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1.
J Nanosci Nanotechnol ; 21(3): 1703-1710, 2021 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-33404436

RESUMO

In this study, pulsed laser deposition method (PLD) was employed to grow MgxZn1-xO films on quartz substrates. The optimal deposition temperature of 300 °C for MgxZn1-xO film was decided and Mg0.38Zn0.62O, Mg0.56Zn0.44O and Mg0.69Zn0.31O films were grown respectively using MgxZn1-xO targets with different Mg contents (x = 0.3, 0.5 and 0.7). As-deposited Mg0.38Zn0.62O film possessed the mixed-phase (hexagonal and cubic phase) structure, appropriate band gap of 4.68 eV and smaller surface roughness of 1.72 nm, and the solar-blind photodetector (PD) based on it was fabricated. The key features of our PD are the cutoff wavelength of 265 nm lying in solar-blind band, lower dark current (Idark) of 88 pA, higher peak responsivity of 0.10 A/W and bigger Ilight/Idark ratio of 1688, which provide the new idea for the application of solar-blind PDs based on MgxZn1-xO films.

2.
Neurotherapeutics ; 17(3): 1087-1103, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32096091

RESUMO

Alzheimer's disease (AD) is a multifactorial neurodegenerative disease for which there are limited therapeutic strategies. Protein phosphatase 2A (PP2A) activity is decreased in AD brains, which promotes the hyperphosphorylation of Tau and APP, thus participate in the formation of neurofibrillary tangles (NFTs) and ß-amyloid (Aß) overproduction. In this study, the effect of synthetic tricyclic sulfonamide PP2A activators (aka SMAPs) on reducing AD-like pathogenesis was evaluated in AD cell models and AD-like hyperhomocysteinemia (HHcy) rat models. SMAPs effectively increased PP2A activity, and decreased tau phosphorylation and Aß40/42 levels in AD cell models. In HHcy-AD rat models, cognitive impairments induced by HHcy were rescued by SMAP administration. HHcy-induced tau hyperphosphorylation and Aß overproduction were ameliorated through increasing PP2A activity on compound treatment. Importantly, SMAP therapy also prevented neuronal cell spine loss and neuronal synapse impairment in the hippocampus of HHcy-AD rats. In summary, our data reveal that pharmacological PP2A reactivation may be a novel therapeutic strategy for AD treatment, and that the tricyclic sulfonamides constitute a novel candidate class of AD therapeutic.

3.
J Nanosci Nanotechnol ; 20(4): 2550-2557, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-31492275

RESUMO

In this study, pulsed laser deposition method (PLD) was employed to grow MgxZn1-xO films on quartz substrates. The optimal deposition temperature of 300 °C for MgxZn1-xO film was decided and Mg0.38Zn0.62O, Mg0.56Zn0.44O and Mg0.69Zn0.31O films were grown respectively using MgxZn1-xO targets with different Mg contents (x = 0.3, 0.5 and 0.7). As-deposited Mg0.38Zn0.62O film possessed the mixed-phase (hexagonal and cubic phase) structure, appropriate band gap of 4.68 eV and smaller surface roughness of 1.72 nm, and the solar-blind photodetector (PD) based on it was fabricated. The key features of our PD are the cutoff wavelength of 265 nm lying in solar-blind band, lower dark current (Idark) of 88 pA, higher peak responsivity of 0.10 A/W and bigger Ilight/Idark ratio of 1688, which provide the new idea for the application of solar-blind PDs based on MgxZn1-xO films.

4.
J Nanosci Nanotechnol ; 20(3): 1790-1798, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-31492344

RESUMO

Tungsten oxide microflowers (WO3 MFs) were fabricated by a simple hydrothermal process through adjusting the pH of the solution by HCl. These MFs possess the outer diameters of about 2 µm and are composed of numerous nanoplates with the average pore size of 10.9 nm. Chemiresistive activity of as-fabricated WO3 MFs sensor was attempted towards oxidizing and reducing target gases, revealing a superior selectivity to NO2 with a maximum response of 22.95 (2 ppm NO2) @105 °C compared to other target gases. One of the key features of as-fabricatedWO3 MFs sensor is the lower detection limit of 125 ppb and operating temperature of 105 °C to NO2 with better reproducibility, signifying commercial prospective of the developed sensor materials. Finally, the gas sensing mechanism of WO3 MFs sensor has been proposed.

