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[PMID]:28457510
[Au] Autor:Kanawaku Y; Hirakawa K; Koike K; Kanetake J; Ohno Y
[Ad] Endereço:Department of Legal Medicine, Nippon Medical School, 1-1-5 Sendagi Bunkyo-ku, Tokyo 113-8602, Japan. Electronic address: ykanawaku@nifty.com.
[Ti] Título:Pattern recognition analysis of proton nuclear magnetic resonance spectra of postmortem cerebrospinal fluid from rats with drug-induced seizure or coma.
[So] Source:Leg Med (Tokyo);25:52-58, 2017 Mar.
[Is] ISSN:1873-4162
[Cp] País de publicação:Ireland
[La] Idioma:eng
[Ab] Resumo:Cerebrospinal fluid (CSF) is routinely subjected to gross evaluation in postmortem investigations; however, its use in chemical evaluations has not been fully realized. Analysis of nuclear magnetic resonance (NMR) spectra with pattern recognition methods was applied to CSF samples. Rats were treated with pentylenetetrazol (PTZ) to induce seizure or pentobarbital (PB) to induce coma, and postmortem CSF was collected after CO gas euthanization. Pattern recognition analysis of the NMR data was performed on individual postmortem CSF samples. The aim of this study was to determine if pattern recognition analysis of NMR data could be used to classify the rats according to their drug treatment. The applicability of NMR data with pattern recognition analysis using postmortem CSF was also assessed. Partial Least Squares-Discriminant Analysis (PLS-DA) score plots indicated that the PTZ, PB, and NS (control) groups were clustered and clearly separated. PLS-DA correlation loading plots showed respective spectral and category variances of 41% and 42% for factor 1, and 17% and 27% for factor 2. Thus, factors 1 and 2 together described 58% (41%+17%) and 69% (42%+27%) of the variation, respectively. NMR study of postmortem CSF has the potential to be utilized as both a novel forensic neurochemistry method and in the clinical setting.
[Mh] Termos MeSH primário: Líquido Cefalorraquidiano/efeitos dos fármacos
Coma/induzido quimicamente
Espectroscopia de Ressonância Magnética
Mudanças Depois da Morte
Convulsões/induzido quimicamente
[Mh] Termos MeSH secundário: Animais
Convulsivantes/toxicidade
Análise Discriminante
Hipnóticos e Sedativos/toxicidade
Metabolômica
Pentobarbital/toxicidade
Pentilenotetrazol/toxicidade
Ratos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Convulsants); 0 (Hypnotics and Sedatives); I4744080IR (Pentobarbital); WM5Z385K7T (Pentylenetetrazole)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180307
[Lr] Data última revisão:
180307
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170502
[St] Status:MEDLINE


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[PMID]:29220646
[Au] Autor:Hu P; Fabyanic E; Kwon DY; Tang S; Zhou Z; Wu H
[Ad] Endereço:Department of Genetics, University of Pennsylvania, Philadelphia PA 19104, USA; Epigenetics Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia PA 19104, USA.
[Ti] Título:Dissecting Cell-Type Composition and Activity-Dependent Transcriptional State in Mammalian Brains by Massively Parallel Single-Nucleus RNA-Seq.
[So] Source:Mol Cell;68(5):1006-1015.e7, 2017 Dec 07.
[Is] ISSN:1097-4164
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Massively parallel single-cell RNA sequencing can precisely resolve cellular diversity in a high-throughput manner at low cost, but unbiased isolation of intact single cells from complex tissues such as adult mammalian brains is challenging. Here, we integrate sucrose-gradient-assisted purification of nuclei with droplet microfluidics to develop a highly scalable single-nucleus RNA-seq approach (sNucDrop-seq), which is free of enzymatic dissociation and nucleus sorting. By profiling ∼18,000 nuclei isolated from cortical tissues of adult mice, we demonstrate that sNucDrop-seq not only accurately reveals neuronal and non-neuronal subtype composition with high sensitivity but also enables in-depth analysis of transient transcriptional states driven by neuronal activity, at single-cell resolution, in vivo.
