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1.
Toxicol Lett ; 319: 138-147, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31730887

RESUMO

Alzheimer's disease (AD) is a neurodegenerative disease that can be induced by heavy metals such as lead. However, there is limited information on the role of blood-brain barrier (BBB) in lead induced AD-like pathology. This study investigates the potential mechanism of lead exposure aggravating the progression of Alzheimer's disease in mice through the BBB. 200 mg/L and 500 mg/L lead acetate were given to C57BL/6J and APP/PS1 mice through drinking water from a week before mating, until the offspring were 7-months-old. 8 female juvenile mice in each group were selected for this investigation. Lead exposure increased blood lead concentration which revealed the internal exposure level, accelerated Aß1-42 deposition in APP/PS1 mouse cortexes and abnormal change in Zonula Occludin-1 (ZO-1) and Claudin-5 protein. It also increased the expression of p-tau in both the C57BL/6J and APP/PS1 mice, and decreased mRNA and protein expression in low-density lipoprotein receptor (LRP-1). Additionally, it increased the mRNA and protein expression of amyloid beta precursor protein (APP) and beta secretase 1 (BACE-1). The activated astrocytes increased in the brains of APP/PS1 mice, and coalesced around the Aß1-42 deposition after lead exposure. The main vessels in deutocerebrum were attached with Aß1-42 deposition. These results offer insight into the mechanism of preventing lead induced AD through cerebrovascular pathways.


Assuntos
Doença de Alzheimer/patologia , Barreira Hematoencefálica/patologia , Exposição Ambiental/efeitos adversos , Chumbo/toxicidade , Doença de Alzheimer/induzido quimicamente , Precursor de Proteína beta-Amiloide/biossíntese , Precursor de Proteína beta-Amiloide/genética , Animais , Barreira Hematoencefálica/efeitos dos fármacos , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Córtex Cerebral/patologia , Claudina-5/efeitos dos fármacos , Claudina-5/genética , Progressão da Doença , Feminino , Chumbo/sangue , Camundongos , Camundongos Endogâmicos C57BL , Compostos Organometálicos/toxicidade , Proteína da Zônula de Oclusão-1/efeitos dos fármacos , Proteína da Zônula de Oclusão-1/genética
2.
Chemosphere ; 238: 124602, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31545211

RESUMO

Polybrominated diphenyl ethers (PBDEs) have been known to exhibit neurotoxicity in rats; however, the underlying mechanism remains unknown and there is no available intervention. In this study, we aimed to investigate the role of oxidative and nitrosative stress in the neurotoxicity in the cerebral cortex and primary neurons in rats following the BDE-153 treatment. Compared to the untreated group, BDE-153 treatment significantly induced the neurotoxic effects in rats, as manifested by the increased lactate dehydrogenase (LDH) activities and cell apoptosis rates, and the decreased neurotrophic factor contents and cholinergic enzyme activities in rats' cerebral cortices and primary neurons. When compared to the untreated group, the oxidative and nitrosative stress had occurred in the cerebral cortex or primary neurons in rats following the BDE-153 treatment, as manifested by the increments in levels of reactive oxygenspecies (ROS), malondialdehyde (MDA), nitric oxide (NO), and neuronal nitric oxide synthase (nNOS) mRNA and protein expressions, along with the decline in levels of superoxide dismutase (SOD) activity, glutathione (GSH) content, and peroxiredoxin I (Prx I) and Prx II mRNA and protein expressions. In addition, the ROS scavenger N-acetyl-l-cysteine (NAC) or NO scavenger NG-Nitro-l-arginine (L-NNA) significantly rescued the LDH leakage and cell survival, reversed the neurotrophin contents and cholinergic enzymes, mainly via regaining balance between oxidation/nitrosation and antioxidation. Overall, our findings suggested that oxidative and nitrosative stresses are involved in the neurotoxicity induced by BDE-153, and that the antioxidation is a potential targeted intervention.