5.
J Nanosci Nanotechnol ; 19(12): 8135-8142, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31196336

RESUMO

Precisely controlled dimensions of heterostructured ZnO nanorod arrays were grown on micropatterned Au films supported by Si substrate using chemical vapor deposition (CVD). The field emission properties were attributed to pointed nanorods, thickness of catalyst, preferential growth, density, morphology of ZnO and Molybdenum (Mo) decorated ZnO nanorod arrays (Mo/ZnO). The selective restrained heterostructure approach resulted in excellent control over periodicity, location and density of ZnO nanorod arrays. Overall, field emission properties of bare ZnO nanorod arrays showed a low turn-on field of ~4.7 V/µm and a high field enhancement factor (ß) ~1686 to 7.3 V/µm and (ß) ~807 for Mo/ZnO. It was also found that the field emission properties were significantly influenced by densely decorated Mo nanoparticles on as-grown ZnO nanorod arrays.

6.
Cell Rep ; 24(3): 713-723, 2018 07 17.
Artigo em Inglês | MEDLINE | ID: mdl-30021167

RESUMO

Protein phosphatase 2A (PP2A) inhibition causes hyperphosphorylation of tau and APP in Alzheimer's disease (AD). However, the mechanisms underlying the downregulation of PP2A activity in AD brain remain unclear. We demonstrate that Cancerous Inhibitor of PP2A (CIP2A), an endogenous PP2A inhibitor, is overexpressed in AD brain. CIP2A-mediated PP2A inhibition drives tau/APP hyperphosphorylation and increases APP ß-cleavage and Aß production. Increase in CIP2A expression also leads to tau mislocalization to dendrites and spines and synaptic degeneration. In mice, injection of AAV-CIP2A to hippocampus induced AD-like cognitive deficits and impairments in long-term potentiation (LTP) and exacerbated AD pathologies in neurons. Indicative of disease exacerbating the feedback loop, we found that increased CIP2A expression and PP2A inhibition in AD brains result from increased Aß production. In summary, we show that CIP2A overexpression causes PP2A inhibition and AD-related cellular pathology and cognitive deficits, pointing to CIP2A as a potential target for AD therapy.


Assuntos
Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Autoantígenos/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteínas de Membrana/metabolismo , Transtornos da Memória/metabolismo , Sinapses/patologia , Proteínas tau/metabolismo , Doença de Alzheimer/complicações , Doença de Alzheimer/patologia , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Células HEK293 , Hipocampo/patologia , Hipocampo/fisiopatologia , Humanos , Potenciação de Longa Duração , Transtornos da Memória/complicações , Transtornos da Memória/patologia , Camundongos Endogâmicos C57BL , Degeneração Neural/metabolismo , Degeneração Neural/patologia , Neurônios/metabolismo , Neurônios/patologia , Fosforilação , Proteína Fosfatase 2/antagonistas & inibidores , Proteína Fosfatase 2/metabolismo , Ratos Sprague-Dawley , Sinapses/metabolismo
7.
Mol Neurobiol ; 55(1): 835-850, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-28064424

RESUMO

Clinical data have shown women are more susceptible to depression. This study was performed to identify differentially regulated proteins from hippocampus in chronic unpredicted mild stress (CUMS)-exposed male and female young rats. After 7 weeks of CUMS, depressed male (M-D) and female rats (F-D) and unstressed male (M-C) and female controls (F-C) were studied. By proteomics analysis, 74 differential proteins in F-C/M-C, 79 in F-D/M-D, 77 in F-D/F-C, and 32 in M-D/M-C were found. Further, the synapse-related proteins, cytoskeleton protein tau, and stress-related kinases in hippocampus were assayed by Western blotting. F-C rats were found to have lower levels of metabotropic glutamate receptor 1 (mGluR1) and mGluR2 and higher levels of N-methyl-D-aspartate receptor 2B (NR2B), synapsin1, total tau, and dephosphorylated tau than M-C rats. Both F-D and M-D rats had lower levels of glutamate transporter SLC1α2, mGluR1, and mGluR2, and higher levels of total tau and phosphorylated tau than their controls. Compared with their controls, M-D rats had lower NR1 and higher NR2B, and F-D rats had lower NR2A, NR2B, PSD95, and synapsin1. F-C rats had higher JNK and lower phosphorylation levels of ERK at Thr202/Thr204, JNK at Thr183/Thr185, and GSK-3ß at Ser9 than M-C ones. Both M-D and F-D rats had decreased phosphorylation of ERK at Thr202/Thr204 and GSK-3ß at Ser9, and increased JNK phosphorylation at Thr183/Thr185 compared with their controls. All these data illustrate the biochemical complexity behind the genders, and may also aid in the development of more accurate treatment strategies for depression.


