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1.
Nat Neurosci ; 22(7): 1110-1121, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31160741

RESUMO

Learning to predict rewards based on environmental cues is essential for survival. The orbitofrontal cortex (OFC) contributes to such learning by conveying reward-related information to brain areas such as the ventral tegmental area (VTA). Despite this, how cue-reward memory representations form in individual OFC neurons and are modified based on new information is unknown. To address this, using in vivo two-photon calcium imaging in mice, we tracked the response evolution of thousands of OFC output neurons, including those projecting to VTA, through multiple days and stages of cue-reward learning. Collectively, we show that OFC contains several functional clusters of neurons distinctly encoding cue-reward memory representations, with only select responses routed downstream to VTA. Unexpectedly, these representations were stably maintained by the same neurons even after extinction of the cue-reward pairing, and supported behavioral learning and memory. Thus, OFC neuronal activity represents a long-term cue-reward associative memory to support behavioral adaptation.


Assuntos
Adaptação Psicológica/fisiologia , Aprendizagem por Associação/fisiologia , Sinalização do Cálcio , Condicionamento Clássico/fisiologia , Memória de Longo Prazo/fisiologia , Neurônios/fisiologia , Córtex Pré-Frontal/fisiologia , Recompensa , Estimulação Acústica , Animais , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/fisiologia , Sinais (Psicologia) , Comportamento de Ingestão de Líquido/fisiologia , Extinção Psicológica , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas do Tecido Nervoso/fisiologia , Neurônios/enzimologia , Optogenética , Técnicas de Patch-Clamp , Córtex Pré-Frontal/citologia , Análise de Célula Única , Área Tegmentar Ventral/fisiologia
2.
J Stroke Cerebrovasc Dis ; 28(7): 1832-1840, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31078389

RESUMO

GOAL: The present study aimed to examine whether Am80 (tamibarotene) protects the hippocampus against cerebral ischemia-reperfusion (I/R) injury and whether phosphoinositide-3-kinase/Akt (PI3K/Akt) pathway mediates this effect. MATERIALS AND METHODS: Rats were subjected to 90 minutes of middle cerebral artery occlusion followed by 24 hours of reperfusion. The animals were randomly divided into 7 groups: sham-operated group; I/R group; groups pretreated with 2 mg/kg, 6 mg/kg, and 10 mg/kg of Am80; Am80 (6 mg/kg) combined with the selective PI3K inhibitor wortmannin (0.6 mg/kg), and wortmannin (0.6 mg/kg) only group. After 24 hours of reperfusion, neurological deficits and infarct volume were measured. Pathological changes in hippocampal neurons were analyzed by transmission electron microscopy. Neuronal survival was examined by TUNEL staining. The expression of Bcl-2, Bax, and Akt, and Akt phosphorylation (p-Akt) were measured by Western blotting and quantitative real-time polymerase chain reaction. FINDINGS: The pretreatment with Am80 improved the neurologic deficit score, reduced infarct volume, and decreased the number of TUNEL-positive cells in the hippocampus. Moreover, Am80 pretreatment downregulated the expression of Bax, upregulated the expression of Bcl-2, and increased the level of p-Akt. Wortmannin abolished in part the increase in p-Act and the neuroprotective effect exerted on the ischemic by Am80 pretreatment. CONCLUSIONS: Our results documented that Am80 pretreatment protects ischemic hippocampus after cerebral I/R by regulating the expression of apoptosis-related proteins through the activation of the PI3K/Akt signaling pathway.


Assuntos
Benzoatos/farmacologia , Hipocampo/efeitos dos fármacos , Infarto da Artéria Cerebral Média/prevenção & controle , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Fosfatidilinositol 3-Quinase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Traumatismo por Reperfusão/prevenção & controle , Tetra-Hidronaftalenos/farmacologia , Animais , Apoptose/efeitos dos fármacos , Modelos Animais de Doenças , Hipocampo/enzimologia , Hipocampo/ultraestrutura , Infarto da Artéria Cerebral Média/enzimologia , Infarto da Artéria Cerebral Média/patologia , Masculino , Neurônios/enzimologia , Neurônios/ultraestrutura , Fosforilação , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Ratos Sprague-Dawley , Traumatismo por Reperfusão/enzimologia , Traumatismo por Reperfusão/patologia , Transdução de Sinais/efeitos dos fármacos , Proteína X Associada a bcl-2/metabolismo
3.
Med Sci Monit ; 25: 2886-2895, 2019 Apr 19.
Artigo em Inglês | MEDLINE | ID: mdl-31002658