Assuntos
Córtex Cerebral/patologia , Éteres Difenil Halogenados/toxicidade , Síndromes Neurotóxicas/patologia , Estresse Nitrosativo/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Bifenil Polibromatos/toxicidade , Acetilcisteína/farmacologia , Animais , Antioxidantes/metabolismo , Apoptose/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Córtex Cerebral/efeitos dos fármacos , Glutationa/metabolismo , Éteres Difenil Halogenados/metabolismo , Masculino , Malondialdeído/metabolismo , Fatores de Crescimento Neural/metabolismo , Neurônios/efeitos dos fármacos , Neurotrofina 3/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo I/metabolismo , Estresse Nitrosativo/fisiologia , Estresse Oxidativo/fisiologia , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos
3.
Zhonghua Bing Li Xue Za Zhi ; 48(11): 856-860, 2019 Nov 08.
Artigo em Chinês | MEDLINE | ID: mdl-31775434

RESUMO

Objective: To investigate the expression of LC3B, p-AMPKα and p27 in cortical tuberous sclerosis complex (TSC). Methods: Nineteen specimens of surgically resected TSC cortical tubers were collected at Xuanwu Hospital, Capital Medical University, from 2014 to 2017. The expression of the three proteins in the lesions and the adjacent relatively normal regions was detected by immunohistochemical staining (EnVision two-step method). Results: LC3B was mainly expressed in the dysmorphic neuron and giant cell in TSC cortical tubers and in the adjacent relatively normal neurons, and the expression was diffuse or perinuclear cytoplasmic. There was no significant difference in the average optical density between abnormal cells and neurons adjacent to the lesions (0.343±0.195 vs. 0.419±0.088, P>0.05). p-AMPKα was localized in the cytoplasm of dysmorphic neurons and giant cell in TSC cortical tubers. The average optical density of abnormal cells in the lesions was significantly higher than that of neurons adjacent to the lesions (0.306±0.123 vs. 0.233±0.654, P<0.05). P27 showed nuclear positivity, mainly expressed in the neurons and glial cells close to TSC cortical tubers, while the positive rate in the abnormal cells in TSC cortical tubers was low (15/19 vs. 7/19, P<0.05). Conclusion: There is no significant decrease in the level of autophagy in dysmorphic neurons and giant cells in TSC cortical tubers, which may be related to the compensatory mechanism of AMPK signaling pathway, but without activation of downstream p27.


Assuntos
Proteínas Relacionadas à Autofagia/metabolismo , Inibidor de Quinase Dependente de Ciclina p27/metabolismo , Proteínas Associadas aos Microtúbulos/metabolismo , Proteínas Quinases/metabolismo , Esclerose Tuberosa/metabolismo , Córtex Cerebral/patologia , Humanos , Neuroglia/metabolismo , Neurônios/metabolismo
4.
Anticancer Res ; 39(9): 4905-4909, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31519594

RESUMO

BACKGROUND/AIM: The differentiation between cerebral metastases (CM) and high-grade gliomas (HGG) can be difficult on magnetic resonance imaging (MRI). The aim of this study was to evaluate the usefulness of searching two MRI signs (signal alteration in the adjacent cortex, SAAC, and peripheral rim sign, PRS), in order to distinguish between these entities. PATIENTS AND METHODS: A total of 61 patients were retrospectively enrolled (28 HGG, 33 CM). Fluid Attenuated Inversion Recovery (FLAIR) sequences were used to assess SAAC and contrast-enhanced T1-weighted sequences for PRS. RESULTS: A positive SAAC sign was present in 61% of HGG, and 12% of CM. Conversely, in SAAC-negative lesions, PRS was observed in 78% of CM and in 32% of HGG. Their association had a higher frequency in HGG than in the CM group (21 vs. 3%). CONCLUSION: While SAAC is specific for HGG and PRS, in the absence of SAAC, is relatively specific for CMs, their combined presence is highly suggestive of HGG.