[Mh] Termos MeSH primário: Núcleo Celular/metabolismo
Córtex Cerebral/metabolismo
Sequenciamento de Nucleotídeos em Larga Escala
Neurônios/metabolismo
RNA/genética
Convulsões/genética
Análise de Sequência de RNA/métodos
Análise de Célula Única/métodos
Transcrição Genética
[Mh] Termos MeSH secundário: Animais
Núcleo Celular/patologia
Centrifugação com Gradiente de Concentração
Córtex Cerebral/patologia
Córtex Cerebral/fisiopatologia
Modelos Animais de Doenças
Células-Tronco Embrionárias Humanas/metabolismo
Seres Humanos
Cinética
Masculino
Camundongos
Camundongos Endogâmicos C57BL
Técnicas Analíticas Microfluídicas
Células NIH 3T3
Inibição Neural
Neurônios/patologia
Pentilenotetrazol
RNA/metabolismo
Convulsões/metabolismo
Convulsões/patologia
Convulsões/fisiopatologia
Transmissão Sináptica
Transfecção
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
63231-63-0 (RNA); WM5Z385K7T (Pentylenetetrazole)
[Em] Mês de entrada:1712
[Cu] Atualização por classe:180228
[Lr] Data última revisão:
180228
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171209
[St] Status:MEDLINE


  3 / 5239 MEDLINE  
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[PMID]:29244918
[Au] Autor:Kuznetsova LV; Karpova MN; Zinkovski KA; Klishina NY
[Ti] Título:Аnticonvulsant effects of citicoline and diazepam at their combined application on model of the acute generalized convulsions induced by pentylenetetrazole in Wistar rats.
[So] Source:Patol Fiziol Eksp Ter;60(4):20-3, 2016 Oct-Dec.
[Is] ISSN:0031-2991
[Cp] País de publicação:Russia (Federation)
[La] Idioma:eng
[Ab] Resumo:The purpose: Studying of efficiency of the combined application of the citicoline possessing nootropic and anticonvulsive action and antiepileptic drug of diazepam on the acute generalized convulsions (AGC) caused by a convulsant pentylentetrazole (PTZ). Methods: Experiments are executed on the male Wistar rats (n = 68) weighing 160-190 g on the AGС model caused by of PTZ in a dose of 80 mg/kg, intraperitoneally (i.p.). For studying of efficiency of the combined use of drugs determined the minimum anticonvulsive action of a citicoline (Tserakson, «Nicomed Ferrer Internacional, S.A.¼) and diazepam (Relanium, Warsaw pharmaceutical plant of Polf AO, Warsaw, Poland). For this citicoline were administered i.p. in doses 500 and 300 mg/kg 1 hour before the PTZ and diazepam - in doses of 0,5 and 0,25 mg/kg 30 min before administration of PTZ. Control animals were injected with saline to the same extent and under the same experimental conditions. Results: It is shown that the combined administration of a citicoline and diazepam in minimum active doses (300 and 0.25 mg/kg respectively), increases anticonvulsive properties of both drugs. Conclusion: The combined administration of citicoline with diazepam in minimally active doses enhances anticonvulsant properties of both drugs, thereby reducing the risk of development of side effects. In addition, the research may serve as experimental justification for the use of drugs in case of convulsions for the purpose beneficial effect on cognitive function and delays of progressing of neurodegenerative processes.
[Mh] Termos MeSH primário: Anticonvulsivantes/farmacologia
Citidina Difosfato Colina/farmacologia
Diazepam/farmacologia
Pentilenotetrazol/efeitos adversos
Convulsões
[Mh] Termos MeSH secundário: Animais
Masculino
Pentilenotetrazol/farmacologia
Ratos
Ratos Wistar
Convulsões/induzido quimicamente
Convulsões/tratamento farmacológico
Convulsões/fisiopatologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Anticonvulsants); 536BQ2JVC7 (Cytidine Diphosphate Choline); Q3JTX2Q7TU (Diazepam); WM5Z385K7T (Pentylenetetrazole)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180118
[Lr] Data última revisão:
180118
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171216
[St] Status:MEDLINE


  4 / 5239 MEDLINE  
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[PMID]:28958944
[Au] Autor:Gao W; Bi Y; Ding L; Zhu W; Ye M
[Ad] Endereço:Department of Neurosurgery, The First Affiliated Hospital of Suzhou University, Suzhou 215000, China.