RESUMO

BACKGROUND Sleep deprivation (SD) is common in humans, and sleep loss has a significant influence on health and produces related diseases. Orexin-A has been demonstrated to play a role in physiological processes, including feeding, sleep/wake cycle, and energy metabolism. The aim of this study was to investigate the effect of SD on rats and to define the underlying mechanism. MATERIAL AND METHODS We constructed an SD rat model. The Morris water maze test was used to assess rat learning and memory. Imaging of hippocampus and hippocampal tissue in rats were captured by magnetic resonance imaging or electron microscopy. We used the CCK-8 kit to assess cell viability. The level of protein was measured using Western blot analysis, and qRT-PCR was used to evaluate mRNA level. RESULTS SD rats had poorer learning and memory and had damage to the hippocampus. SD resulted in shrinkage of hippocampal volume and encephalocele size. SD increased the expression of Orexin-A, OX1R, OX2R, and PARP-1, and decreased the expression of ERK1/2 and p-ERK1/2. Orexin-A (0-10 µM) improved neuron viability, whereas orexin-A (10-100 µM) attenuated neuron viability. SB334867 treatment reduced the viability of neurons treated with orexin-A. NU1025 treatment increased cell viability, especially in neurons treated with orexin-A. SB334867 treatment decreased the p-ERK1/2 levels in neurons treated with orexin-A. NU1025 increased the expression of p-ERK1/2 in neurons treated with orexin-A. CONCLUSIONS SD decreases learning and memory through damage to the hippocampus. Higher concentrations of orexin-A had a major negative effect on hippocampal neurons via OX1R and PARP-1 through inhibition of the ERK1/2 signaling pathway.


Assuntos
Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Privação do Sono/enzimologia , Animais , Modelos Animais de Doenças , Hipocampo/efeitos dos fármacos , Hipocampo/enzimologia , Hipocampo/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Sistema de Sinalização das MAP Quinases/fisiologia , Masculino , Memória/efeitos dos fármacos , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/enzimologia , Neurônios/metabolismo , Neuropeptídeos/metabolismo , Orexinas/metabolismo , Orexinas/farmacologia , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Privação do Sono/metabolismo
4.
Geroscience ; 41(1): 51-67, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30729413

RESUMO

Nicotinamide adenine dinucleotide (reduced form: NADH) serves as a vital redox-energy currency for reduction-oxidation homeostasis and fulfilling energetic demands. While NADH exists as free and bound forms, only free NADH is utilized for complex I to power oxidative phosphorylation, especially important in neurons. Here, we studied how much free NADH remains available for energy production in mitochondria of old living neurons. We hypothesize that free NADH in neurons from old mice is lower than the levels in young mice and even lower in neurons from the 3xTg-AD Alzheimer's disease (AD) mouse model. To assess free NADH, we used lifetime imaging of NADH autofluorescence with 2-photon excitation to be able to resolve the pool of NADH in mitochondria, cytoplasm, and nuclei. Primary neurons from old mice were characterized by a lower free/bound NADH ratio than young neurons from both non-transgenic (NTg) and more so in 3xTg-AD mice. Mitochondrial compartments maintained 26 to 41% more reducing NADH redox state than cytoplasm for each age, genotype, and sex. Aging diminished the mitochondrial free NADH concentration in NTg neurons by 43% and in 3xTg-AD by 50%. The lower free NADH with age suggests a decline in capacity to regenerate free NADH for energetic supply to power oxidative phosphorylation which further worsens in AD. Applying this non-invasive approach, we showed the most explicit measures yet of bioenergetic deficits in free NADH with aging at the subcellular level in live neurons from in-bred mice and an AD model.


Assuntos
Envelhecimento/metabolismo , Doença de Alzheimer/enzimologia , Mitocôndrias/enzimologia , NAD/classificação , NAD/metabolismo , Neurônios/enzimologia , Animais , Modelos Animais de Doenças , Genótipo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Microscopia de Fluorescência , Mitocôndrias/patologia , Neurônios/ultraestrutura , Imagem Óptica , Oxirredução , Fosforilação Oxidativa , Caracteres Sexuais , Proteínas tau/genética
5.
Eur J Med Chem ; 167: 161-186, 2019 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-30771604

RESUMO

Neuroinflammation and cholinergic deficit are key detrimental processes involved in Alzheimer's disease. Hence, in the search for novel and effective treatment strategies, the multi-target-directed ligand paradigm was applied to the rational design of two series of new hybrids endowed with anti-inflammatory and anticholinesterase activity via triple targeting properties, namely able to simultaneously hit cholinesterases, cyclooxygenase-2 (COX-2) and 15-lipoxygenase (15-LOX) enzymes. Among the synthesized compounds, triazoles 5b and 5d, and thiosemicarbazide hybrid 6e emerged as promising new hits, being able to effectively inhibit human butyrylcholinesterase (hBChE), COX-2 and 15-LOX enzymes with a higher inhibitory potency than the reference inhibitors tacrine (for hBChE inhibition), celecoxib (for COX-2 inhibition) and both NDGA and Zileuton (for 15-LOX inhibition). In addition, compound 6e proved to be a submicromolar mixed-type inhibitor of human acetylcholinesterase (hAChE). The anti-neuroinflammatory activity of the three most promising hybrids was confirmed in a cell-based assay using PC12 neuron cells, showing decreased expression levels of inflammatory cytokines IL-1ß and TNF-α. Importantly, despite the structural resemblance to tacrine, they showed ideal safety profiles on hepatic and murine brain cell lines and were safe up to 100 µM when assayed in PC12 cells. All three hybrids were also predicted to have superior BBB permeability than tacrine in the PAMPA assay, and good physicochemical properties, drug-likeness and ligand efficiency indices. Finally, molecular docking studies highlighted key structural elements impacting selectivity and activity toward the selected target enzymes. To the best of our knowledge, compounds 5b, 5d and 6e are the first balanced, safe and multi-target compounds hitting the disease at the three mentioned hubs.