Assuntos
Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/secundário , Córtex Cerebral/patologia , Glioma/diagnóstico , Imagem por Ressonância Magnética , Adulto , Idoso , Idoso de 80 Anos ou mais , Diagnóstico Diferencial , Feminino , Humanos , Imagem por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Curva ROC , Intensificação de Imagem Radiográfica , Reprodutibilidade dos Testes
6.
Postgrad Med ; 131(7): 509-522, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31422718

RESUMO

Objectives: Visual hallucinations (VH) are common in Lewy body disease (LBD), and have been associated with cognitive and structural brain alterations. Evidence so far concerns mainly Parkinson's disease (PD), but little is known about symptom-specific pathophysiological mechanisms across the LBD spectrum, especially related to the presence of dementia. The aim of the present pilot study was to investigate the neuroanatomical, and neuropsychological characteristics related to VH in two forms of LBD, namely dementia with Lewy bodies (DLB) and PD without dementia. Methods: Whole brain voxel-based morphometry (VBM) analyses on 3D MRI acquired structural brain scans, and neuropsychological testing were performed on 28 clinically diagnosed DLB (11 with VH, 17 NVH), and 24 PD (9 with VH, and 15 NVH) patients. In order to assess differences in gray matter (GM) regional volumes, and cognitive performance, hallucinating patients for each group were compared with corresponding non-hallucinating ones. Results: DLB patients with VH presented significantly worse visual attention deficits compared to those without, which persisted even when controlling for visual perception. Whole brain VBM analysis revealed decreased GM volume in DLB with VH in the right superior and medial frontal gyri, putamen, caudate nucleus and insula. Subcortical regional volumes were also significantly associated with visual attention performance. Hallucinating PD patients, instead, presented more severe executive dysfunction, but VBM showed no volumetric differences between the two PD subgroups. Post hoc region of interest analyses revealed striatal GM loss in PD with VH. Conclusion: Frontal and striatal GM atrophy may contribute to the emergence of VH in DLB, which may be fostered by the more severe attention deficits. Striatal GM loss and executive dysfunction, instead, appeared to underlie VH in PD without dementia.


Assuntos
Núcleo Caudado/diagnóstico por imagem , Lobo Frontal/diagnóstico por imagem , Substância Cinzenta/diagnóstico por imagem , Alucinações/diagnóstico por imagem , Doença por Corpos de Lewy/diagnóstico por imagem , Doença de Parkinson/diagnóstico por imagem , Putamen/diagnóstico por imagem , Idoso , Idoso de 80 Anos ou mais , Atenção , Estudos de Casos e Controles , Núcleo Caudado/patologia , Córtex Cerebral/diagnóstico por imagem , Córtex Cerebral/patologia , Feminino , Lobo Frontal/patologia , Substância Cinzenta/patologia , Alucinações/psicologia , Humanos , Doença por Corpos de Lewy/psicologia , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Tamanho do Órgão , Doença de Parkinson/psicologia , Putamen/patologia , Percepção Visual
7.
Nat Commun ; 10(1): 3827, 2019 08 23.
Artigo em Inglês | MEDLINE | ID: mdl-31444357

RESUMO

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease of unknown etiology. Although defects in nucleocytoplasmic transport (NCT) may be central to the pathogenesis of ALS and other neurodegenerative diseases, the molecular mechanisms modulating the nuclear pore function are still largely unknown. Here we show that genetic and pharmacological modulation of actin polymerization disrupts nuclear pore integrity, nuclear import, and downstream pathways such as mRNA post-transcriptional regulation. Importantly, we demonstrate that modulation of actin homeostasis can rescue nuclear pore instability and dysfunction caused by mutant PFN1 as well as by C9ORF72 repeat expansion, the most common mutation in ALS patients. Collectively, our data link NCT defects to ALS-associated cellular pathology and propose the regulation of actin homeostasis as a novel therapeutic strategy for ALS and other neurodegenerative diseases.