Assuntos
Hipocampo/metabolismo , Proteômica , Caracteres Sexuais , Estresse Psicológico/metabolismo , Animais , Comportamento Animal , Doença Crônica , Citoesqueleto/metabolismo , Depressão/metabolismo , Feminino , Ontologia Genética , Masculino , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Ratos Sprague-Dawley , Sinapses/metabolismo , Proteínas tau/metabolismo
8.
Yao Xue Xue Bao ; 51(3): 434-8, 2016 03.
Artigo em Chinês | MEDLINE | ID: mdl-29859025

RESUMO

Tapentadol is a novel drug of opioid pain reliever, which is extensively metabolized primarily through conjugation. Tapentadol glucuronide and tapentadol sulfate are major drug-related metabolites in circulation. The objectives of this study were to develop a simple and rapid method to determine tapentadol and evaluate the effects of conjugated metabolites on tapentadol quantification using liquid chromatography with tandem mass spectrometry in dog plasma. The analyte and tramadol(IS) were extracted from plasma by protein precipitation with methanol, and chromatographied on a XDB C(18)(50 mm × 4.6 mm, 1.8 µm) column using a mobile phase of methanol and 5 mmol·L(-1) ammonium acetate(0.01% ammonia). Mass spectrometric detection was performed using the m/z 222 → 121 transition for tapentadol and the m/z 264 → 58 transition for the internal standard tramadol, the m/z 398 → m/z 121 transition for glucuronides conjugate and the m/z 302 → m/z 222 transition for sulfate conjugate. Conjugated metabolites could undergo in-source conversion to generate an ion that interfered the quantification of tapentadol. Chromatographic separation was achieved to elimination interferences due to in-source conversion of the conjugated metabolites. The standard curves were demonstrated to be linear in the range of 0.100 to 20.0 ng·m L(-1) for tapentadol. The intra- and inter-day precisions were within 5.1%, and accuracy ranged from -3.2% to 0. This method was successfully applied to the pharmacokinetics of tapentadol hydrochloride sustained release tablets in Beagle dogs.


Assuntos
Cães/sangue , Fenóis/sangue , Animais , Cromatografia Líquida , Preparações de Ação Retardada/farmacocinética , Glucuronídeos/sangue , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Comprimidos , Espectrometria de Massas em Tandem , Tapentadol
9.
Mol Neurobiol ; 53(3): 2054-2064, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25899174

RESUMO

Endothelin1 (ET1) is a potent vasoconstrictor that is also known to be a neuropeptide that is involved in neural circuits. We examined the role of ET1 that has been implicated in the anxiogenic process. We found that infusing ET1 into the IL cortex increased anxiety-like behaviors. The ET(A) receptor (ET(A)R) antagonist (BQ123) but not the ET(B) receptor (ET(B)R) antagonist (BQ788) alleviated ET1-induced anxiety. ET1 had no effect on GABAergic neurotransmission or NMDA receptor (NMDAR)-mediated neurotransmission, but increased AMPA receptor (AMPAR)-mediated excitatory synaptic transmission. The changes in AMPAR-mediated excitatory postsynaptic currents were due to presynaptic mechanisms. Finally, we found that the AMPAR antagonists (CNQX) and BQ123 reversed ET1's anxiogenic effect, with parallel and corresponding electrophysiological changes. Moreover, infusing CNQX + BQ123 into the IL had no additional anxiolytic effect compared to CNQX treatment alone. Altogether, our findings establish a previously unknown anxiogenic action of ET1 in the IL cortex. AMPAR-mediated glutamatergic neurotransmission may underlie the mechanism of ET1-ET(A)R signaling pathway in the regulation of anxiety.


