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1.
Nat Neurosci ; 22(7): 1099-1109, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31235907

RESUMO

Parkinson's disease, the most common age-related movement disorder, is a progressive neurodegenerative disease with unclear etiology. Key neuropathological hallmarks are Lewy bodies and Lewy neurites: neuronal inclusions immunopositive for the protein α-synuclein. In-depth ultrastructural analysis of Lewy pathology is crucial to understanding pathogenesis of this disease. Using correlative light and electron microscopy and tomography on postmortem human brain tissue from Parkinson's disease brain donors, we identified α-synuclein immunopositive Lewy pathology and show a crowded environment of membranes therein, including vesicular structures and dysmorphic organelles. Filaments interspersed between the membranes and organelles were identifiable in many but not all α-synuclein inclusions. Crowding of organellar components was confirmed by stimulated emission depletion (STED)-based super-resolution microscopy, and high lipid content within α-synuclein immunopositive inclusions was corroborated by confocal imaging, Fourier-transform coherent anti-Stokes Raman scattering infrared imaging and lipidomics. Applying such correlative high-resolution imaging and biophysical approaches, we discovered an aggregated protein-lipid compartmentalization not previously described in the Parkinsons' disease brain.


Assuntos
Membranas Intracelulares/ultraestrutura , Corpos de Lewy/ultraestrutura , Doença por Corpos de Lewy/patologia , Lipídeos de Membrana/análise , Organelas/ultraestrutura , Doença de Parkinson/patologia , alfa-Sinucleína/análise , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Hipocampo/química , Hipocampo/ultraestrutura , Humanos , Imagem Tridimensional , Corpos de Lewy/química , Doença por Corpos de Lewy/metabolismo , Mesencéfalo/química , Mesencéfalo/ultraestrutura , Microscopia Confocal , Microscopia Eletrônica/métodos , Microscopia de Fluorescência , Doença de Parkinson/metabolismo , Substância Negra/química , Substância Negra/ultraestrutura , Sequenciamento Completo do Exoma
2.
Environ Sci Pollut Res Int ; 26(21): 22030-22039, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31140091

RESUMO

In order to explore the effects of combined traffic noise (CTN) on learning and memory function, young Sprague-Dawley (SD) rats were exposed to CTN from highway and high-speed railway for 52 days, whose day-night equivalent continuous A-weighted sound pressure level (Ldn) was 70 dB(A) (corresponding sound pressure level was 80 dB). The synaptic ultrastructure and the expressions of phosphorylated calcium/calmodulin-dependent protein kinase II (p-CaMKII) and N-methyl-D-aspartate receptor 1 (NMDAR1 or NR1) in the hippocampus were tested by transmission electron microscopy (TEM) and Western blot, respectively. Results showed that there was no significant difference in the synaptic ultrastructure and the expressions of p-CaMKII and NR1 in the hippocampus of young rats between the experimental group and control group. Compared with single high-speed railway noise (HSRN) with Ldn of 70 dB(A), CTN had less influences on learning and memory function, which was closely related to smaller intermittency of CTN and less anxiety caused by CTN. In comparison with white noise with a sound pressure level of 80 dB, CTN had less impacts on learning and memory function, which was mainly associated with CTN's smaller R-weighted sound pressure level based on rats' auditory sensitivity.


Assuntos
Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Hipocampo/ultraestrutura , Ruído dos Transportes , Receptores de N-Metil-D-Aspartato/metabolismo , Animais , Ansiedade , Hipocampo/metabolismo , Aprendizagem , Masculino , Memória , Fosforilação , Ratos , Ratos Sprague-Dawley
3.
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
4.
Chem Biol Interact ; 307: 223-233, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31018114

RESUMO

OBJECTIVE: The aim of this study is to investigate the role of mircoRNA-200c-3p (miR-200c-3p) on hippocampal neuron injury in epileptic rats through the regulation of the AKT signaling pathway by targeting RECK. METHODS: The epilepsy rat model was induced by intraperitoneal injection of lithium chloride-pilocarpine. Successful modeled rats were injected with miR-200c-3p inhibitors, inhibitors NC, siRNA-negative control (NC) and RECK-siRNA. The astrocyte activation, levels of oxidative stress indexes, contents of inflammatory factors and the AKT signaling pathway-related proteins in hippocampus tissues were evaluated. RESULTS: High expression of miR-200c-3p and low expression of RECK were found in the hippocampus tissues of epileptic rats. Downregulation of miR-200c-3p or upregulation of RECK decreased apoptosis of hippocampal neurons, expression of GFAP, content of MDA and increased the activities of GSH-Px and SOD, decreased expression of TNF-α, IL-1ß and IL-6 as well as expression of p-PI3K/t-PI3K and p-Akt/t-Akt in hippocampus tissues of epileptic rats. CONCLUSION: Our study provides evidence that downregulation of miR-200c-3p reduces damage of hippocampal neurons in epileptic rats by upregulating RECK and inactivating the AKT signaling pathway.