[Ti] Título:SSa ameliorates the Glu uptaking capacity of astrocytes in epilepsy via AP-1/miR-155/GLAST.
[So] Source:Biochem Biophys Res Commun;493(3):1329-1335, 2017 Nov 25.
[Is] ISSN:1090-2104
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Neuronal glutamate (Glu) release has been reported to mediate the neuronal injury of epilepsy, while Saikosaponin a (Ssa) was shown to ameliorate the epilepsy that induced by pentylenetetrazol (PTZ). However, potential interactions between glutamate release and Ssa has not been fully identified. METHODS: Herein, PTZ-induced rat model were established to evaluate the neuron injury, while Ssa was used to treat the model rat. Rat astrocytes were isolated and induced by PTZ to construct cell models of epilepsy, real-time PCR and western blot were used to determine genes' expression. Luciferase reporter assay were performed to validate the relationship between miR-155-5p and glutamate aspartate transporter (GLAST). The level of Glu was sampled for HPLC measurement. RESULTS: Ssa treatment could decrease the level of Glu in hippocampus of rat. PTZ-induced astrocytes pretreated with Ssa significantly decreased the expression of AP-1 and miR-155, but increased the expression of GLAST, furthermore, PTZ stimulation enables astrocytes to uptake large amount of extracellular Glu. AP-1 could bind with the promoter of miR-155 to promote its transcription. MiR-155 tragets GLAST to govern its expression. CONCLUSION: Ssa treatment played pivotal roles in PTZ-induced epilepsy by promoting the expression of GLAT1 and uptaking of Glu, which was mediated by the expression of AP-1 and miR-155.
[Mh] Termos MeSH primário: Astrócitos/efeitos dos fármacos
Epilepsia/tratamento farmacológico
Transportador 1 de Aminoácido Excitatório/metabolismo
Ácido Glutâmico/metabolismo
Ácido Oleanólico/análogos & derivados
Saponinas/farmacologia
[Mh] Termos MeSH secundário: Animais
Astrócitos/metabolismo
Modelos Animais de Doenças
Epilepsia/induzido quimicamente
Epilepsia/metabolismo
Hipocampo/efeitos dos fármacos
Hipocampo/metabolismo
MicroRNAs/metabolismo
Ácido Oleanólico/farmacologia
Pentilenotetrazol/toxicidade
Proteínas Proto-Oncogênicas c-fos/metabolismo
Ratos Wistar
Fator de Transcrição AP-1/metabolismo
Ácido gama-Aminobutírico/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Excitatory Amino Acid Transporter 1); 0 (Fosb protein, rat); 0 (MIRN155 microRNA, rat); 0 (MicroRNAs); 0 (Proto-Oncogene Proteins c-fos); 0 (Saponins); 0 (Slc1a3 protein, rat); 0 (Transcription Factor AP-1); 3KX376GY7L (Glutamic Acid); 56-12-2 (gamma-Aminobutyric Acid); 6SMK8R7TGJ (Oleanolic Acid); UR635J3F00 (saikosaponin); WM5Z385K7T (Pentylenetetrazole)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171027
[Lr] Data última revisão:
171027
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170930
[St] Status:MEDLINE


  5 / 5239 MEDLINE  
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[PMID]:28833036
[Au] Autor:Nemes AD; O'Dwyer R; Najm IM; Ying Z; Gonzalez-Martinez J; Alexopoulos AV
[Ad] Endereço:Epilepsy Center, Neurological Institute, Cleveland Clinic, Cleveland, Ohio, U.S.A.
[Ti] Título:Treatment with lacosamide impedes generalized seizures in a rodent model of cortical dysplasia.
[So] Source:Epilepsia;58(10):1755-1761, 2017 Oct.