Assuntos
Actinas/metabolismo , Esclerose Amiotrófica Lateral/patologia , Neurônios Motores/patologia , Poro Nuclear/patologia , Profilinas/metabolismo , Acrilamidas/farmacologia , Actinas/ultraestrutura , Transporte Ativo do Núcleo Celular/efeitos dos fármacos , Transporte Ativo do Núcleo Celular/genética , Esclerose Amiotrófica Lateral/genética , Biópsia , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Proteína C9orf72/genética , Proteína C9orf72/metabolismo , Linhagem Celular , Córtex Cerebral/citologia , Córtex Cerebral/patologia , Embrião de Mamíferos , Fibroblastos , Humanos , Microscopia Eletrônica de Transmissão , Neurônios Motores/citologia , Mutação , Poro Nuclear/efeitos dos fármacos , Poro Nuclear/ultraestrutura , Cultura Primária de Células , Profilinas/genética , Multimerização Proteica/efeitos dos fármacos , Multimerização Proteica/genética , Pele/citologia , Pele/patologia , Tiazóis/farmacologia , Tiazolidinas/farmacologia
8.
J Clin Neurosci ; 68: 123-127, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31326285

RESUMO

The aim of this study is to evaluate the abnormal cortical structures associated with newly diagnosed benign epilepsy with centrotemporal spikes (BECTS) patients and assessed the effects of comorbid attention-deficit/hyperactivity (ADHD) on these abnormalities. Newly diagnosed BECTS patients (n = 33, 23 males) and age-matched healthy controls (n = 48) were evaluated by surface and volumetric MRI. CAT12 toolbox (HYPERLINK "http://www.neuro.uni-jena.de/cat/"\t"_blank" http://www.neuro.uni-jena.de/cat/, version r1109), SPM12(HYPERLINK"http://www.fil.ion.ucl.ac.uk/spm/software/spm12/"\t"_blank"http://www.fil.ion.ucl.ac.uk/spm/software/spm12/, version 6225) and MATLAB (9.5, Mathworks, Natick, MA) were used to gather CT estimates. An additional comparison was performed between BECTS children with (n = 13) and without ADHD (n = 20). BECTS patients had significantly smaller volume in left postcentral gyrus when compared to healthy controls. BECTS patients with ADHD had significantly thinner superior-inferior frontal cortex, superior temporal cortex, left pericalcarine, lingual and fusiform cortex to healthy controls. Also BECTS without ADHD patients had thinner cortical areas when compared to healthy controls, however the significance was more relevant in the BECTS with ADHD. The left fusiform cortex of BECTS patients with ADHD patients was significantly thinner than BECTS patients without ADHD. Our results showed that BECTS affects frontal, temporal, parietal and occipital lobes by cortical thinning. Our study supports the need for better characterization of patients with BECTS so identification of different phenotypes can occur. Further studies are needed to investigate the relationship between BECTS and ADHD.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/patologia , Córtex Cerebral/patologia , Epilepsia Rolândica/patologia , Adolescente , Transtorno do Deficit de Atenção com Hiperatividade/complicações , Transtorno do Deficit de Atenção com Hiperatividade/epidemiologia , Criança , Pré-Escolar , Comorbidade , Epilepsia Rolândica/complicações , Epilepsia Rolândica/epidemiologia , Feminino , Humanos , Imagem por Ressonância Magnética/métodos , Masculino
9.
Nutrients ; 11(8)2019 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-31344808