Assuntos
Hipocampo/metabolismo , MicroRNAs/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Regiões 3' não Traduzidas , Animais , Antagomirs/metabolismo , Apoptose , Modelos Animais de Doenças , Regulação para Baixo , Epilepsia/genética , Epilepsia/patologia , Proteínas Ligadas por GPI/antagonistas & inibidores , Proteínas Ligadas por GPI/genética , Proteínas Ligadas por GPI/metabolismo , Hipocampo/patologia , Hipocampo/ultraestrutura , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Masculino , MicroRNAs/antagonistas & inibidores , MicroRNAs/genética , Fosfatidilinositol 3-Quinases/metabolismo , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Ratos , Ratos Wistar , Transdução de Sinais , Proteínas Supressoras de Tumor/antagonistas & inibidores , Proteínas Supressoras de Tumor/genética , Regulação para Cima
5.
Epilepsy Res ; 152: 35-41, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30875635

RESUMO

Generalized seizures trigger excessive neuronal firing that imposes large demands on the brain glucose/lactate availability and utilization, which synchronization requires an integral mitochondrial oxidative capability. We investigated whether a single convulsive crisis affects brain glucose/lactate availability and mitochondrial energy production. Adult male Wistar rats received a single injection of pentylentetrazol (PTZ, 60 mg/kg, i.p.) or saline. The cerebrospinal fluid (CSF) levels of glucose and lactate, mitochondrial respirometry, [14C]-2-deoxy-D-glucose uptake, glycogen content and cell viability in hippocampus were measured. CSF levels of glucose and lactate (mean ± SD) in control animals were 68.08 ± 11.62 mg/dL and 1.17 ± 0.32 mmol/L, respectively. Tonic-clonic seizures increased glucose levels at 10 min (96.25 ± 13.19) peaking at 60 min (113.03 ± 16.34) returning to control levels at 24 h (50.12 ± 12.81), while lactate increased at 10 min (3.23 ± 1.57) but returned to control levels at 360 min after seizures (1.58 ± 0.21). The hippocampal [14C]-2-deoxy-D-glucose uptake, glycogen content, and cell viability decreased up to 60 min after the seizures onset. Also, an uncoupling between mitochondrial oxygen consumption and ATP synthesis via FoF1-ATP synthase was observed at 10 min, 60 min and 24 h after seizures. In summary, after a convulsive seizure glucose and lactate levels immediately rise within the brain, however, considering the acute impact of this metabolic crisis, mitochondria are not able to increase energy production thereby affecting cell viability.


Assuntos
Glucose/líquido cefalorraquidiano , Ácido Láctico/líquido cefalorraquidiano , Mitocôndrias/metabolismo , Convulsões/líquido cefalorraquidiano , Animais , Desoxiglucose/metabolismo , Modelos Animais de Doenças , Transporte de Elétrons/efeitos dos fármacos , Etanolaminas/toxicidade , Glicogênio/metabolismo , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Hipocampo/ultraestrutura , Masculino , Mitocôndrias/efeitos dos fármacos , Ratos , Ratos Wistar , Convulsões/induzido quimicamente , Fatores de Tempo
6.
Nat Commun ; 10(1): 1285, 2019 03 20.
Artigo em Inglês | MEDLINE | ID: mdl-30894537

RESUMO

Dendritic spines are the postsynaptic sites that receive most of the excitatory synaptic inputs, and thus provide the structural basis for synaptic function. Here, we describe an accurate method for measurement and analysis of spine morphology based on structured illumination microscopy (SIM) and computational geometry in cultured neurons. Surface mesh data converted from SIM images were comparable to data reconstructed from electron microscopic images. Dimensional reduction and machine learning applied to large data sets enabled identification of spine phenotypes caused by genetic mutations in key signal transduction molecules. This method, combined with time-lapse live imaging and glutamate uncaging, could detect plasticity-related changes in spine head curvature. The results suggested that the concave surfaces of spines are important for the long-term structural stabilization of spines by synaptic adhesion molecules.


Assuntos
Espinhas Dendríticas/ultraestrutura , Hipocampo/ultraestrutura , Microscopia/estatística & dados numéricos , Neurônios/ultraestrutura , Imagem com Lapso de Tempo/estatística & dados numéricos , Animais , Carbocianinas/química , Conjuntos de Dados como Assunto , Espinhas Dendríticas/fisiologia , Embrião de Mamíferos , Corantes Fluorescentes/química , Ácido Glutâmico/metabolismo , Hipocampo/fisiologia , Aprendizado de Máquina , Masculino , Camundongos , Camundongos Endogâmicos ICR , Camundongos Transgênicos , Microscopia/métodos , Redução Dimensional com Múltiplos Fatores , Plasticidade Neuronal/fisiologia , Neurônios/fisiologia , Cultura Primária de Células , Coloração e Rotulagem/métodos , Imagem com Lapso de Tempo/métodos
7.
Oxid Med Cell Longev ; 2019: 8639618, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30918581