Assuntos
Ansiedade/metabolismo , Endotelina-1/metabolismo , Sistema Límbico/metabolismo , 6-Ciano-7-nitroquinoxalina-2,3-diona/farmacologia , 6-Ciano-7-nitroquinoxalina-2,3-diona/uso terapêutico , Animais , Ansiedade/tratamento farmacológico , Comportamento Animal , Ácido Glutâmico/metabolismo , Sistema Límbico/efeitos dos fármacos , Sistema Límbico/patologia , Masculino , Camundongos Endogâmicos C57BL , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Peptídeos Cíclicos/farmacologia , Peptídeos Cíclicos/uso terapêutico , Receptores de AMPA/metabolismo , Receptores de Endotelina/metabolismo , Transmissão Sináptica/efeitos dos fármacos
10.
Neurol Sci ; 35(4): 531-6, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24057116

RESUMO

The objective of the study was to investigate the role of neuregulin-ErbB signaling in neuropathic pain in different types of injury. Neuregulin-1(NRG-1) was injected into animals with either formalin-induced pain model or spared nerve injury (SNI) model. Formalin tests or paw withdrawal tests were performed to study the role of NRG-1 in neuropathic pain. siRNA specific to different erbB receptors were then introduced to test which specific signaling pathway was required for NRG-1 signaling in the different pain models. NRG-1 inhibits neuropathic pain after SNI in a dose-dependent manner, while NRG-1 aggravates formalin-induced neuropathic pain. ErbB2 and erbB4 receptors were activated after neuregulin administration. Knockdown of ErbB2 relieves the aggravation of NRG-1 on formalin-induced neuropathic pain, and knockdown of ErbB4 could relieve the inhibition of NRG-1 on neuropathic pain in the SNI model. NRG-1 has two distinct functions depending on the different receptor activation in different models of neuropathic pain. These novel findings may provide new therapeutic approaches for the treatment of neuropathic pain in different injury types.


Assuntos
Neuralgia/metabolismo , Neuregulina-1/fisiologia , Receptor ErbB-2/metabolismo , Animais , Formaldeído , Hiperalgesia/complicações , Hiperalgesia/metabolismo , Masculino , Neuralgia/induzido quimicamente , Neuralgia/complicações , Neuregulina-1/farmacologia , Ratos
11.
Neurobiol Aging ; 34(3): 745-56, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-22892311

RESUMO

The activity of protein phosphatase (PP) 2A is downregulated and promotes the hyperphosphorylation of tau in the brains of Alzheimer's disease (AD), but the mechanism for PP2A inactivation has not been elucidated. We have reported that PP2A phosphorylation at tyrosine 307 (Y307) is involved in PP2A inactivation. Here, we further studied the upstream mechanisms for PP2A phosphorylation and inactivation. We found that zinc, a heavy metal ion that is widely distributed in the normal brain and accumulated in the susceptible regions of AD brain, could induce PP2A inhibition, phosphorylation of PP2A at Y307 and tau hyperphosphorylation both in rat brains and cultured N2a cells, while zinc chelating prevented these changes completely. Upregulation of PP2A chemically or genetically attenuated zinc-induced tau hyperphosphorylation, whereas mutation of Y307 to phenylalanine abolished the zinc-induced tyrosine phosphorylation and inactivation of PP2A. Zinc could activate Src, while PP2, a specific Src family kinases inhibitor, attenuated zinc-induced PP2A phosphorylation and inactivation, indicating that zinc induces PP2A Y307 phosphorylation and inactivation through Src activation. In human tau transgenic mice, zinc chelator rescued PP2A activity, prevented Src activation, and reduced hyperphosphorylated and insoluble tau levels. We concluded that zinc induces PP2A inactivation and tau hyperphosphorylation through Src-dependent pathway, regulation of zinc homeostasis may be a promising therapeutic for AD and the related tauopathies.