RESUMO

Obesity is considered a risk factor for neurodegeneration. Because fermentation of soybean increases contents of various bioactive compounds with anti-obesity and anti-diabetic activities, we investigated the protective effect of doenjang, a Korean traditional fermented soybean paste, against neuroinflammation and neurodegeneration in the cortex and hippocampus of mice fed a high-fat (HF) diet. C57BL/6J mice were fed a low-fat diet, an HF diet, an HF-containing steamed soybean diet, or an HF-containing doenjang (DJ) diet for 11 weeks. Doenjang consumption alleviated hippocampal neuronal loss, which was increased by the HF diet. Accordingly, we observed higher cell proliferation and neurotrophic factor mRNA levels in the DJ group. Contents of oxidative metabolites and mRNA levels of oxidative stress- and neuroinflammation-related genes were lower in the DJ group compared to the HF group. Dietary doenjang reduced ß-amyloid peptide (Aß) levels by regulating gene expressions involved in Aß production and degradation. Furthermore, doenjang consumption reduced tau hyperphosphorylation induced by HF feeding. Overall, doenjang was more effective than steamed soybean in suppressing neuroinflammation and neurodegeneration in mice fed an HF diet. These results suggest that bioactive compounds produced during the fermentation and aging of soybean may be involved in the enhanced neuroprotective effects of doenjang.


Assuntos
Córtex Cerebral/patologia , Dieta Hiperlipídica , Hipocampo/patologia , Inflamação/prevenção & controle , Degeneração Neural , Doenças Neurodegenerativas/prevenção & controle , Alimentos de Soja , Peptídeos beta-Amiloides/metabolismo , Ração Animal , Animais , Córtex Cerebral/metabolismo , Modelos Animais de Doenças , Hipocampo/metabolismo , Inflamação/etiologia , Inflamação/metabolismo , Inflamação/patologia , Peroxidação de Lipídeos , Masculino , Camundongos Endogâmicos C57BL , Doenças Neurodegenerativas/etiologia , Doenças Neurodegenerativas/metabolismo , Doenças Neurodegenerativas/patologia , Estresse Oxidativo , Fosforilação , Carbonilação Proteica , Proteínas tau/metabolismo
10.
Arkh Patol ; 81(3): 19-26, 2019.
Artigo em Russo | MEDLINE | ID: mdl-31317927

RESUMO

OBJECTIVE: To determine the structural changes in the cerebral cortex tissues, which are characteristic of the severe course of chronic obstructive pulmonary disease (COPD) and ischemic cerebral stroke (ICS). MATERIAL AND METHODS: The autopsy material of the microcirculatory bed of the cerebral cortex from 18 people aged 48-64 years who had died from COPD, ICS, and a concurrence of these conditions underwent histological examination and morphometric analysis. RESULTS: The state of the brain from the persons who died from ICS was characterized by a decline in the total number of neurons and glial elements, by structural and regional blood flow changes with obvious venous hyperemia, stasis, and red blood cell aggregation in the vessels. There was pericellular and perivascular edema in the perifocal area of the brain from people who died from COPD, as well as morphological signs of cerebral hemodynamic disorders. The brain structural features in ICS concurrent with COPD included a double decrease in the numerical density of capillaries, their hyperemia, perivascular edema, and venous plethora, a substantial change in the diameter of non-muscular venules, parenchymal atrophy, and stromal sclerosis, indicating the presence of a chronic process. CONCLUSION: Patients with ICS in the presence of COPD versus those who died from the isolated variants of these conditions were recorded to have an obvious decrease in the numerical density of capillaries, their hyperemia, and a pronounced change in the structure of the cerebral vein wall, which is a consequence of multisystem processes associated with COPD.


Assuntos
Isquemia Encefálica , Córtex Cerebral , Doença Pulmonar Obstrutiva Crônica , Acidente Vascular Cerebral , Administração por Inalação , Corticosteroides , Idoso , Isquemia Encefálica/complicações , Córtex Cerebral/patologia , Humanos , Microcirculação , Pessoa de Meia-Idade , Doença Pulmonar Obstrutiva Crônica/complicações , Acidente Vascular Cerebral/complicações
11.
J Clin Neurosci ; 67: 276-277, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31266715

RESUMO

High altitude exposure could be related to neurological events such as stroke-like episodes, even if the exact pathogenic mechanism is still debated. We describe the case of a caucasian woman who had a bilateral insular ischemic stroke after a rapid ascent above 4000 m in which a secondary embolic dissemination due to a right insular stroke, maybe related to high altitude hemoconcentration, could be hypothesized. In our opinion a prolonged cardiac rhythm monitoring have to be considered especially when no other embolic sources are found and for lesions involving the insular cortex.