RESUMO

Background: The potential mechanism of postoperative cognitive impairment is still largely unclear. The activation of NLRP3 inflammasome had been reported to be involved in neurodegenerative diseases, including postoperative cognitive change, and is closely related to mitochondrial ROS and mitophagy. Honokiol (HNK) owns multiple organic protective effects. This study is aimed at observing the neuroprotective effect of HNK in postoperative cognitive change and examining the role of HNK in the regulation of mitophagy and the relationship between these effects and NLRP3 inflammasome activation in mice induced by surgery/anesthesia. Methods: In this study, mice were divided into several groups: control group, surgery group, surgery+HNK group, and surgery+HNK+3-methyladenine (3-MA) group. Hippocampal tissue samples were harvested and used for proinflammatory cytokines, mitochondrial ROS, and malondialdehyde (MDA) assay. The process of mitophagy and the activation of NLRP3 inflammasome were observed by Western blot, immunohistochemistry, and transmission electron microscopy. Results: The results showed that HNK treatment obviously recovered the postoperative decline and enhanced the expressions of LC3-II, Beclin-1, Parkin, and PINK1 at protein levels after surgery/sevoflurane treatment, which are both an autophagy marker and a mitophagy marker. In addition, HNK attenuated mitochondrial structure damage and reduced mtROS and MDA generation, which are closely associated with NLRP3 inflammasome activation. Honokiol-mediated mitophagy inhibited the activation of NLRP3 inflammasome and neuroinflammation in the hippocampus. Using 3-MA, an autophagy inhibitor, the neuroprotective effects of HNK on mitophagy and NLRP3 inflammasome activation were eliminated. Conclusion: These results indicated that HNK-mediated mitophagy ameliorates postoperative cognitive impairment induced by surgery/sevoflurane. This neuroprotective effect may be involved in inhibiting the activation of NLRP3 inflammasome and suppressing inflammatory responses in the hippocampus.


Assuntos
Compostos de Bifenilo/uso terapêutico , Disfunção Cognitiva/tratamento farmacológico , Hipocampo/metabolismo , Inflamassomos/metabolismo , Lignanas/uso terapêutico , Degradação Mitocondrial/efeitos dos fármacos , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Complicações Pós-Operatórias/tratamento farmacológico , Sevoflurano/efeitos adversos , Animais , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Compostos de Bifenilo/farmacologia , Disfunção Cognitiva/etiologia , Giro Denteado/metabolismo , Giro Denteado/patologia , Feminino , Hipocampo/ultraestrutura , Lignanas/farmacologia , Camundongos Endogâmicos C57BL , Microglia/efeitos dos fármacos , Microglia/metabolismo , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Mitocôndrias/ultraestrutura , Neurônios/efeitos dos fármacos , Neurônios/patologia , Estresse Oxidativo/efeitos dos fármacos , Complicações Pós-Operatórias/etiologia , Espécies Reativas de Oxigênio/metabolismo
8.
J Agric Food Chem ; 67(9): 2709-2715, 2019 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-30701967

RESUMO

Exposure to nanosized titanium oxide (nano-TiO2) has been proven to suppress brain growth in mouse offspring; however, whether retardation of axonal or dendritic outgrowth is associated with activation of the mitogen-activated protein kinase (MAPK) pathway remains unclear. In the present study, pregnant mice were exposed to nano-TiO2 at 1.25, 2.5, and 5 mg/kg body weight, and the molecular mechanism of axonal or dendritic outgrowth retardation was investigated. The results suggested that nano-TiO2 crossed the blood-fetal barrier and blood-brain barrier and deposited in the brain of offspring, which retarded axonal and dendritic outgrowth, including the absence of axonal outgrowth, and decreased dendritic filament length, dendritic branching number, and dendritic spine density. Importantly, maternal exposure to nano-TiO2 increased phosphorylated (p)-extracellular signal-regulated kinase1/2 (ERK1/2, +24.35% to +59.4%), p-p38 (+60.82% to 181.85%), and p-c-jun N-terminal kinase (JNK, +28.28% to 97.28%) expression in the hippocampus of the offspring. These findings suggested that retardation of axonal and dendritic outgrowth in mouse offspring caused by maternal exposure to nano-TiO2 may be related to excessive activation of the ERK1/2/MAPK signaling pathway. Therefore, the potential toxicity of nano-TiO2 is a concern, especially in pregnant woman or children who are exposed to nano-TiO2.


Assuntos
Axônios/efeitos dos fármacos , Dendritos/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Transdução de Sinais/efeitos dos fármacos , Titânio/toxicidade , Animais , Axônios/fisiologia , Química Encefálica/efeitos dos fármacos , Dendritos/fisiologia , Feminino , Hipocampo/ultraestrutura , Troca Materno-Fetal , Camundongos , Nanopartículas , Gravidez , Efeitos Tardios da Exposição Pré-Natal , Titânio/análise
9.
Toxicology ; 414: 27-34, 2019 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-30629985

RESUMO

OBJECTIVE: We investigated the impact of subchronic low-dose exposure to nonylphenol (NP) on depression-like behaviors and synaptic morphological plasticity in the context of a high-sucrose/high-fat diet in rats. METHODS: Male Sprague Dawley (SD) rats were randomly divided into 8 groups (n = 10 per group), as follows: rats fed a normal-diet (ND), as the control (C-ND); rats fed a normal diet and gavaged with NP at a dose of 0.02 mg/kg/day (NP-L-ND), 0.2 mg/kg/day (NP-M-ND) or 2 mg/kg/day (NP-H-ND); rats fed a high-sucrose/high-fat diet (HSHFD), as the HSHFD control (C-HSHFD); rats fed a HSHFD and gavaged with NP at a dose of 0.02 mg/kg/day (NP-L-HSHFD), 0.2 mg/kg/day (NP-M-HSHFD) or 2 mg/kg/day (NP-H-HSHFD). Elevated plus maze was used to evaluate anxiety behavior. Open field test was used to evaluate locomotor activity. Cyclooxygenase-2 expression in hippocampal tissue was measured by immunohistochemistry. The ultrastructure of hippocampal mitochondria and the synaptic plasticity were observed by transmission electron microscopy. RESULTS: Significant interactions between HSHFD and NP-H were observed, reflected by the time spent exploring the open arms, time spent in the center area, distance traveled in the center area and total distance traveled (p < 0.05). Exposure to NP-H-HSHFD resulted in swelling of the mitochondria, associated with an increased number of disordered and partially disrupted cristae compared with the control group. Synaptic interface curvatures and postsynaptic density thickness decreased as the NP dose increased among the treatment groups. Co-exposure to HSHFD and NP showed an increase in synaptic cleft width compared with the HSHFD-only and NP-only exposure groups (p < 0.05). COX-2 expression and integral optical density value increased as the NP dose increased among the NP treatment groups (p < 0.05). CONCLUSION: Subchronic low-dose exposure to NP might induce alterations in depression-like behaviors, synaptic morphological plasticity and COX-2 expression in the hippocampus. Co-exposure to NP and HSHFD had significantly more dissimilarities.