Assuntos
Encéfalo , Proteína Fosfatase 2 , Tauopatias/metabolismo , Oligoelementos/farmacologia , Zinco/farmacologia , Quinases da Família src , Proteínas tau , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Linhagem Celular Tumoral , Humanos , Camundongos , Camundongos Transgênicos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Fosforilação/efeitos dos fármacos , Fosforilação/fisiologia , Proteína Fosfatase 2/efeitos dos fármacos , Proteína Fosfatase 2/metabolismo , Pirimidinas/farmacologia , Ratos , Ratos Sprague-Dawley , Tirosina/efeitos dos fármacos , Tirosina/metabolismo , Quinases da Família src/efeitos dos fármacos , Quinases da Família src/metabolismo , Proteínas tau/efeitos dos fármacos , Proteínas tau/metabolismo
12.
J Biol Chem ; 287(14): 11174-82, 2012 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-22334661

RESUMO

Hyperphosphorylated tau is the major component of neurofibrillary tangles in Alzheimer disease (AD), and the tangle distribution largely overlaps with zinc-containing glutamatergic neurons, suggesting that zinc released in synaptic terminals may play a role in tau phosphorylation. To explore this possibility, we treated cultured hippocampal slices or primary neurons with glutamate or Bic/4-AP to increase the synaptic activity with or without pretreatment of zinc chelators, and then detected the phosphorylation levels of tau. We found that glutamate or Bic/4-AP treatment caused tau hyperphosphorylation at multiple AD-related sites, including Ser-396, Ser-404, Thr-231, and Thr-205, while application of intracellular or extracellular zinc chelators, or blockade of zinc release by extracellular calcium omission almost abolished the synaptic activity-associated tau hyperphosphorylation. The zinc release and translocation of excitatory synapses in the hippocampus were detected, and zinc-induced tau hyperphosphorylation was also observed in cultured brain slices incubated with exogenously supplemented zinc. Tau hyperphosphorylation induced by synaptic activity was strongly associated with inactivation of protein phosphatase 2A (PP2A), and this inactivation can be reversed by pretreatment of zinc chelator. Together, these results suggest that synaptically released zinc promotes tau hyperphosphorylation through PP2A inhibition.


Assuntos
Inibidores Enzimáticos/farmacologia , Proteína Fosfatase 2/antagonistas & inibidores , Sinapses/efeitos dos fármacos , Sinapses/metabolismo , Zinco/metabolismo , Proteínas tau/metabolismo , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Animais , Hipocampo/citologia , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Masculino , Fosforilação/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Transmissão Sináptica/efeitos dos fármacos , Zinco/farmacologia
13.
Zhongguo Zhong Yao Za Zhi ; 30(11): 847-50, 2005 Jun.
Artigo em Chinês | MEDLINE | ID: mdl-16110869

RESUMO

OBJECTIVE: To evaluate the effect of tea polyphenol(TP) on the rat with alcoholic liver damage. METHOD: Rats were divided into 3 groups, in which 2 groups were stomach perfused with alcohol to result in ALD, and 1 group of them stomach perfused with TP simultaneously. Another group was normal control groups (stomach perfused with drinking water). In the end of 12 weeks, the liver specimen of each rat was observed by anglicizing its tissue damage, and all data collected was performed by statistical analysis in quantum and semi-quantum. Meanwhile cytokines gene express of each group is determined. RESULT: In the end of 12 weeks, alcoholic hepatitis appeared in rat liver. Hepatic injury in alcohol group and TP group were found, but could not be found in normal group. Compared with pure alcohol group, alcoholic liver damage mainly showing with steatosis in TP group were slight, in addition showing liver cellular swelling with small area, with less spot and focal necrosis, none bridging necrosis. Steatosis were slight relatively, mega-bubble steatosis were less found. Collagen deposition of TP group were less than those of pure alcohol group. Gene expression of. cytokine have diversity statistically such as IL-3, IL-4, IL-1R2, IL-6R, IL-7R2, IL-3Ra, IL-R1, IL-13, IL-1R1, IL-7R2, EPO-R, LIFR, IL-1R2, IL-5R2, CSF1, CD27, IL-6R. CONCLUSION: TP is able to attenuate alcoholic liver damage. It's mechanism is possibly due to modulating cytokines gene expression of cytokine.