Assuntos
Doença da Altitude/complicações , Isquemia Encefálica/diagnóstico , Montanhismo , Acidente Vascular Cerebral/diagnóstico , Isquemia Encefálica/etiologia , Córtex Cerebral/diagnóstico por imagem , Córtex Cerebral/patologia , Feminino , Humanos , Pessoa de Meia-Idade , Acidente Vascular Cerebral/etiologia
13.
Int J Mol Sci ; 20(14)2019 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-31340538

RESUMO

WW domain-containing oxidoreductase (Wwox) is a putative tumor suppressor. Several germline mutations of Wwox have been associated with infant neurological disorders characterized by epilepsy, growth retardation, and early death. Less is known, however, about the pathological link between Wwox mutations and these disorders or the physiological role of Wwox in brain development. In this study, we examined age-related expression and histological localization of Wwox in forebrains as well as the effects of loss of function mutations in the Wwox gene in the immature cortex of a rat model of lethal dwarfism with epilepsy (lde/lde). Immunostaining revealed that Wwox is expressed in neurons, astrocytes, and oligodendrocytes. lde/lde cortices were characterized by a reduction in neurite growth without a reduced number of neurons, severe reduction in myelination with a reduced number of mature oligodendrocytes, and a reduction in cell populations of astrocytes and microglia. These results indicate that Wwox is essential for normal development of neurons and glial cells in the cerebral cortex.


Assuntos
Sistemas de Transporte de Aminoácidos Acídicos/deficiência , Antiporters/deficiência , Córtex Cerebral/metabolismo , Nanismo/genética , Epilepsia/genética , Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/genética , Doenças Mitocondriais/genética , Neurogênese/genética , Transtornos Psicomotores/genética , Proteínas Supressoras de Tumor/genética , Oxidorredutase com Domínios WW/genética , 2',3'-Nucleotídeo Cíclico 3'-Fosfodiesterase/genética , 2',3'-Nucleotídeo Cíclico 3'-Fosfodiesterase/metabolismo , Proteína da Polipose Adenomatosa do Colo/genética , Proteína da Polipose Adenomatosa do Colo/metabolismo , Sistemas de Transporte de Aminoácidos Acídicos/genética , Sistemas de Transporte de Aminoácidos Acídicos/metabolismo , Animais , Antiporters/genética , Antiporters/metabolismo , Astrócitos/metabolismo , Astrócitos/patologia , Contagem de Células , Córtex Cerebral/crescimento & desenvolvimento , Córtex Cerebral/patologia , Modelos Animais de Doenças , Nanismo/metabolismo , Nanismo/patologia , Epilepsia/metabolismo , Epilepsia/patologia , Regulação da Expressão Gênica no Desenvolvimento , Mutação em Linhagem Germinativa , Proteína Glial Fibrilar Ácida/genética , Proteína Glial Fibrilar Ácida/metabolismo , Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/metabolismo , Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/patologia , Masculino , Doenças Mitocondriais/metabolismo , Doenças Mitocondriais/patologia , Proteína Básica da Mielina/genética , Proteína Básica da Mielina/metabolismo , Neurônios/metabolismo , Neurônios/patologia , Oligodendroglia/metabolismo , Oligodendroglia/patologia , Prosencéfalo/crescimento & desenvolvimento , Prosencéfalo/metabolismo , Prosencéfalo/patologia , Transtornos Psicomotores/metabolismo , Transtornos Psicomotores/patologia , Ratos , Ratos Transgênicos , Transdução de Sinais , Proteínas Supressoras de Tumor/deficiência , Oxidorredutase com Domínios WW/deficiência
14.
Chem Biol Interact ; 308: 279-287, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31150628