Assuntos
Acetilcolina/deficiência , Doença de Alzheimer/tratamento farmacológico , Inflamação/tratamento farmacológico , Neurônios/patologia , Doença de Alzheimer/patologia , Animais , Linhagem Celular , Inibidores da Colinesterase/química , Inibidores de Ciclo-Oxigenase 2/química , Desenho de Drogas , Humanos , Inibidores de Lipoxigenase/química , Camundongos , Simulação de Acoplamento Molecular , Neurônios/efeitos dos fármacos , Neurônios/enzimologia , Células PC12 , Ratos , Semicarbazidas/química , Semicarbazidas/farmacologia , Triazóis/química , Triazóis/farmacologia
6.
Peptides ; 113: 1-10, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30590076

RESUMO

The Neuropeptide EI (NEI, glutamic acid- isoleucine amide) participates in neuroendocrine function. Previously we demonstrated that NEI concentration is regulated by thyroid hormones in discrete hypothalamic areas in rats. We observed that the thyroid status affects the dopaminergic regulation of the pituitary hormones. In this study we explored possible interactions between NEI and tyrosine hydroxylase (TH) containing elements in selected hypothalamic areas of male rats. Neuronal somas, terminals and boutons were assessed by confocal microscopy, in hypo- and hyperthyroid animals. We observed a remodeling of the contacts between the TH and NEI immunoreactive elements in the incerto-hypothalamic area (IHy, also known as rostromedial zona incerta) according to thyroid function. However, in the dorsolateral zone of the peduncular part of the lateral hypothalamus (DL-PLH) the thyroid hormones affect the dendritic trees of the neurons without perturbing the overall NEI/TH contacts. Also, we demonstrated that TRH Receptor 1 (TRH-R1) is colocalized in NEI immunoreactive neurons in the peduncular part of the lateral hypothalamus (PLH) and NEI precursor mRNA expression increased by hypothyroidism indicating that NEI neurons are responsive to the feedback mechanisms of the Hypothalamic Pituitary-Thyroid Axis (HPT). In conclusion, the hypothyroid status seems to increase the interactions between the NEI neurons and the dopaminergic pathways while hyperthyroidism either decreases or displays no effects. Altogether these observations support the participation of the IHy and PLH NEI as a modulating component of the HPT suggesting that altered neuroendocrine, behavioral and cognitive dysfunctions induced by dysthyroidism could be in part mediated by NEI.


Assuntos
Hipertireoidismo/metabolismo , Hipotálamo/metabolismo , Hipotireoidismo/metabolismo , Plasticidade Neuronal , Oligopeptídeos , Tirosina 3-Mono-Oxigenase , Animais , Hipertireoidismo/enzimologia , Hipertireoidismo/fisiopatologia , Hipotálamo/enzimologia , Hipotálamo/fisiopatologia , Hipotireoidismo/enzimologia , Hipotireoidismo/fisiopatologia , Masculino , Neurônios/enzimologia , Neurônios/metabolismo , Neurônios/fisiologia , Ratos , Ratos Wistar
7.
Neuroscience ; 399: 53-64, 2019 02 10.
Artigo em Inglês | MEDLINE | ID: mdl-30579834

RESUMO

The ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) enzymes are secreted, multi-domain matrix-associated zinc metalloendopeptidases that modify extracellular matrix components and play crucial roles in development and numerous diseases. ADAMTS18 is a member of the ADAMTS family, and genome-wide association studies made an initial association of ADAMTS18 with white matter integrity in healthy people of 72-74 years old. However, the potential roles of ADAMTS18 in central nervous system remain unclear. In this study, we showed that Adamts18 mRNA is highly abundant in developing brains, especially in the cerebellum granular cell layer and the hippocampus dentate gyrus (DG) granular cell layer. Adamts18 knockout (KO) mice displayed higher dendritic branching complexity and spine density on hippocampal DG granular cells. Behavioral tests showed that Adamts18 KO mice had reduced levels of depression-like behaviors compared to their wild-type (WT) littermates. The increased neurite formation could be attributed in part to reduced phosphorylation levels of the collapsin response mediator protein-2 (CRMP2) due to activation of the laminin/PI3K/AKT/GSK-3ß signaling pathway. Our findings revealed a critical role of ADAMTS18 in neuronal morphogenesis and emotional control in mice.


Assuntos
Proteínas ADAMTS/deficiência , Transtorno Depressivo/enzimologia , Transtorno Depressivo/patologia , Neurônios/enzimologia , Neurônios/patologia , Proteínas ADAMTS/genética , Animais , Encéfalo/enzimologia , Encéfalo/crescimento & desenvolvimento , Encéfalo/patologia , Modelos Animais de Doenças , Masculino , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Knockout , Plasticidade Neuronal/fisiologia , RNA Mensageiro/metabolismo
8.
Artigo em Inglês | MEDLINE | ID: mdl-30315922

RESUMO

Nonylphenol (NP) and Cadmium (Cd) are two common contaminants that can be detected in aquatic environments. Nevertheless, the combined toxicity of NP and Cd at environmentally relevant concentrations in aquatic organisms has not been thoroughly characterized to date. In the present study, the interactions between NP and Cd on male Sebastiscus marmoratus were studied. After 21 days of exposure, the brain aromatase activity was observed to be significantly induced by 100 ng/L NP and 40 µg/L Cd, whereas all of the concentrations of co-treatment resulted in an increase in brain aromatase activity. Additionally, NP could also reduce plasma testosterone concentration, while NP, Cd and their mixture could induce plasma 17ß-estradiol (E2) concentration and VTG concentration. The interactions between NP and Cd on the reproductive physiology were antagonism. Our results also support the notion of using these indicators as biomarkers for exposure to EDCs and further extend the boundary of biomonitoring to environmental levels.