[Is] ISSN:1528-1167
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:OBJECTIVE: Epilepsy is a common neurologic disorder resulting in spontaneous, recurrent seizures. About 30-40% of patients are not responsive to pharmacologic therapies. This may be due to the differences between individual patients such as etiology, underlying pathophysiology, and seizure focus, and it highlights the importance of new drug discovery and testing in this field. Our goal was to determine the efficacy of lacosamide (LCM), a drug approved for the treatment of focal seizures, in a model of generalized epilepsy with cortical dysplasia (CD). We sought to compare LCM to levetiracetam (LEV), a drug that is currently used for the treatment of both partial and generalized epilepsy and to test its proficiency. METHODS: Pregnant rats were irradiated to produce pups with malformed cortices in a model of CD, which will be referred to as the "first hit." Adult animals, developed normally (NL) and irradiated (XRT), were surgically implanted with electroencephalography (EEG) electrodes. Baseline EEG was recorded on all rats prior to pretreatments with either LCM, LEV, or placebo (PBO). After 30 min, all rats were injected with a subconvulsive dose of pentylenetetrazole (PTZ), a γ-aminobutyric acid receptor A (GABA ) antagonist used to provoke generalized seizures as a "second hit." RESULTS: LCM and LEV were both effective against seizures induced by PTZ. XRT rats had a higher seizure incidence with longer and more severe seizures than NL rats. Seizure duration was decreased with both LCM and LEV in all animals. In XRT rats, there was a significant reduction in acute seizure incidence and severity with both LCM and LEV after PTZ injection. SIGNIFICANCE: Our results suggest that LCM could be used as a potential treatment option for generalized epilepsy with CD as the underlying pathology.
[Mh] Termos MeSH primário: Acetamidas/farmacologia
Anticonvulsivantes/farmacologia
Malformações do Desenvolvimento Cortical/fisiopatologia
Convulsões/fisiopatologia
[Mh] Termos MeSH secundário: Animais
Eletroencefalografia
Feminino
Antagonistas GABAérgicos/toxicidade
Malformações do Desenvolvimento Cortical/etiologia
Pentilenotetrazol/toxicidade
Piracetam/análogos & derivados
Piracetam/farmacologia
Gravidez
Efeitos Tardios da Exposição Pré-Natal
Exposição à Radiação/efeitos adversos
Ratos
Ratos Sprague-Dawley
Convulsões/induzido quimicamente
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Acetamides); 0 (Anticonvulsants); 0 (GABA Antagonists); 230447L0GL (etiracetam); 563KS2PQY5 (lacosamide); WM5Z385K7T (Pentylenetetrazole); ZH516LNZ10 (Piracetam)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171010
[Lr] Data última revisão:
171010
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170824
[St] Status:MEDLINE
[do] DOI:10.1111/epi.13856


  6 / 5239 MEDLINE  
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[PMID]:28806600
[Au] Autor:Sahu M; Siddiqui N; Iqbal R; Sharma V; Wakode S
[Ad] Endereço:Department of Pharmaceutical Chemistry, School of Pharmaceutical Education & Research (Formerly, Faculty of Pharmacy), Jamia Hamdard, New Delhi 110062, India.
[Ti] Título:Design, synthesis and evaluation of newer 5,6-dihydropyrimidine-2(1H)-thiones as GABA-AT inhibitors for anticonvulsant potential.
[So] Source:Bioorg Chem;74:166-178, 2017 Oct.
[Is] ISSN:1090-2120
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Several new 5,6-dihydropyrimidine-2(1H)-thione derivatives have been prepared and investigated for their potencies for anticonvulsant activity against maximal electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ) test in mice. The acute neurotoxicity was measured by rotarod test. Compounds 3c and 3l were found active in both of the animal models. Further, in vitro GABA-AT enzyme activity assay was carried out to investigate the possible mechanism of action through GABA-AT inhibition. The most potent compounds 3c and 3l showed inhibitory potency (IC ) of 18.42µM and 19.23µM, respectively. The molecular modeling was performed for all the synthesized compounds. The docking results were found in concordant with the observed animal studies.