Assuntos
Comportamento Animal/efeitos dos fármacos , Depressão/induzido quimicamente , Dieta Hiperlipídica , Sacarose na Dieta , Disruptores Endócrinos/toxicidade , Hipocampo/efeitos dos fármacos , Plasticidade Neuronal/efeitos dos fármacos , Fenóis/toxicidade , Animais , Ciclo-Oxigenase 2/metabolismo , Depressão/patologia , Depressão/fisiopatologia , Depressão/psicologia , Modelos Animais de Doenças , Hipocampo/metabolismo , Hipocampo/fisiopatologia , Hipocampo/ultraestrutura , Locomoção/efeitos dos fármacos , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Ratos Sprague-Dawley , Medição de Risco
10.
Int J Mol Sci ; 20(2)2019 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-30634540

RESUMO

The Kv4 family of voltage-gated K⁺ channels underlie the fast transient (A-type) outward K⁺ current. Although A-type currents are critical to determine somato-dendritic integration in central neurons, relatively little is known about the precise subcellular localisation of the underlying channels in hippocampal circuits. Using histoblot and immunoelectron microscopic techniques, we investigated the expression, regional distribution and subcellular localisation of Kv4.2 and Kv4.3 in the adult brain, as well as the ontogeny of their expression during postnatal development. Histoblot demonstrated that Kv4.2 and Kv4.3 proteins were widely expressed in the brain, with mostly non-overlapping patterns. During development, levels of Kv4.2 and Kv4.3 increased with age but showed marked region- and developmental stage-specific differences. Immunoelectron microscopy showed that labelling for Kv4.2 and Kv4.3 was differentially present in somato-dendritic domains of hippocampal principal cells and interneurons, including the synaptic specialisation. Quantitative analyses indicated that most immunoparticles for Kv4.2 and Kv4.3 were associated with the plasma membrane in dendritic spines and shafts, and that the two channels showed very similar distribution patterns in spines of principal cells and along the surface of granule cells. Our data shed new light on the subcellular localisation of Kv4 channels and provide evidence for their non-uniform distribution over the plasma membrane of hippocampal neurons.


Assuntos
Expressão Gênica , Hipocampo/metabolismo , Canais de Potássio Shal/genética , Canais de Potássio Shal/metabolismo , Animais , Encéfalo/metabolismo , Encéfalo/ultraestrutura , Hipocampo/crescimento & desenvolvimento , Hipocampo/ultraestrutura , Imuno-Histoquímica , Espaço Intracelular/metabolismo , Masculino , Camundongos , Transporte Proteico , Ratos
11.
Eur Neuropsychopharmacol ; 29(2): 195-210, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-30554860

RESUMO

Methylphenidate (MPH) is the classic treatment for attention deficit hyperactivity disorder (ADHD) among children and adults. Despite its beneficial effects, non-medical use of MPH is nowadays a problem with high impact on society. Thus, our goal was to uncover the neurovascular and cognitive effects of MPH chronic use during a critical period of development in control conditions. For that, male Wistar Kyoto rats were treated with MPH (1.5 or 5 mg/kg/day at weekdays, per os) from P28 to P55. We concluded that the higher dose of MPH caused hippocampal blood-brain barrier (BBB) hyperpermeability by vesicular transport (transcytosis) concomitantly with the presence of peripheral immune cells in the brain parenchyma. These observations were confirmed by in vitro studies, in which the knockdown of caveolin-1 in human brain endothelial cells prevented the increased permeability and leukocytes transmigration triggered by MPH (100 µM, 24 h). Furthermore, MPH led to astrocytic atrophy and to a decrease in the levels of several synaptic proteins and impairment of AKT/CREB signaling, together with working memory deficit assessed in the Y-maze test. On the contrary, we verified that the lower dose of MPH (1.5 mg/kg/day) increased astrocytic processes and upregulated several neuronal proteins as well as signaling pathways involved in synaptic plasticity culminating in working memory improvement. In conclusion, the present study reveals that a lower dose of MPH in normal rats improves memory performance being associated with the modulation of astrocytic morphology and synaptic machinery. However, a higher dose of MPH leads to BBB dysfunction and memory impairment.