RESUMO

The dose-dependent neuroprotective role of licorice-derived glycyrrhizin during subacute neuroterminal norepinephrine (NE) depletion was studied in rat brain. Experimental design included thirty 5-week-old male rats randomly divided into five groups. Compared to the saline-injected control group, the group receiving daily intraperitoneal injection of fusaric acid (FA; 5 mg/kg/b.w.) for 30 days showed pharmacological depletion of NE. The neuroprotective effects of three successively increasing oral doses of glycyrrhizin were examined in FA-treated rats. Neurochemical parameters and histo-/immunohistopathological changes in the hippocampus were examined. FA generated global hippocampal stress with altered neurobiochemical parameters, accompanied by immune-confirmed inflammatory tissue damage, and noticeable behavioral changes. Although glycyrrhizin after FA-induced intoxication did not correct the recorded drop in the NE level, it decreased the dopamine levels to control levels. Similarly, glycyrrhizin at a high dose restored the serotonin level to its normal value and blocked the FA-induced increase in the level of its metabolite, 5-hydroxyindoleacetic acid. The FA-induced rise in γ-aminobutyric acid (GABA) and histamine was alleviated after administration of a high dose of glycyrrhizin. This was accompanied by improvements in the bioenergetic status and neuronal regenerative capacity through recovery of ATP and brain-derived neurotrophic factor levels to the pre-intoxicated values. High doses of glycyrrhizin also ameliorated the FA-generated behavioral changes and oxidative damage, manifested by the reduction in the expression of cortical pro-apoptotic caspase 3 in the same group. This study suggests that glycyrrhizin can potentially mend most of the previously evoked neuronal damage induced by FA intoxication in the brain of an experimental rat model.


Assuntos
Córtex Cerebral/efeitos dos fármacos , Ácido Glicirrízico/farmacologia , Hipocampo/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Norepinefrina/metabolismo , Acetilcolinesterase/metabolismo , Animais , Comportamento Animal/efeitos dos fármacos , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Córtex Cerebral/metabolismo , Córtex Cerebral/patologia , Dopamina/metabolismo , Relação Dose-Resposta a Droga , Ácido Fusárico/toxicidade , Hipocampo/metabolismo , Hipocampo/patologia , Masculino , Síndromes Neurotóxicas/tratamento farmacológico , Síndromes Neurotóxicas/patologia , Síndromes Neurotóxicas/veterinária , Ratos , Ratos Sprague-Dawley , Serotonina/metabolismo , Regulação para Cima/efeitos dos fármacos , Ácido gama-Aminobutírico/metabolismo
15.
Muscle Nerve ; 60(4): 443-452, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31241177

RESUMO

INTRODUCTION: There is an unmet need for mechanism-based biomarkers and effective disease modifying treatments in amyotrophic lateral sclerosis (ALS). Previous findings have provided evidence that histone deacetylases (HDAC) are altered in ALS, providing a rationale for testing HDAC inhibitors as a therapeutic option. METHODS: We measured class I and II HDAC protein and transcript levels together with acetylation levels of downstream substrates by using Western blotting in postmortem tissue of ALS and controls. [11 C]Martinostat, a novel HDAC positron emission tomography ligand, was also used to assess in vivo brain HDAC alterations in patients with ALS and healthy controls (HC). RESULTS: There was no significant difference in HDAC levels between patients with ALS and controls as measured by Western blotting and reverse-transcription quantitative polymerase chain reaction. Similarly, no differences were detected in [11 C]Martinostat-positron emission tomography uptake in ALS participants compared with HCs. DISCUSSION: These findings provide evidence that alterations in HDAC isoforms are not a dominant pathological feature at the bulk tissue level in ALS.