Assuntos
Cádmio/toxicidade , Genitália Masculina/efeitos dos fármacos , Infertilidade Masculina/veterinária , Perciformes/fisiologia , Fenóis/toxicidade , Poluentes Químicos da Água/toxicidade , Animais , Aromatase/química , Aromatase/metabolismo , Encéfalo/efeitos dos fármacos , Encéfalo/enzimologia , Sinergismo Farmacológico , Disruptores Endócrinos/toxicidade , Biomarcadores Ambientais/efeitos dos fármacos , Estradiol/agonistas , Estradiol/sangue , Doenças dos Peixes/sangue , Doenças dos Peixes/induzido quimicamente , Doenças dos Peixes/metabolismo , Doenças dos Peixes/fisiopatologia , Proteínas de Peixes/agonistas , Proteínas de Peixes/metabolismo , Genitália Masculina/fisiopatologia , Infertilidade Masculina/induzido quimicamente , Infertilidade Masculina/metabolismo , Infertilidade Masculina/fisiopatologia , Masculino , Proteínas do Tecido Nervoso/agonistas , Proteínas do Tecido Nervoso/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/enzimologia , Concentração Osmolar , Perciformes/sangue , Testosterona/antagonistas & inibidores , Testosterona/sangue , Testes de Toxicidade Crônica , Vitelogeninas/sangue , Vitelogeninas/química
9.
Mol Cell ; 73(5): 1001-1014.e8, 2019 03 07.
Artigo em Inglês | MEDLINE | ID: mdl-30527540

RESUMO

In Parkinson's disease (PD), α-synuclein (αS) pathologically impacts the brain, a highly lipid-rich organ. We investigated how alterations in αS or lipid/fatty acid homeostasis affect each other. Lipidomic profiling of human αS-expressing yeast revealed increases in oleic acid (OA, 18:1), diglycerides, and triglycerides. These findings were recapitulated in rodent and human neuronal models of αS dyshomeostasis (overexpression; patient-derived triplication or E46K mutation; E46K mice). Preventing lipid droplet formation or augmenting OA increased αS yeast toxicity; suppressing the OA-generating enzyme stearoyl-CoA-desaturase (SCD) was protective. Genetic or pharmacological SCD inhibition ameliorated toxicity in αS-overexpressing rat neurons. In a C. elegans model, SCD knockout prevented αS-induced dopaminergic degeneration. Conversely, we observed detrimental effects of OA on αS homeostasis: in human neural cells, excess OA caused αS inclusion formation, which was reversed by SCD inhibition. Thus, monounsaturated fatty acid metabolism is pivotal for αS-induced neurotoxicity, and inhibiting SCD represents a novel PD therapeutic approach.


Assuntos
Antiparkinsonianos/farmacologia , Descoberta de Drogas/métodos , Inibidores Enzimáticos/farmacologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Metabolômica/métodos , Neurônios/efeitos dos fármacos , Doença de Parkinson/tratamento farmacológico , Estearoil-CoA Dessaturase/antagonistas & inibidores , alfa-Sinucleína/toxicidade , Animais , Caenorhabditis elegans/efeitos dos fármacos , Caenorhabditis elegans/enzimologia , Caenorhabditis elegans/genética , Linhagem Celular , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/enzimologia , Córtex Cerebral/patologia , Diglicerídeos/metabolismo , Modelos Animais de Doenças , Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios Dopaminérgicos/enzimologia , Neurônios Dopaminérgicos/patologia , Humanos , Células-Tronco Pluripotentes Induzidas/efeitos dos fármacos , Células-Tronco Pluripotentes Induzidas/enzimologia , Células-Tronco Pluripotentes Induzidas/patologia , Gotículas Lipídicas/efeitos dos fármacos , Gotículas Lipídicas/enzimologia , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Terapia de Alvo Molecular , Degeneração Neural , Células-Tronco Neurais/efeitos dos fármacos , Células-Tronco Neurais/enzimologia , Células-Tronco Neurais/patologia , Neurônios/enzimologia , Neurônios/patologia , Ácido Oleico/metabolismo , Doença de Parkinson/enzimologia , Doença de Parkinson/genética , Doença de Parkinson/patologia , Ratos Sprague-Dawley , Saccharomyces cerevisiae/efeitos dos fármacos , Saccharomyces cerevisiae/enzimologia , Saccharomyces cerevisiae/genética , Estearoil-CoA Dessaturase/metabolismo , Triglicerídeos/metabolismo , alfa-Sinucleína/genética
10.
PLoS Genet ; 14(12): e1007623, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30566533

RESUMO

The human 1q21.1 deletion of ten genes is associated with increased risk of schizophrenia. This deletion involves the ß-subunit of the AMP-activated protein kinase (AMPK) complex, a key energy sensor in the cell. Although neurons have a high demand for energy and low capacity to store nutrients, the role of AMPK in neuronal physiology is poorly defined. Here we show that AMPK is important in the nervous system for maintaining neuronal integrity and for stress survival and longevity in Drosophila. To understand the impact of this signaling system on behavior and its potential contribution to the 1q21.1 deletion syndrome, we focused on sleep, an important role of which is proposed to be the reestablishment of neuronal energy levels that are diminished during energy-demanding wakefulness. Sleep disturbances are one of the most common problems affecting individuals with psychiatric disorders. We show that AMPK is required for maintenance of proper sleep architecture and for sleep recovery following sleep deprivation. Neuronal AMPKß loss specifically leads to sleep fragmentation and causes dysregulation of genes believed to play a role in sleep homeostasis. Our data also suggest that AMPKß loss may contribute to the increased risk of developing mental disorders and sleep disturbances associated with the human 1q21.1 deletion.