Assuntos
Estimulantes do Sistema Nervoso Central/farmacologia , Hipocampo/efeitos dos fármacos , Memória/efeitos dos fármacos , Metilfenidato/farmacologia , Transcitose/efeitos dos fármacos , Animais , Animais Recém-Nascidos , Antioxidantes/metabolismo , Células Cultivadas , Células Endoteliais/efeitos dos fármacos , Hipocampo/anatomia & histologia , Hipocampo/ultraestrutura , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Proteínas do Tecido Nervoso/metabolismo , Neuroglia/efeitos dos fármacos , Neuroglia/ultraestrutura , Neurônios/efeitos dos fármacos , Neurônios/ultraestrutura , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo , Transcitose/fisiologia , Regulação para Cima/efeitos dos fármacos
12.
Biomed Pharmacother ; 109: 853-864, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30551539

RESUMO

BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disorder and the commonest cause of dementia among the aged people. D-galactose (D-gal) is a senescence agent, while aluminium is a known neurotoxin linked to pathogenesis of AD. The combined administration of rats with d-gal and aluminium chloride (AlCl3) is considered to be an easy and a cheap method to obtain an animal model of AD. The plant Centella asiatica (CA) is reported to exert neuroprotective effects both in vitro and in vivo. Therefore, this study explored the protective effects of CA on cognition and brain ultrastructure in d-gal and AlCl3 induced rats. MATERIALS AND METHODS: Rats were exposed to d-gal 60 mg/kg/b.wt/day + AlCl3 200 mg/kg/b.wt/day and CA (200, 400 and 800 mg/kg/b.wt/day) and 1 mg/kg/b.wt/day of donepezil for 70 days. Different cognitive paradigms viz. T maze spontaneous alternation, modified elevated plus maze and novel object recognition test, were used to evaluate full lesions of the hippocampus, spatial learning and memory and non-spatial learning and memory respectively. Nissl's staining was used to determine the survival of hippocampus CA1 pyramidal cells, while transmission electron microscopy was used to check the ultrastructural changes. RESULTS: The results revealed that d-gal and AlCl3 could significantly impair behavior and cognitive functions, besides causing damage to the hippocampal CA1 pyramidal neurons in rats. In addition, it also caused ultrastructural morphological alterations in rat hippocampus. Conversely, co-administration o;f CA, irrespective of the dosage used, alleviated the cognitive impairments and pathological changes in the rats comparable to donepezil. CONCLUSION: In conclusion the results suggest that CA could protect cognitive impairments and morphological alterations caused by d-gal and AlCl3 toxicity in rats. Biochemical and molecular studies are ongoing to elucidate the probable pharmacodynamics of CA.


Assuntos
Cloreto de Alumínio/toxicidade , Disfunção Cognitiva/prevenção & controle , Galactose/toxicidade , Hipocampo/efeitos dos fármacos , Hipocampo/ultraestrutura , Triterpenos/uso terapêutico , Animais , Disfunção Cognitiva/induzido quimicamente , Disfunção Cognitiva/patologia , Relação Dose-Resposta a Droga , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Ratos , Ratos Wistar , Resultado do Tratamento , Triterpenos/farmacologia
13.
Microsc Res Tech ; 82(1): 53-60, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30575203

RESUMO

Scanning electron microscopy in ambient conditions (Air-SEM) was developed recently and has been used mainly for industrial applications. We assessed the potential application of Air-SEM for the analysis of biological tissues by using rat brain, kidney, human tooth, and bone. Hard tissues prepared by grinding and frozen sections were observed. Basic cytoarchitecture of bone and tooth was identified in the without heavy metal staining. Kidney tissue prepared using routine SEM methodology yielded images comparable to those of field emission (FE)-SEM. Sharpness was lower than that of FE-SEM, but foot process of podocytes was observed at high magnification. Air-SEM observation of semithin sections of kidney samples revealed glomerular basement membrane and podocyte processes, as seen using conventional SEM. Neuronal structures of soma, dendrites, axons, and synapses were clearly observed by Air-SEM with STEM detector and were comparable to conventional transmission electron microscopy images. Correlative light and electron microscopy observation of zebrafish embryos based on fluorescence microscopy and Air-SEM indicated the potential for a correlative approach. However, the image quality should be improved before becoming routine use in biomedical research.


Assuntos
Osso e Ossos/ultraestrutura , Encéfalo/ultraestrutura , Embrião não Mamífero/ultraestrutura , Hipocampo/ultraestrutura , Rim/ultraestrutura , Microscopia Eletrônica de Varredura/métodos , Costelas/ultraestrutura , Dente/ultraestrutura , Idoso , Ar , Animais , Feminino , Hipocampo/citologia , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microscopia de Fluorescência , Pessoa de Meia-Idade , Podócitos/ultraestrutura , Ratos , Ratos Sprague-Dawley , Suínos , Vácuo , Peixe-Zebra/embriologia
14.
Ecotoxicol Environ Saf ; 170: 673-681, 2019 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-30580161

RESUMO

Atrazine (ATR) is a commonly used artificial synthetic herbicide world-wide, which has been implicated as a potential threat to human health. Previous studies have demonstrated that exposure to ATR affects hippocampus-dependent learning and memory in rodents, but the exact molecular mechanism remains to be elucidated. In this study, we investigated the effect of ATR on the hippocampus of postnatal day 35 male Sprague Dawley (SD) rats administered doses of either 10 or 100 mg/kg body weight (BW)/day of ATR for a period of 30 days. A Morris water maze (MWM) test revealed that ATR treatment impaired memory performance in the spatial probe test, especially amongst the high-dose group. Moreover, analysis by electron microscopy showed that hippocampal neuron ultrastructure in the dentate gyrus (DG) and cornu ammonis 1 (CA1) sub-regions was impaired in the ATR-treated groups. Finally, a downregulation in the mRNA and protein expression levels of members of the MEK/ERK/CREB pathway and downstream factors brain-derived neurotrophic factor (BDNF) and Zif268 was observed in hippocampal tissue following ATR treatment. Taken together, these results suggest that developmental exposure to ATR is able to induce functional and morphological lesions in the hippocampus of SD rats, and that the MEK/ERK/CREB signaling pathway may be involved in this process.