Assuntos
Flavonoides/farmacologia , Interleucinas/biossíntese , Hepatopatias Alcoólicas/metabolismo , Fenóis/farmacologia , Receptores de Interleucina/biossíntese , Chá , Animais , Flavonoides/isolamento & purificação , Expressão Gênica , Interleucinas/genética , Fígado/metabolismo , Fígado/patologia , Hepatopatias Alcoólicas/genética , Hepatopatias Alcoólicas/patologia , Análise de Sequência com Séries de Oligonucleotídeos , Fenóis/isolamento & purificação , Plantas Medicinais/química , Polifenóis , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Receptores de Interleucina/genética , Chá/química
14.
Proc Natl Acad Sci U S A ; 101(25): 9453-7, 2004 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-15197280

RESUMO

New neurons are generated in adult mammalians and may contribute to repairing the brain after injury. Here, we show that the number of new neurons in the dentate gyrus of adult rats increased in cerebral ischemic stroke and correlated with activation of the cAMP-response-element-binding protein (CREB). Inhibition of endogenous CREB by expression of a dominant-negative mutant of CREB (CREB-S133A or CREB-R287L) blocked ischemia-induced neurogenesis in the dentate gyrus of adult rats, whereas expression of constitutively active CREB, VP16-CREB, increased the number of new neurons. Thus, our findings provide roles and regulatory mechanisms for CREB in adult neurogenesis and possibly suggest a practical strategy for replacing dead neurons in brain injury.


Assuntos
Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Giro Denteado/fisiopatologia , Ataque Isquêmico Transitório/fisiopatologia , Regeneração Nervosa/fisiologia , Neurônios/fisiologia , Animais , Feminino , Imuno-Histoquímica , Masculino , Mutagênese , Mutagênese Sítio-Dirigida , Ratos , Proteínas Recombinantes/metabolismo , Caracteres Sexuais
15.
J Neurosci ; 23(3): 732-6, 2003 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-12574400

RESUMO

Several thousand new neurons are produced each day in the adult mammalian hippocampus, among which only excitatory granule cells (GCs) have thus far been identified. In the present study, we used mutant Semliki Forest Virus vectors to express enhanced green fluorescent protein in the hippocampus, and observed that approximately 14% of newly generated neurons in the dentate gyrus of adult rats are GABAergic basket cells (BCs). With the use of double whole-cell patch-clamp recordings from BC-GC pairs in hippocampal slices, we demonstrate that newly generated BCs in the dentate gyrus form inhibitory synapses with principal GCs. These data show for the first time that functional inhibitory neurons are recruited in the dentate gyrus of adult rats.


Assuntos
Hipocampo/citologia , Inibição Neural/fisiologia , Neurônios/citologia , Animais , Bromodesoxiuridina , Contagem de Células , Diferenciação Celular/fisiologia , Divisão Celular/fisiologia , Potenciais Pós-Sinápticos Excitadores/fisiologia , Feminino , Genes Reporter , Vetores Genéticos/administração & dosagem , Vetores Genéticos/fisiologia , Glutamato Descarboxilase/análise , Glutamato Descarboxilase/biossíntese , Proteínas de Fluorescência Verde , Hipocampo/crescimento & desenvolvimento , Hipocampo/virologia , Imuno-Histoquímica , Isoenzimas/análise , Isoenzimas/biossíntese , Proteínas Luminescentes/genética , Masculino , Neurônios/classificação , Neurônios/metabolismo , Neurônios/virologia , Técnicas de Patch-Clamp , Fenótipo , Ratos , Ratos Sprague-Dawley , Vírus da Floresta de Semliki/genética , Vírus da Floresta de Semliki/fisiologia , Transmissão Sináptica/fisiologia , Ácido gama-Aminobutírico/metabolismo
16.
J Neurosci ; 23(3): 826-36, 2003 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-12574411

RESUMO

Long-term depression (LTD) is an activity-dependent weakening of synaptic efficacy at individual inhibitory synapses, a possible cellular model of learning and memory. Here, we show that the induction of LTD of inhibitory transmission recruits activated calcineurin (CaN) to dephosphorylate type-A GABA receptor (GABA(A)Rs) via the direct binding of CaN catalytic domain to the second intracellular domain of the GABA(A)R-gamma(2) subunits. Prevention of the CaN-GABA(A) receptor complex formation by expression of an autoinhibitory domain of CaN in the hippocampus of transgenic mice blocks the induction of LTD. Conversely, genetic expression of the CaN catalytic domain in the hippocampus depresses inhibitory synaptic responses, occluding LTD. Thus, an activity-dependent physical and functional interaction between CaN and GABA(A) receptors is both necessary and sufficient for inducing LTD at CA1 individual inhibitory synapses.