Assuntos
Proteínas Quinases Ativadas por AMP/genética , Anormalidades Múltiplas/enzimologia , Anormalidades Múltiplas/genética , Megalencefalia/enzimologia , Megalencefalia/genética , Neurônios/enzimologia , Esquizofrenia/enzimologia , Esquizofrenia/genética , Sono/genética , Sono/fisiologia , Proteínas Quinases Ativadas por AMP/antagonistas & inibidores , Proteínas Quinases Ativadas por AMP/deficiência , Animais , Deleção Cromossômica , Cromossomos Humanos Par 1/enzimologia , Cromossomos Humanos Par 1/genética , Proteínas de Drosophila/deficiência , Proteínas de Drosophila/genética , Drosophila melanogaster/enzimologia , Drosophila melanogaster/genética , Feminino , Técnicas de Silenciamento de Genes , Predisposição Genética para Doença , Humanos , Aprendizagem/fisiologia , Longevidade/genética , Longevidade/fisiologia , Masculino , Modelos Animais , Neurônios/citologia , Fatores de Risco , Transdução de Sinais , Transtornos do Sono-Vigília/enzimologia , Transtornos do Sono-Vigília/genética
11.
Proc Natl Acad Sci U S A ; 115(38): E8919-E8928, 2018 09 18.
Artigo em Inglês | MEDLINE | ID: mdl-30185559

RESUMO

Seizures induced by visual stimulation (photosensitive epilepsy; PSE) represent a common type of epilepsy in humans, but the molecular mechanisms and genetic drivers underlying PSE remain unknown, and no good genetic animal models have been identified as yet. Here, we show an animal model of PSE, in Drosophila, owing to defective cortex glia. The cortex glial membranes are severely compromised in ceramide phosphoethanolamine synthase (cpes)-null mutants and fail to encapsulate the neuronal cell bodies in the Drosophila neuronal cortex. Expression of human sphingomyelin synthase 1, which synthesizes the closely related ceramide phosphocholine (sphingomyelin), rescues the cortex glial abnormalities and PSE, underscoring the evolutionarily conserved role of these lipids in glial membranes. Further, we show the compromise in plasma membrane structure that underlies the glial cell membrane collapse in cpes mutants and leads to the PSE phenotype.


Assuntos
Córtex Cerebral/enzimologia , Proteínas de Drosophila/genética , Epilepsia Reflexa/genética , Proteínas de Membrana/genética , Proteínas do Tecido Nervoso/genética , Neuroglia/enzimologia , Transferases (Outros Grupos de Fosfato Substituídos)/genética , Animais , Animais Geneticamente Modificados , Membrana Celular/enzimologia , Córtex Cerebral/citologia , Modelos Animais de Doenças , Drosophila melanogaster , Humanos , Masculino , Mutação , Neuroglia/citologia , Neurônios/citologia , Neurônios/enzimologia , Esfingomielinas/metabolismo
12.
DNA Cell Biol ; 37(11): 861-865, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30234372

RESUMO

Phosphodiesterase-5 inhibitors (PDE5Is) have been shown to modulate cell death/cell survival in different in vivo and in vitro models of disease by activating many signaling pathways. This review aimed at elucidating how PDE5Is can inhibit apoptosis. In this study, we describe many signaling pathways involved with the mechanism of action of PDE5Is that ultimately inhibit apoptosis and thus promote cell survival.


Assuntos
Apoptose/efeitos dos fármacos , Nucleotídeo Cíclico Fosfodiesterase do Tipo 5/genética , Encefalomielite Autoimune Experimental/tratamento farmacológico , Neurônios/efeitos dos fármacos , Inibidores da Fosfodiesterase 5/farmacologia , Citrato de Sildenafila/farmacologia , Animais , Apoptose/genética , Autofagia/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , GMP Cíclico/agonistas , GMP Cíclico/metabolismo , Proteínas Quinases Dependentes de GMP Cíclico/genética , Proteínas Quinases Dependentes de GMP Cíclico/metabolismo , Nucleotídeo Cíclico Fosfodiesterase do Tipo 5/metabolismo , Encefalomielite Autoimune Experimental/enzimologia , Encefalomielite Autoimune Experimental/genética , Encefalomielite Autoimune Experimental/patologia , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Regulação da Expressão Gênica , Humanos , Camundongos , Neurônios/enzimologia , Neurônios/patologia , Transdução de Sinais , Medula Espinal/efeitos dos fármacos , Medula Espinal/enzimologia , Medula Espinal/patologia
13.
Biomed Pharmacother ; 106: 1484-1489, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30119223