Assuntos
Atrazina/toxicidade , Herbicidas/toxicidade , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Sistema de Sinalização das MAP Quinases , Animais , Atrazina/metabolismo , Fator Neurotrófico Derivado do Encéfalo/genética , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Regulação para Baixo , Proteína 1 de Resposta de Crescimento Precoce/genética , Proteína 1 de Resposta de Crescimento Precoce/metabolismo , Herbicidas/metabolismo , Hipocampo/ultraestrutura , Humanos , Sistema de Sinalização das MAP Quinases/genética , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Memória/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neurônios/ultraestrutura , Síndromes Neurotóxicas/etiologia , Síndromes Neurotóxicas/metabolismo , Ratos , Ratos Sprague-Dawley
15.
Radiología (Madr., Ed. impr.) ; 60(5): 404-412, sept.-oct. 2018. ilus, tab
Artigo em Espanhol | IBECS | ID: ibc-175301

RESUMO

Objetivo: Evaluar las subestructuras hipocampales utilizando resonancia magnética en pacientes con esclerosis hipocampal (EH), comparando los resultados con el análisis morfológico y la volumetría global del hipocampo. Método: Se incluyeron 25 controles y 25 pacientes con EH, cuyo diagnóstico fue extraído del informe de la junta institucional de epilepsia. Se utilizó FreeSurfer para el procesamiento de los estudios y la obtención de los datos volumétricos. El volumen fue valorado de manera global y por subestructura: fimbria, subiculum, presubiculum, fisura hipocampal, CA1, CA2-CA3, CA4 y giro dentado (GD). Se consideró p <0,05 como estadísticamente significativo. Resultados: Se observó una disminución estadísticamente significativa en el hipocampo homolateral al foco epileptógeno en 19 de los 25 casos (76,0%). A excepción de la fisura hipocampal, se observó una disminución en todas las subestructuras hipocampales homolaterales en la EH derecha (CA1, p = 0,0223; CA2-CA3, p = 0,0066; CA4-GD, p = 0,0066; fimbria, p = 0,0046; presubiculum, p = 0,0087; subiculum, p = 0,0017) y la EH izquierda (CA1, p <0,0001; CA2-CA3, p <0,0001; CA4-GD, p <0,0001; fimbria, p = 0,0183; presubiculum, p <0,0001; subiculum, p <0,0001). En cuatro casos de EH izquierda, ninguna de las subestructuras presentó alteración estadísticamente significativa; sin embargo, se observó una tendencia de atrofia, principalmente en CA2-CA3 y CA4-GD. Conclusión: Los hallazgos sugieren la utilidad de la evaluación de las subestructuras hipocampales para mejorar el desempeño de la imagen en el diagnóstico de la EH


Objective: The pathological classification of hippocampal sclerosis is based on the loss of neurons in the substructures of the hippocampus. This study aimed to evaluate these substructures in patients with hippocampal sclerosis by magnetic resonance imaging and to compare the usefulness of this morphological analysis compared to that of volumetric analysis of the entire hippocampus. Material and methods: We included 25 controls and 25 patients with hippocampal sclerosis whose diagnosis was extracted from the institutional epilepsy board. We used FreeSurfer to process the studies and obtain the volumetric data. We evaluated overall volume and volume by substructure: fimbria, subiculum, presubiculum, hippocampal sulcus, CA1, CA2–CA3, CA4, and dentate gyrus (DG). We considered p < 0.05 statistically significant. Results: We observed statistically significant decreases in the volume of the hippocampus ipsilateral to the epileptogenic focus in 19 (76.0%) of the 25 cases. With the exception of the hippocampal sulcus, we observed a decrease in all ipsilateral hippocampal substructures in patients with right hippocampal sclerosis (CA1, p=0.0223; CA2–CA3, p=0.0066; CA4–GD, p=0.0066; fimbria, p=0.0046; presubiculum, p=0.0087; subiculum, p=0.0017) and in those with left hippocampal sclerosis (CA1, p<0.0001; CA2–CA3, p<0. 0001; CA4–GD, p<0. 0001; fimbria, p=0.0183; presubiculum, p<0. 0001; subiculum, p<0. 0001). In four patients with left hippocampal sclerosis, none of the substructures had statistically significant alterations, although a trend toward atrophy was observed, mainly in CA2–CA3 and CA4–GD. Conclusion: The findings suggest that it can be useful to assess the substructures of the hippocampus to improve the performance of diagnostic imaging in patients with hippocampal sclerosis


