosina/análogos & derivados
Antagonistas do Receptor A1 de Adenosina/administração & dosagem
Regulação Alostérica
Tonsila do Cerebelo/efeitos dos fármacos
Tonsila do Cerebelo/metabolismo
Animais
Diazepam/administração & dosagem
Etanol/administração & dosagem
Comportamento Exploratório/efeitos dos fármacos
Hipocampo/efeitos dos fármacos
Hipocampo/metabolismo
Masculino
Camundongos
Atividade Motora/efeitos dos fármacos
Córtex Pré-Frontal/efeitos dos fármacos
Córtex Pré-Frontal/metabolismo
Reflexo de Endireitamento/efeitos dos fármacos
Teste de Desempenho do Rota-Rod
Xantinas/administração & dosagem
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (2-amino-4-((4-(phenyl)piperazin-1-yl)methyl)-5-(4-fluorophenyl)thiophen-3-yl)-(4-chlorophenyl)methanone); 0 (Adenosine A1 Receptor Agonists); 0 (Adenosine A1 Receptor Antagonists); 0 (Anti-Anxiety Agents); 0 (Piperazines); 0 (Receptor, Adenosine A1); 0 (Thiophenes); 0 (Xanthines); 37739-05-2 (2-chloro-N(6)cyclopentyladenosine); 3K9958V90M (Ethanol); 9PTP4FOI9E (1,3-dipropyl-8-cyclopentylxanthine); K72T3FS567 (Adenosine); Q3JTX2Q7TU (Diazepam)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170713
[Lr] Data última revisão:
170713
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160919
[St] Status:MEDLINE


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[PMID]:27578262
[Au] Autor:Porcu A; Lobina C; Giunta D; Solinas M; Mugnaini C; Castelli MP
[Ad] Endereço:Department of Biomedical Sciences, Division of Neuroscience and Clinical Pharmacology, University of Cagliari, Cagliari, Italy.
[Ti] Título:In vitro and in vivo pharmacological characterization of SSD114, a novel GABAB positive allosteric modulator.
[So] Source:Eur J Pharmacol;791:115-123, 2016 Nov 15.
[Is] ISSN:1879-0712
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Positive allosteric modulators (PAMs) of the GABA receptor have emerged as a novel approach to the pharmacological manipulation of the GABA receptor, enhancing the effects of receptor agonists with few side effects. Here, we identified N-cyclohexyl-4-methoxy-6-(4-(trifluoromethyl)phenyl)pyrimidin-2-amine (SSD114) as a new compound with activity as a GABA PAM in in vitro and in vivo assays. SSD114 potentiated GABA-stimulated [ S]GTPγS binding to native GABA receptors, whereas it had no effect when used alone. Its effect on GTPγS stimulation was suppressed when GABA-induced activation was blocked with CGP54626, a competitive antagonist of the GABA receptor. SSD114 failed to potentiate WIN55,212,2-, morphine- and quinpirole-induced [ S]GTPγS binding to cortical and striatal membranes, respectively, indicating that it is a selective GABA PAM. Increasing SSD114 fixed concentrations induced a leftward shift of the GABA concentration-response curve, enhancing the potency of GABA rather than its efficacy. SSD114 concentration-response curves in the presence of fixed concentrations of GABA (1, 10, and 20µM) revealed a potentiating effect on GABA-stimulated binding of [ S]GTPγS to rat cortical membranes, with EC values in the low micromolar range. Bioluminescence resonance energy transfer (BRET) experiments in Chinese Hamster Ovary (CHO)-cells expressing GABA receptors showed that SSD114 potentiates the GABA inhibition of adenylyl-cyclase mediated by GABA receptors. Our compound is also effective in vivo potentiating baclofen-induced sedation/hypnosis in mice, with no effect when tested alone. These findings indicate that SSD114, a molecule with a different chemical structure compared to known GABA PAMs, is a novel GABA PAM with potential usefulness in the GABA -receptor research field.
[Mh] Termos MeSH primário: Cicloexilaminas/farmacologia
Pirimidinas/farmacologia
Receptores de GABA-B/metabolismo
[Mh] Termos MeSH secundário: Regulação Alostérica/efeitos dos fármacos
Animais
Baclofeno/farmacologia
Células CHO
Membrana Celular/efeitos dos fármacos
Membrana Celular/metabolismo
Córtex Cerebral/citologia
Cricetinae
Cricetulus
Cicloexilaminas/metabolismo
Masculino
Camundongos
Pirimidinas/metabolismo
Ratos
Receptores de GABA-B/química
Reflexo de Endireitamento/efeitos dos fármacos
Ácido gama-Aminobutírico/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Cyclohexylamines); 0 (N-cyclohexyl-4-methoxy-6-(4-(trifluoromethyl)phenyl)pyrimidin-2-amine); 0 (Pyrimidines); 0 (Receptors, GABA-B); 56-12-2 (gamma-Aminobutyric Acid); H789N3FKE8 (Baclofen)
[Em] Mês de entrada:1703
[Cu] Atualização por classe:170821
[Lr] Data última revisão:
170821
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160901
[St] Status:MEDLINE



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