RESUMO

In the present study, an attempt was made to determine whether administration of fucoxanthin could attenuate cerebral ischemic/reperfusion (I/R) injury and its possible mechanisms using an in vivo middle cerebral artery occlusion (MCAO) model and an in vitro oxygen-glucose deprivation and reoxygenation (OGD/R) model. Fucoxanthin was intragastrically administrated in different doses (30 mg/kg, 60 mg/kg, and 90 mg/kg, respectively) to the rats 1 h before MCAO induction. The neurological function, infarct area and brain water content of rats were then evaluated. Rat cortical neuron were pretreated with different doses of fucoxanthin (5 µM, 10 µM, and 20 µM) and then subjected to OGD/R. Expression levels of proteins in the brain tissues and cultured cells were determined by western blotting. Our results demonstrated that fucoxanthin pretreatment improved the neurologic deficit score, lowered the infarct volume and reduced the expression of apoptosis-associated proteins in brain tissues. In addition, fucoxanthin also suppresses OGD/R-induced apoptosis and ROS accumulation in cultured neurons. Furthermore, we found that fucoxanthin could significantly activate the Nrf2/HO-1 signaling through inducing Nrf2 nuclear translocation with enhanced HO-1 expression, and Nrf2 knockdown obviously abrogated the beneficial role of fucoxanthin in OGD/R-treated neurons. These findings suggested that fucoxanthin could be exploited as a therapeutic target for protecting neurons from cerebral I/R injury.


Assuntos
Apoptose/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Heme Oxigenase (Desciclizante)/metabolismo , Infarto da Artéria Cerebral Média/prevenção & controle , Fator 2 Relacionado a NF-E2/metabolismo , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Traumatismo por Reperfusão/prevenção & controle , Xantofilas/farmacologia , Animais , Proteínas Reguladoras de Apoptose/metabolismo , Encéfalo/enzimologia , Encéfalo/patologia , Encéfalo/fisiopatologia , Células Cultivadas , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Infarto da Artéria Cerebral Média/enzimologia , Infarto da Artéria Cerebral Média/patologia , Infarto da Artéria Cerebral Média/fisiopatologia , Masculino , Fator 2 Relacionado a NF-E2/genética , Neurônios/enzimologia , Neurônios/patologia , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo , Traumatismo por Reperfusão/enzimologia , Traumatismo por Reperfusão/patologia , Traumatismo por Reperfusão/fisiopatologia , Transdução de Sinais/efeitos dos fármacos , Superóxido Dismutase/metabolismo
14.
Int J Mol Sci ; 19(8)2018 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-30071692

RESUMO

Heme oxygenase 1 (HO-1) up-regulation is recognized as a pivotal mechanism of cell adaptation to stress. Under control of different transcription factors but with a prominent role played by Nrf2, HO-1 induction is crucial also in nervous system response to damage. However, several lines of evidence have highlighted that HO-1 expression is associated to neuronal damage and neurodegeneration especially in Alzheimer's and Parkinson's diseases. In this review, we summarize the current literature regarding the role of HO-1 in nervous system pointing out different molecular mechanisms possibly responsible for HO-1 up-regulation in nervous system homeostasis and neurodegeneration.


Assuntos
Doença de Alzheimer/enzimologia , Regulação Fúngica da Expressão Gênica , Heme Oxigenase-1/biossíntese , Neurônios/enzimologia , Doença de Parkinson/enzimologia , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Animais , Sobrevivência Celular , Heme Oxigenase-1/genética , Humanos , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Neurônios/patologia , Doença de Parkinson/genética , Doença de Parkinson/patologia
15.
Biomed Res ; 39(3): 149-158, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29899190

RESUMO

Gonadotropin-releasing hormone (GnRH) is secreted from hypothalamic neurons (GnRH neurons) and stimulates anterior pituitary gonadotrophs to synthesize and secrete gonadotropins. In addition to gonadotrophs, GnRH neurons also express GnRH receptors, and the autocrine action of GnRH is reportedly involved in the regulation of functions of GnRH neurons. There is accumulating evidence that extracellular signal-regulated kinase (ERK), one of mitogen-activated protein kinases (MAPKs), is activated by GnRH and involved in various effects of GnRH in GnRH neurons. In the present study, we performed microarray analysis to examine the types of genes whose expression was regulated by GnRH in immortalized mouse GnRH neurons (GT1-7 cells). We found that 257 genes among 55,681 genes examined were up-regulated after 30-min treatment of GT1-7 cells with GnRH. These up-regulated genes included four dual-specificity MAPK phosphatases (DUSPs), DUSP1, DUSP2, DUSP5, and DUSP6. Reverse transcription-polymerase chain reaction analysis confirmed that the mRNA levels of DUSP5 and DUSP6 were robustly increased within 30 min. U0126, an inhibitor of ERK activation, completely inhibited the increases in the mRNA levels of DUSP5 and DUSP6. Immunoblotting analysis revealed that ERK activation peaked at 5 min and declined steeply at 60 min, whereas DUSP5 and DUSP6 proteins were increased from 60 min. It was notable that down-regulation of DUSP6 augmented GnRH-induced ERK activation approximately 1.7-fold at 60 min. These results suggested that the up-regulation of DUSP6 regulates the duration of ERK activation at least in part.