[Mh] Termos MeSH primário: 4-Aminobutirato Transaminase/antagonistas & inibidores
Anticonvulsivantes/farmacologia
Desenho de Drogas
Inibidores Enzimáticos/farmacologia
Pirimidinas/farmacologia
Convulsões/tratamento farmacológico
Tionas/farmacologia
[Mh] Termos MeSH secundário: 4-Aminobutirato Transaminase/metabolismo
Animais
Anticonvulsivantes/síntese química
Anticonvulsivantes/química
Relação Dose-Resposta a Droga
Eletrochoque
Inibidores Enzimáticos/síntese química
Inibidores Enzimáticos/química
Camundongos
Modelos Moleculares
Estrutura Molecular
Pentilenotetrazol
Pirimidinas/síntese química
Pirimidinas/química
Relação Estrutura-Atividade
Tionas/síntese química
Tionas/química
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (5,6-dihydropyrimidine-2(1H)-thione); 0 (Anticonvulsants); 0 (Enzyme Inhibitors); 0 (Pyrimidines); 0 (Thiones); EC 2.6.1.19 (4-Aminobutyrate Transaminase); WM5Z385K7T (Pentylenetetrazole)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171010
[Lr] Data última revisão:
171010
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170815
[St] Status:MEDLINE


  7 / 5239 MEDLINE  
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Wajner, Moacir
Texto completo
[PMID]:28762469
[Au] Autor:Vendramin Pasquetti M; Meier L; Loureiro S; Ganzella M; Junges B; Barbieri Caus L; Umpierrez Amaral A; Koeller DM; Goodman S; Woontner M; Gomes de Souza DO; Wajner M; Calcagnotto ME
[Ad] Endereço:Postgraduate Program in Biological Sciences: Biochemistry, Department of Biochemistry, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
[Ti] Título:Impairment of GABAergic system contributes to epileptogenesis in glutaric acidemia type I.
[So] Source:Epilepsia;58(10):1771-1781, 2017 Oct.
[Is] ISSN:1528-1167
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:OBJECTIVES: Glutaric acidemia type I (GA-I) is an inherited neurometabolic disorder caused by deficiency of glutaryl-CoA dehydrogenase (GCDH) and characterized by increased levels of glutaric, 3-OH-glutaric, and glutaconic acids in the brain parenchyma. The increment of these organic acids inhibits glutamate decarboxylase (GAD) and consequently lowers the γ-aminobutyric acid (GABA) synthesis. Untreated patients exhibit severe neurologic deficits during development, including epilepsy, especially following an acute encephalopathy outbreak. In this work, we evaluated the role of the GABAergic system on epileptogenesis in GA-I using the Gcdh mice exposed to a high lysine diet (Gcdh -Lys). METHODS: Spontaneous recurrent seizures (SRS), seizure susceptibility, and changes in brain oscillations were evaluated by video-electroencephalography (EEG). Cortical GABAergic synaptic transmission was evaluated using electrophysiologic and neurochemical approaches. RESULTS: SRS were observed in 72% of Gcdh -Lys mice, whereas no seizures were detected in age-matched controls (Gcdh or Gcdh receiving normal diet). The severity and number of PTZ-induced seizures were higher in Gcdh -Lys mice. EEG spectral analysis showed a significant decrease in theta and gamma oscillations and predominant delta waves in Gcdh -Lys mice, associated with increased EEG left index. Analysis of cortical synaptosomes revealed a significantly increased percentage of glutamate release and decreased GABA release in Gcdh -Lys mice that were associated with a decrease in cortical GAD immunocontent and activity and confirmed by reduced frequency of inhibitory events in cortical pyramidal cells. SIGNIFICANCE: Using an experimental model with a phenotype similar to that of GA-I in humans-the Gcdh mice under high lysine diet (Gcdh -Lys)-we provide evidence that a reduction in cortical inhibition of Gcdh -Lys mice, probably induced by GAD dysfunction, leads to hyperexcitability and increased slow oscillations associated with neurologic abnormalities in GA-I. Our findings offer a new perspective on the pathophysiology of brain damage in GA-I.