Assuntos
Humanos , Masculino , Feminino , Adulto Jovem , Adulto , Pessoa de Meia-Idade , Hipocampo/ultraestrutura , Esclerose/diagnóstico por imagem , Epilepsia/diagnóstico por imagem , Estudos de Casos e Controles , Fibras Musgosas Hipocampais/ultraestrutura , Giro Para-Hipocampal/ultraestrutura , Imagem por Ressonância Magnética/métodos , Estudos Retrospectivos
16.
Int J Immunopathol Pharmacol ; 32: 2058738418780066, 2018 Jan-Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29873261

RESUMO

Reduced glucose utilization and deficient energy metabolism that occur in the early stages of Alzheimer's disease correlate with impaired cognition, and this information is evidence that Alzheimer's disease is a metabolic disease that is associated with brain insulin/insulin-like growth factor resistance. This research aimed to investigate the effects of Banxia Xiexin decoction (BXD) on cognitive deficits in APPswe/PS1dE9 double transgenic mice and verify the hypothesis that BXD treatment improves cognitive function via improving insulin signalling, glucose metabolism and synaptic plasticity in the hippocampus of APPswe/PS1dE9 double transgenic mice. We used 3-month-old APPswe/PS1dE9 double transgenic mice as the case groups and wild-type littermates of the double transgenic mice from the same colony as the control group. Forty-five APPswe/PS1dE9 double transgenic mice were randomly divided into the model group, donepezil group and BXD group. The mice in the control and model groups were administered 0.5% carboxymethyl cellulose orally. The Morris water maze and step-down test were conducted to evaluate the cognitive performance of APPswe/PS1dE9 double transgenic mice after BXD treatment. Ultrastructure of synapses was observed in the hippocampal CA1 area. Proteins involved in insulin signalling pathways and glucose transports in the hippocampus were assessed through immunohistochemical staining and western blot. After 3 months intervention, we found that BXD treatment improved cognitive performance and the synaptic quantity and ultrastructure, restored insulin signalling and increased the expression of glucose transporter 1 (GLUT1) and GLUT3 levels. These findings suggest that the beneficial effect of BXD on cognition may be due to the improvement of insulin signalling, glucose metabolism and synaptic plasticity.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Cognição/efeitos dos fármacos , Proteínas Facilitadoras de Transporte de Glucose/metabolismo , Hipocampo/efeitos dos fármacos , Insulina/metabolismo , Extratos Vegetais/uso terapêutico , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Precursor de Proteína beta-Amiloide/genética , Animais , Comportamento Animal/efeitos dos fármacos , Modelos Animais de Doenças , Hipocampo/metabolismo , Hipocampo/ultraestrutura , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos Transgênicos , Presenilina-1/genética , Sinapses/efeitos dos fármacos , Sinapses/ultraestrutura
17.
Food Chem Toxicol ; 115: 499-510, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29614384

RESUMO

Proteomic studies were carried out in immature (3 week), adult (18 week) and aged (48 week) rats to understand the age dependent vulnerability to lindane induced neurodegeneration. 2-D and western blot analysis of protein extracts of hippocampus and substantia-nigra isolated from lindane treated rats (2.5 mg/kg; p.o. X 21 days) revealed marked dysregulation in the expression of proteins related to ubiquitin proteasome pathway, antioxidant activity, chaperones, energy metabolism, calcium homeostasis and proteins involved in neurodegeneration. These alterations were associated with marked increase in reactive oxygen species formation, lipid peroxidation, reduced glutathione content and antioxidant enzyme activities in lindane treated rats. Aged rats, in particular showed higher magnitude of alteration in these proteins when compared to immature or adult rats. Proteins involved in apoptosis and autophagy also showed marked alterations in their expression, particularly in the aged rats. Ultrastructural analysis revealed greater number of autophagic vesicle in hippocampus and substantia-nigra in treated aged rats. The data suggest that proteomic approaches could be used to investigate the vulnerability to lindane induced neurodegeneration in rats.


Assuntos
Hexaclorocicloexano/toxicidade , Hipocampo/efeitos dos fármacos , Inseticidas/toxicidade , Proteômica , Substância Negra/efeitos dos fármacos , Fatores Etários , Animais , Antioxidantes/metabolismo , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Western Blotting , Eletroforese em Gel Bidimensional , Glutationa/metabolismo , Hipocampo/metabolismo , Hipocampo/ultraestrutura , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Microscopia Eletrônica de Transmissão , Chaperonas Moleculares/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo , Substância Negra/metabolismo , Substância Negra/ultraestrutura
18.
Bull Exp Biol Med ; 164(5): 680-684, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29577192

RESUMO

Functional interactions of sympathetic fibers innervating the iris with the neurons of central origin in intraocular transplants of the rat hippocampus were studied by optic, confocal, and electron microscopy. After formaldehyde fixation, fluorescent dye Dil was applied to the upper cervical ganglion; the dye migrated to the transplant by lateral diffusion via axons. Sympathetic nerves labeled with fluorescent dye grew into the neurotransplants along perivascular membranes of blood vessels. In addition, some fluorescent axons were identified in the transplant parenchyma. Electron microscopy showed large bundles of the peripheral type axons in the vascular adventitia and Schwann-axonal complexes in the transplant neuropil. Autonomic axons formed synaptic contacts with transplanted neurons.