Assuntos
Fosfatase 6 de Especificidade Dupla/biossíntese , Fosfatases de Especificidade Dupla/biossíntese , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Hormônio Liberador de Gonadotropina/farmacologia , Hipotálamo/enzimologia , Neurônios/enzimologia , Regulação para Cima/efeitos dos fármacos , Animais , Linhagem Celular Transformada , Hipotálamo/citologia , Camundongos , Neurônios/citologia
16.
Pharmacol Rep ; 70(4): 677-683, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29940507

RESUMO

BACKGROUND: Many studies have indicated a relationship between diabetes and Alzheimer's disease (AD). However, the molecular mechanism underlying this association has not been clarified. Among several factors, insulin degrading enzyme (IDE), which plays roles in the degradation of both insulin and amyloid ß (Aß), has gained interest as a potential target in efforts to solve this puzzle. This study sought to examine the effects of varying insulin and/or glucose concentrations on IDE expression. METHODS: Experiments were performed on primary cultured rat neurons and cortices of rats with streptozotocin (STZ)-induced diabetes. IDE protein and mRNA expression levels were measured by western blot and RT-PCR, respectively. RESULTS: In primary cultured cortical neurons, removal of insulin for 5days reduced the expression of IDE. A five-day treatment with a high concentration of glucose in insulin-free media reduced IDE levels, while a high concentration of glucose in the presence of insulin had no effect. In groups treated with glucose or insulin intermittently, the reduction in IDE levels was observed only in neurons exposed to high glucose together with no insulin for 5days. Shorter incubation periods (48h), either continuously or intermittently, did not affect IDE levels. IDE expression in the cortex of rats with STZ-induced diabetes was found to be decreased. CONCLUSION: Our data suggest that insulin deprivation, rather than high glucose, is a significant determinant of IDE regulation. As evidence indicates potential roles for IDE in diabetes and AD, understanding the mechanisms regulating IDE expression may be important in developing new treatment strategies.


Assuntos
Córtex Cerebral/citologia , Córtex Cerebral/metabolismo , Diabetes Mellitus Experimental/metabolismo , Insulina/deficiência , Insulisina/biossíntese , Neurônios/metabolismo , Animais , Córtex Cerebral/enzimologia , Diabetes Mellitus Experimental/enzimologia , Relação Dose-Resposta a Droga , Glucose/farmacologia , Insulina/metabolismo , Masculino , Neurônios/enzimologia , Cultura Primária de Células , Ratos , Fatores de Tempo
17.
Biomed Pharmacother ; 103: 1545-1551, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29864941

RESUMO

BACKGROUND: General anesthesia in spinal cord may lead to unexpected but irreversible neurotoxicity. We investigated whether resveratrol (RSV) may protect bupivacaine (BUP)-induced neuro-apoptosis in spinal cord dorsal root ganglia (DRG). METHODS: Mouse DRG cells were cultured in vitro, pre-treated with RSV and then 5 mM BUP. A concentration-dependent effect of RSV on reducing BUP-induced apoptosis of DRG neurons (DRGNs) was evaluated using a TUNEL assay. QRT-PCR and western blot assays were also conducted to evaluate gene and protein expressions of tropomyosin receptor kinase A/B/C (TrkA/B/C) and activated (phosphorylated) Trk receptors, phospho-TrkA/B/C. In addition, a functional TrkA blocking antibody MNAC13 was applied in DRG culture to further measure the functional role of Trk receptor in RSV-initiated apoptotic protection on BUP-damaged DRGNs. RESULTS: BUP promoted significant apoptosis in DRG. RSV exhibited protective effects against BUP-induced neuro-apoptosis in a concentration-dependent manner. qRT-PCR and western blot showed that RSV did not alter TrkA/B/C gene or protein expression, but significantly upregulated phospho-TrkA. Conversely, application of MNAC13 decreased phospho-TrkA and reversed RSV-initiated neuro-protection on BUP-induced DRGN apoptosis. CONCLUSION: Resveratrol may protect anesthesia-induced DRG neuro-apoptosis, and activation of TrkA signaling pathway may be the underlying mechanism in this process.


Assuntos
Apoptose/efeitos dos fármacos , Bupivacaína/efeitos adversos , Gânglios Espinais/patologia , Neurônios/enzimologia , Neurônios/patologia , Fármacos Neuroprotetores/farmacologia , Proteínas Quinases/metabolismo , Estilbenos/farmacologia , Animais , Ativação Enzimática/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Neurônios/efeitos dos fármacos , Neuroproteção/efeitos dos fármacos , Resveratrol , Transdução de Sinais/efeitos dos fármacos
18.
Biochem Biophys Res Commun ; 502(4): 435-441, 2018 08 25.
Artigo em Inglês | MEDLINE | ID: mdl-29856999

RESUMO

Methylmercury (MeHg) is the causative substance of Minamata disease, which is associated with various neurological disorders such as sensory disturbance and ataxia. It has been suggested low-level dietary intake of MeHg from MeHg-containing fish during gestation adversely affects the fetus. In our study, we investigated the toxicological effects of MeHg exposure on neuronal differentiation focusing on epigenetics. We used human fetal brain-derived immortalized cells (LUHMES cells) as a human neuronal differentiation model. Cell viability, neuronal, and catecholamine markers in LUHMES cells were assessed after exposure to MeHg (0-1000 nM) for 6 days (from day 2 to day 8 of neuronal differentiation). Cell viability on day 8 was not affected by exposure to 1 nM MeHg for 6 days. mRNA levels of AADC, DBH, TUJ1, and SYN1 also were unaffected by MeHg exposure. In contrast, levels of TH, the rate-limiting enzyme for dopamine synthesis, were significantly decreased after MeHg exposure. Acetylated histone H3, acetylated histone H3 lysine 9, and tri-methyl histone H3 lysine 9 levels at the TH gene promoter were not altered by MeHg exposure. However, tri-methylation of histone H3 lysine 27 levels, related to transcriptional repression, were significantly increased at the TH gene promotor after MeHg exposure. In summary, MeHg exposure during neuronal differentiation led to epigenetic changes that repressed TH gene expression. This study provides useful insights into the toxicological mechanisms underlying the effects of developmental MeHg exposure during neuronal differentiation.