[Mh] Termos MeSH primário: Erros Inatos do Metabolismo dos Aminoácidos/genética
Encefalopatias Metabólicas/genética
Encéfalo/efeitos dos fármacos
Epilepsia/genética
Glutaril-CoA Desidrogenase/deficiência
Glutaril-CoA Desidrogenase/genética
Ácido gama-Aminobutírico/efeitos dos fármacos
[Mh] Termos MeSH secundário: Erros Inatos do Metabolismo dos Aminoácidos/metabolismo
Animais
Western Blotting
Encefalopatias Metabólicas/metabolismo
Cromatografia Líquida de Alta Pressão
Epilepsia/metabolismo
Antagonistas GABAérgicos/farmacologia
Glutamato Descarboxilase
Ácido Glutâmico/efeitos dos fármacos
Ácido Glutâmico/metabolismo
Glutaril-CoA Desidrogenase/metabolismo
Camundongos
Camundongos Knockout
Pentilenotetrazol/farmacologia
Sinaptossomos/efeitos dos fármacos
Sinaptossomos/metabolismo
Ácido gama-Aminobutírico/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (GABA Antagonists); 3KX376GY7L (Glutamic Acid); 56-12-2 (gamma-Aminobutyric Acid); EC 1.3.8.6 (Glutaryl-CoA Dehydrogenase); EC 4.1.1.15 (Glutamate Decarboxylase); WM5Z385K7T (Pentylenetetrazole)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171010
[Lr] Data última revisão:
171010
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170802
[St] Status:MEDLINE
[do] DOI:10.1111/epi.13862


  8 / 5239 MEDLINE  
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[PMID]:28733354
[Au] Autor:Drexel M; Romanov RA; Wood J; Weger S; Heilbronn R; Wulff P; Tasan RO; Harkany T; Sperk G
[Ad] Endereço:Department of Pharmacology, Medical University Innsbruck, 6020 Innsbruck, Austria, guenther.sperk@i-med.ac.at meinrad.drexel@i-med.ac.at.
[Ti] Título:Selective Silencing of Hippocampal Parvalbumin Interneurons Induces Development of Recurrent Spontaneous Limbic Seizures in Mice.
[So] Source:J Neurosci;37(34):8166-8179, 2017 Aug 23.
[Is] ISSN:1529-2401
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Temporal lobe epilepsy (TLE) is the most frequent form of focal epilepsies and is generally associated with malfunctioning of the hippocampal formation. Recently, a preferential loss of parvalbumin (PV) neurons has been observed in the subiculum of TLE patients and in animal models of TLE. To demonstrate a possible causative role of defunct PV neurons in the generation of TLE, we permanently inhibited GABA release selectively from PV neurons of the ventral subiculum by injecting a viral vector expressing tetanus toxin light chain in male mice. Subsequently, mice were subjected to telemetric EEG recording and video monitoring. Eighty-eight percent of the mice presented clusters of spike-wave discharges (C-SWDs; 40.0 ± 9.07/month), and 64% showed spontaneous recurrent seizures (SRSs; 5.3 ± 0.83/month). Mice injected with a control vector presented with neither C-SWDs nor SRSs. No neurodegeneration was observed due to vector injection or SRS. Interestingly, mice that presented with only C-SWDs but no SRSs, developed SRSs upon injection of a subconvulsive dose of pentylenetetrazole after 6 weeks. The initial frequency of SRSs declined by ∼30% after 5 weeks. In contrast to permanent silencing of PV neurons, transient inhibition of GABA release from PV neurons through the designer receptor hM4Di selectively expressed in PV-containing neurons transiently reduced the seizure threshold of the mice but induced neither acute nor recurrent seizures. Our data demonstrate a critical role for perisomatic inhibition mediated by PV-containing interneurons, suggesting that their sustained silencing could be causally involved in the development of TLE. Development of temporal lobe epilepsy (TLE) generally takes years after an initial insult during which maladaptation of hippocampal circuitries takes place. In human TLE and in animal models of TLE, parvalbumin neurons are selectively lost in the subiculum, the major output area of the hippocampus. The present experiments demonstrate that specific and sustained inhibition of GABA release from parvalbumin-expressing interneurons (mostly basket cells) in sector CA1/subiculum is sufficient to induce hyperexcitability and spontaneous recurrent seizures in mice. As in patients with nonlesional TLE, these mice developed epilepsy without signs of neurodegeneration. The experiments highlight the importance of the potent inhibitory action mediated by parvalbumin cells in the hippocampus and identify a potential mechanism in the development of TLE.