Assuntos
Calcineurina/metabolismo , Hipocampo/metabolismo , Depressão Sináptica de Longo Prazo/fisiologia , Inibição Neural/fisiologia , Receptores de GABA-A/metabolismo , Sinapses/metabolismo , Animais , Estimulação Elétrica , Hipocampo/citologia , Técnicas In Vitro , Substâncias Macromoleculares , Camundongos , Camundongos Mutantes , Camundongos Transgênicos , Técnicas de Patch-Clamp , Fosforilação , Ligação Proteica/fisiologia , Subunidades Proteicas/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo
17.
J Neurosci ; 23(1): 223-9, 2003 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-12514219

RESUMO

The generation of new neurons in the adult mammalian hippocampus is thought to play a role in repairing the brain after injury. Here, we show that 7 d after focal cerebral ischemia, newly divided cells in the dentate gyrus of adult rats increased to approximately sevenfold, compared with sham controls. In the same area, this enhanced dentate neurogenesis was associated with activation of inducible nitric oxide synthase (iNOS). Inhibition of iNOS by aminoguanidine prevented ischemia-induced neurogenesis in the dentate gyrus. In null mutant mice lacking the iNOS gene, increased neurogenesis was not observed after focal cerebral ischemia. This study demonstrates that expression of iNOS is necessary for ischemia-stimulated cell birth in the dentate gyrus and indicates that activation of iNOS may provide a possible strategy for functional recovery from cerebral ischemic insult.


Assuntos
Isquemia Encefálica/enzimologia , Giro Denteado/citologia , Giro Denteado/enzimologia , Neurônios/citologia , Óxido Nítrico Sintase/fisiologia , Animais , Arginina/farmacologia , Isquemia Encefálica/genética , Isquemia Encefálica/patologia , Divisão Celular , Inibidores Enzimáticos/farmacologia , Deleção de Genes , Proteínas de Fluorescência Verde , Cinética , Proteínas Luminescentes/análise , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neuroglia/citologia , Neurônios/enzimologia , Óxido Nítrico Sintase/biossíntese , Óxido Nítrico Sintase/genética , Óxido Nítrico Sintase Tipo II , RNA Mensageiro/biossíntese , Ratos , Ratos Sprague-Dawley , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transcrição Genética
18.
EMBO J ; 21(12): 2977-89, 2002 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-12065411

RESUMO

Src kinase regulation of N-methyl-D-aspartate (NMDA) subtype glutamate receptors in the central nervous system (CNS) has been found to play an important role in processes related to learning and memory, ethanol sensitivity and epilepsy. However, little is known regarding the mechanisms underlying the regulation of Src family kinase activity in the control of NMDA receptors. Here we report that the distal phosphatase domain (D2) of protein tyrosine phosphatase alpha (PTPalpha) binds to the PDZ2 domain of post-synaptic density 95 (PSD95). Thus, Src kinase, its activator (PTPalpha) and substrate (NMDA receptors) are linked by the same scaffold protein, PSD95. Removal of PTPalpha does not affect the association of Src with NMDA receptors, but turns off the constitutive regulation of NMDA receptors by the kinase. Further more, we found that application of the PTPalpha catalytic domains (D1 + D2) into neurones enhances NMDA receptor-mediated synaptic responses. Conversely, the blockade of endogenous PTPalpha inhibits NMDA receptor activity and the induction of long-term potentiation in hippocampal neurones. Thus, PTPalpha is a novel up-regulator of synaptic strength in the CNS.


Assuntos
Neurônios/metabolismo , Estrutura Secundária de Proteína , Proteínas Tirosina Fosfatases/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Transmissão Sináptica/fisiologia , Animais , Células Cultivadas , Proteína 4 Homóloga a Disks-Large , Fibroblastos/fisiologia , Hipocampo/citologia , Humanos , Técnicas In Vitro , Peptídeos e Proteínas de Sinalização Intracelular , Potenciação de Longa Duração/fisiologia , Proteínas de Membrana , Modelos Biológicos , Proteínas do Tecido Nervoso/metabolismo , Neurônios/citologia , Neurônios/efeitos dos fármacos , Técnicas de Patch-Clamp , Ligação Proteica , Proteínas Tirosina Fosfatases/genética , Proteínas Tirosina Fosfatases/farmacologia , Ratos , Ratos Sprague-Dawley , Ratos Wistar , Receptores de N-Metil-D-Aspartato/genética , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismo , Quinases da Família src/metabolismo
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