Assuntos
Epigênese Genética/efeitos dos fármacos , Compostos de Metilmercúrio/toxicidade , Neurônios/efeitos dos fármacos , Tirosina 3-Mono-Oxigenase/genética , Animais , Diferenciação Celular , Linhagem Celular , Feminino , Peixes , Contaminação de Alimentos , Humanos , Intoxicação do Sistema Nervoso por Mercúrio/etiologia , Intoxicação do Sistema Nervoso por Mercúrio/genética , Intoxicação do Sistema Nervoso por Mercúrio/patologia , Metilação , Modelos Neurológicos , Neurônios/citologia , Neurônios/enzimologia , Gravidez , Efeitos Tardios da Exposição Pré-Natal , Regiões Promotoras Genéticas , Tirosina 3-Mono-Oxigenase/antagonistas & inibidores
19.
Rejuvenation Res ; 21(5): 431-441, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29847217

RESUMO

Due to requirement of novel memory enhancer for menopausal women, this study aimed to determine safety and effect of the functional drink containing the extracts of purple corn cob and pandan leaves (PCP) on memory and brain changes in experimental menopause induced by bilateral ovariectomy (OVX). Acute toxicity of PCP was carried out in female Wistar rats. The results showed that LD50 was more than 2000 mg/kg BW. To determine the cognitive enhancing effect of PCP, OVX rats were orally treated with PCP at the doses of 20, 40, and 80 mg/kg BW for 28 days. The spatial memory was assessed every 7 days throughout the study period. At the end of the study, oxidative stress status, acetylcholinesterase (AChE) activity, monoamine oxidase (MAO) activity, neuronal density, and extracellular signal regulated protein kinase 1 and 2 (ERK1/2) signaling in hippocampus were measured. The improved spatial memory, ERK1/2 expression, and neuron density in dentate gyrus of hippocampus were observed in PCP-treated rats. In addition, a reduction of AChE activity was also observed. Unfortunately, no improved oxidative stress status was observed. Taken altogether, PCP exerts the memory-enhancing effect partly through the suppression of AChE and the increase in ERK signaling in the hippocampus.


Assuntos
Colinérgicos/farmacologia , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Neurônios/efeitos dos fármacos , Nootrópicos/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/farmacologia , Folhas de Planta/química , Memória Espacial/efeitos dos fármacos , Acetilcolinesterase/metabolismo , Animais , Feminino , Hipocampo/efeitos dos fármacos , Hipocampo/enzimologia , Transtornos da Memória/etiologia , Transtornos da Memória/prevenção & controle , Neurônios/enzimologia , Ovariectomia , Ratos , Ratos Wistar , Zea mays/química
20.
Pharmacology ; 102(1-2): 42-52, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29843142

RESUMO

BACKGROUND/AIMS: Decreasing levels of aromatase and seladin-1 could be one of the molecular mechanisms of Alzheimer's disease (AD). Aromatase is an enzyme that catalyzes estrogen biosynthesis from androgen precursors, and seladin-1 is an enzyme that converts desmosterol to cholesterol, which is the precursor of all hormones. Verifying the potential relationship between these proteins and accordingly determining new therapeutic targets constitute the aims of this study. METHODS: Changes in protein levels were compared in vitro in aromatase and seladin-1 inhibitor-administered human neuroblastoma (SH-SY5Y) cells in vivo in intracerebroventricular (icv) aromatase or seladin-1 inhibitor-administered rats, as well as in transgenic AD mice in which the genes encoding these proteins were knocked out. RESULTS AND CONCLUSIONS: In the cell cultures, we observed that seladin-1 protein levels increased after aromatase enzyme inhibition. The hippocampal aromatase protein levels decreased following chronic seladin-1 inhibition in icv inhibitor-administered rats; however, the aromatase levels in the dentate gyrus of seladin-1 knockout (SelKO) AD male mice increased. These findings indicate a partial relationship between these proteins and their roles in AD pathology.


Assuntos
Doença de Alzheimer/enzimologia , Aromatase/metabolismo , Hipocampo/enzimologia , Proteínas do Tecido Nervoso/metabolismo , Oxirredutases atuantes sobre Doadores de Grupo CH-CH/metabolismo , Androstenos/farmacologia , Animais , Aromatase/genética , Inibidores da Aromatase/administração & dosagem , Inibidores da Aromatase/farmacologia , Células Cultivadas , Giro Denteado/enzimologia , Feminino , Humanos , Infusões Intraventriculares , Letrozol , Masculino , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Proteínas do Tecido Nervoso/genética , Neurônios/enzimologia , Nitrilos/farmacologia , Oxirredutases atuantes sobre Doadores de Grupo CH-CH/genética , Ratos , Triazóis/farmacologia
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