[Mh] Termos MeSH primário: Hipocampo/fisiopatologia
Interneurônios/fisiologia
Parvalbuminas/antagonistas & inibidores
Parvalbuminas/fisiologia
Convulsões/fisiopatologia
[Mh] Termos MeSH secundário: Animais
Eletroencefalografia/métodos
Hipocampo/efeitos dos fármacos
Potenciais Pós-Sinápticos Inibidores/efeitos dos fármacos
Potenciais Pós-Sinápticos Inibidores/fisiologia
Interneurônios/efeitos dos fármacos
Masculino
Camundongos
Camundongos Endogâmicos C57BL
Camundongos Transgênicos
Técnicas de Cultura de Órgãos
Pentilenotetrazol/toxicidade
Convulsões/induzido quimicamente
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Parvalbumins); WM5Z385K7T (Pentylenetetrazole)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170914
[Lr] Data última revisão:
170914
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170723
[St] Status:MEDLINE
[do] DOI:10.1523/JNEUROSCI.3456-16.2017


  9 / 5239 MEDLINE  
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[PMID]:28733205
[Au] Autor:Garlet QI; Pires LDC; Milanesi LH; Marafiga JR; Baldisserotto B; Mello CF; Heinzmann BM
[Ad] Endereço:Post-Graduation Program in Pharmacology, Federal University of Santa Maria, Santa Maria, RS, Brazil.
[Ti] Título:(+)-Dehydrofukinone modulates membrane potential and delays seizure onset by GABAa receptor-mediated mechanism in mice.
[So] Source:Toxicol Appl Pharmacol;332:52-63, 2017 Oct 01.
[Is] ISSN:1096-0333
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:(+)-Dehydrofukinone (DHF), isolated from Nectandra grandiflora (Lauraceae) essential oil, induces sedation and anesthesia by modulation of GABAa receptors. However, no study has addressed whether DHF modulates other cellular events involved in the control of cellular excitability, such as seizure behavior. Therefore, the aim of the present study was to investigate the effect of DHF on cellular excitability and seizure behavior in mice. For this purpose, we used isolated nerve terminals (synaptosomes) to examine the effect of DHF on the plasma membrane potential, the involvement of GABAa receptors and the downstream activation of Ca mobilization. Finally, we performed an in vivo assay in order to verify whether DHF could impact on seizures induced by pentylenetetrazole (PTZ) in mice. The results showed that DHF induced a GABA-dependent sustained hyperpolarization, sensitive to flumazenil and absent in low-[Cl ] medium. Additionally, (1-100µM) DHF decreased KCl-evoked calcium mobilization over time in a concentration-dependent manner and this effect was prevented by flumazenil. DHF increased the latency to myoclonic jerks (10mg/kg), delayed the onset of generalized tonic-clonic seizures (10, 30 and 100mg/kg), and these effects were also blocked by the pretreatment with flumazenil. Our data indicate that DHF has anticonvulsant properties and the molecular target underlying this effect is likely to be the facilitation of GABAergic neuronal inhibition. The present study highlights the therapeutic potential of the natural compound DHF as a suppressor of neuronal excitability.
[Mh] Termos MeSH primário: Moduladores GABAérgicos/farmacologia
Potenciais da Membrana/efeitos dos fármacos
Receptores de GABA-A/metabolismo
Convulsões/tratamento farmacológico
Sesquiterpenos/farmacologia
[Mh] Termos MeSH secundário: Animais
Anticonvulsivantes/farmacologia
Feminino
Flumazenil/farmacologia
Camundongos
Pentilenotetrazol
Convulsões/induzido quimicamente
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Anticonvulsants); 0 (GABA Modulators); 0 (Receptors, GABA-A); 0 (Sesquiterpenes); 0 (dehydrofukinone); 40P7XK9392 (Flumazenil); WM5Z385K7T (Pentylenetetrazole)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170925
[Lr] Data última revisão:
170925
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170723
[St] Status:MEDLINE


  10 / 5239 MEDLINE  
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[PMID]:28586508
[Au] Autor:Huang X; Zhou C; Tian M; Kang JQ; Shen W; Verdier K; Pimenta A; MacDonald RL
[Ad] Endereço:The Graduate Program of Neuroscience, Vanderbilt University Medical Center, Nashville, Tennessee, U.S.A.