Assuntos
Sistema Nervoso Autônomo/metabolismo , Neurônios/metabolismo , Sistema Nervoso Simpático/citologia , Animais , Sistema Nervoso Autônomo/citologia , Sistema Nervoso Autônomo/ultraestrutura , Encéfalo/citologia , Encéfalo/metabolismo , Encéfalo/ultraestrutura , Hipocampo/citologia , Hipocampo/metabolismo , Hipocampo/ultraestrutura , Microscopia Eletrônica , Regeneração Nervosa/fisiologia , Plasticidade Neuronal/fisiologia , Neurônios/citologia , Neurônios/ultraestrutura , Ratos , Ratos Wistar , Sistema Nervoso Simpático/ultraestrutura
19.
Glia ; 66(7): 1417-1431, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29480581

RESUMO

Astroglial type-1 cannabinoid (CB1 ) receptors are involved in synaptic transmission, plasticity and behavior by interfering with the so-called tripartite synapse formed by pre- and post-synaptic neuronal elements and surrounding astrocyte processes. However, little is known concerning the subcellular distribution of astroglial CB1 receptors. In particular, brain CB1 receptors are mostly localized at cells' plasmalemma, but recent evidence indicates their functional presence in mitochondrial membranes. Whether CB1 receptors are present in astroglial mitochondria has remained unknown. To investigate this issue, we included conditional knock-out mice lacking astroglial CB1 receptor expression specifically in glial fibrillary acidic protein (GFAP)-containing astrocytes (GFAP-CB1 -KO mice) and also generated genetic rescue mice to re-express CB1 receptors exclusively in astrocytes (GFAP-CB1 -RS). To better identify astroglial structures by immunoelectron microscopy, global CB1 knock-out (CB1 -KO) mice and wild-type (CB1 -WT) littermates were intra-hippocampally injected with an adeno-associated virus expressing humanized renilla green fluorescent protein (hrGFP) under the control of human GFAP promoter to generate GFAPhrGFP-CB1 -KO and -WT mice, respectively. Furthermore, double immunogold (for CB1 ) and immunoperoxidase (for GFAP or hrGFP) revealed that CB1 receptors are present in astroglial mitochondria from different hippocampal regions of CB1 -WT, GFAP-CB1 -RS and GFAPhrGFP-CB1 -WT mice. Only non-specific gold particles were detected in mouse hippocampi lacking CB1 receptors. Altogether, we demonstrated the existence of a precise molecular architecture of the CB1 receptor in astrocytes that will have to be taken into account in evaluating the functional activity of cannabinergic signaling at the tripartite synapse.


Assuntos
Astrócitos/metabolismo , Astrócitos/ultraestrutura , Hipocampo/metabolismo , Hipocampo/ultraestrutura , Receptor CB1 de Canabinoide/metabolismo , Animais , Proteína Glial Fibrilar Ácida/genética , Proteína Glial Fibrilar Ácida/metabolismo , Técnicas Imunoenzimáticas , Camundongos Knockout , Microscopia Imunoeletrônica , Mitocôndrias/metabolismo , Mitocôndrias/ultraestrutura , Receptor CB1 de Canabinoide/genética
20.
Neuropharmacology ; 133: 307-318, 2018 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-29412144

RESUMO

Exposure to early-life adversity may program brain function to prepare individuals for adaptation to matching environmental contexts. In this study we tested this hypothesis in more detail by examining the effects of early-life stress - induced by raising offspring with limited nesting and bedding material from postnatal days 2-9 - in various behavioral tasks and on synaptic function in adult mice. Early-life stress impaired adult performance in the hippocampal dependent low-arousing object-in-context recognition memory task. This effect was absent when animals were exposed to a single stressor before training. Early-life stress did not alter high-arousing context and auditory fear conditioning. Early-life stress-induced behavioral modifications were not associated with alterations in the dendritic architecture of hippocampal CA1 pyramidal neurons or principal neurons of the basolateral amygdala. However, early-life stress reduced the ratio of NMDA to AMPA receptor-mediated excitatory postsynaptic currents and glutamate release probability specifically in hippocampal CA1 neurons, but not in the basolateral amygdala. These ex vivo effects in the hippocampus were abolished by acute glucocorticoid treatment. Our findings support that early-life stress can hamper object-in-context learning via pre- and postsynaptic mechanisms that affect hippocampal function but these effects are counteracted by acute stress or elevated glucocorticoid levels.


Assuntos
Potenciais Pós-Sinápticos Excitadores/fisiologia , Glucocorticoides/farmacologia , Hipocampo/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Estresse Psicológico/patologia , Fatores Etários , Análise de Variância , Animais , Animais Recém-Nascidos , Peso Corporal/efeitos dos fármacos , Condicionamento (Psicologia)/efeitos dos fármacos , Condicionamento (Psicologia)/fisiologia , Corticosterona/sangue , Modelos Animais de Doenças , Fármacos atuantes sobre Aminoácidos Excitatórios/farmacologia , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Medo , Feminino , Ácido Glutâmico/farmacologia , Hipocampo/fisiologia , Hipocampo/ultraestrutura , Técnicas In Vitro , Masculino , Transtornos da Memória/etiologia , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/fisiologia , Neurônios/ultraestrutura , Técnicas de Patch-Clamp , Recognição (Psicologia)/efeitos dos fármacos , Coloração pela Prata , Estresse Psicológico/complicações
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