[Ti] Título:Overexpressing wild-type γ2 subunits rescued the seizure phenotype in Gabrg2 Dravet syndrome mice.
[So] Source:Epilepsia;58(8):1451-1461, 2017 Aug.
[Is] ISSN:1528-1167
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:OBJECTIVE: The mutant γ-aminobutyric acid type A (GABA ) receptor γ2(Q390X) subunit (Q351X in the mature peptide) has been associated with the epileptic encephalopathy, Dravet syndrome, and the epilepsy syndrome genetic epilepsy with febrile seizures plus (GEFS+). The mutation generates a premature stop codon that results in translation of a stable truncated and misfolded γ2 subunit that accumulates in neurons, forms intracellular aggregates, disrupts incorporation of γ2 subunits into GABA receptors, and affects trafficking of partnering α and ß subunits. Heterozygous Gabrg2 knock-in (KI) mice had reduced cortical inhibition, spike wave discharges on electroencephalography (EEG), a lower seizure threshold to the convulsant drug pentylenetetrazol (PTZ), and spontaneous generalized tonic-clonic seizures. In this proof-of-principal study, we attempted to rescue these deficits in KI mice using a γ2 subunit gene (GABRG2) replacement therapy. METHODS: We introduced the GABRG2 allele by crossing Gabrg2 KI mice with bacterial artificial chromosome (BAC) transgenic mice overexpressing HA (hemagglutinin)-tagged human γ2 subunits, and compared GABA receptor subunit expression by Western blot and immunohistochemical staining, seizure threshold by monitoring mouse behavior after PTZ-injection, and thalamocortical inhibition and network oscillation by slice recording. RESULTS: Compared to KI mice, adult mice carrying both mutant allele and transgene had increased wild-type γ2 and partnering α1 and ß2/3 subunits, increased miniature inhibitory postsynaptic current (mIPSC) amplitudes recorded from layer VI cortical neurons, reduced thalamocortical network oscillations, and higher PTZ seizure threshold. SIGNIFICANCE: Based on these results we suggest that seizures in a genetic epilepsy syndrome caused by epilepsy mutant γ2(Q390X) subunits with dominant negative effects could be rescued potentially by overexpression of wild-type γ2 subunits.
[Mh] Termos MeSH primário: Epilepsias Mioclônicas/genética
Epilepsias Mioclônicas/terapia
Mutação/genética
Subunidades Proteicas/metabolismo
Receptores de GABA-A/genética
Receptores de GABA-A/metabolismo
[Mh] Termos MeSH secundário: Potenciais de Ação/efeitos dos fármacos
Potenciais de Ação/genética
Animais
Convulsivantes/toxicidade
Estimulação Elétrica
Seres Humanos
Técnicas In Vitro
Potenciais Pós-Sinápticos Inibidores/efeitos dos fármacos
Potenciais Pós-Sinápticos Inibidores/genética
Masculino
Camundongos
Camundongos Endogâmicos C57BL
Camundongos Transgênicos
Vias Neurais/efeitos dos fármacos
Vias Neurais/fisiologia
Técnicas de Patch-Clamp
Pentilenotetrazol/toxicidade
Subunidades Proteicas/genética
Células Piramidais/efeitos dos fármacos
Células Piramidais/fisiologia
Córtex Somatossensorial/citologia
Tálamo/citologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Convulsants); 0 (GABRG2 protein, human); 0 (Protein Subunits); 0 (Receptors, GABA-A); WM5Z385K7T (Pentylenetetrazole)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170817
[Lr] Data última revisão:
170817
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170607
[St] Status:MEDLINE
[do] DOI:10.1111/epi.13810



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