Assuntos
Esclerose Amiotrófica Lateral/genética , Histona Desacetilases/genética , Córtex Motor/metabolismo , Medula Espinal/metabolismo , Adamantano/análogos & derivados , Adulto , Idoso , Idoso de 80 Anos ou mais , Esclerose Amiotrófica Lateral/diagnóstico por imagem , Esclerose Amiotrófica Lateral/metabolismo , Esclerose Amiotrófica Lateral/patologia , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Radioisótopos de Carbono , Estudos de Casos e Controles , Córtex Cerebral/diagnóstico por imagem , Córtex Cerebral/metabolismo , Córtex Cerebral/patologia , Estudos Transversais , Feminino , Histona Desacetilases/metabolismo , Histonas/metabolismo , Humanos , Ácidos Hidroxâmicos , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Imagem Molecular , Córtex Motor/diagnóstico por imagem , Córtex Motor/patologia , Imagem Multimodal , Tomografia por Emissão de Pósitrons , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Medula Espinal/diagnóstico por imagem , Medula Espinal/patologia
16.
Int J Mol Sci ; 20(13)2019 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-31248061

RESUMO

Chronic pain is a condition in which pain progresses from an acute to chronic state and persists beyond the healing process. Chronic pain impairs function and decreases patients' quality of life. In recent years, efforts have been made to deepen our understanding of chronic pain and to develop better treatments to alleviate chronic pain. In this review, we summarize the results of previous studies, focusing on the mechanisms underlying chronic pain development and the identification of neural areas related to chronic pain. We review the association between chronic pain and negative affective states. Further, we describe the structural and functional changes in brain structures that accompany the chronification of pain and discuss various neurotransmitter families involved. Our review aims to provide guidance for the development of future therapeutic approaches that could be used in the management of chronic pain.


Assuntos
Afeto , Encéfalo/patologia , Encéfalo/fisiopatologia , Dor Crônica/etiologia , Dor Crônica/fisiopatologia , Animais , Biomarcadores , Encéfalo/metabolismo , Córtex Cerebral/metabolismo , Córtex Cerebral/patologia , Córtex Cerebral/fisiopatologia , Dor Crônica/terapia , Gerenciamento Clínico , Humanos , Sistema Límbico/metabolismo , Sistema Límbico/patologia , Sistema Límbico/fisiopatologia , Vias Neurais , Transdução de Sinais
17.
Nat Neurosci ; 22(8): 1217-1222, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31235932

RESUMO

Variants in the triggering receptor expressed on myeloid cells 2 (TREM2) have been associated with increased risk for sporadic, late-onset Alzheimer's disease. Here we show that germline knockout of Trem2 or the TREM2R47H variant reduces microgliosis around amyloid-ß plaques and facilitates the seeding and spreading of neuritic plaque tau aggregates. These findings demonstrate a key role for TREM2 and microglia in limiting the development of peri-plaque tau pathologies.


Assuntos
Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Placa Amiloide/genética , Placa Amiloide/metabolismo , Receptores Imunológicos/genética , Receptores Imunológicos/metabolismo , Tauopatias/genética , Tauopatias/metabolismo , Proteínas tau/genética , Proteínas tau/metabolismo , Animais , Córtex Cerebral/patologia , Camundongos , Camundongos Knockout , Microglia/patologia
18.
PLoS One ; 14(5): e0216154, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31071118

RESUMO

Cortical thickness and gyrification abnormalities in anorexia nervosa (AN) have been recently described, but no attempt has been made to explore their organizational patterns to characterize the neurobiology of the disorder in the different stages of its course. The aim of this study was to explore cortical thickness and gyrification patterns by means of graph theory tools in 38 patients with AN, 20 fully recovered patients, and 38 healthy women (HC). All participants underwent high-resolution magnetic resonance imaging. Connectome properties were compared between: 1) AN patients and HC, 2) fully recovered patients and HC, 3) patients with a full remission at a 3-year follow-up assessment and patients who had not recovered. Small-worldness was greater in patients with acute AN in comparison to HC in both cortical thickness and gyrification networks. In the cortical thickness network, patients with AN also showed increased Local Efficiency, Modularity and Clustering coefficients, whereas integration measures were lower in the same group. Patients with a poor outcome showed higher segregation measures and lower small-worldness in the gyrification network, but no differences emerged for the cortical thickness network. For both cortical thickness and gyrification patterns, regional analyses revealed differences between patients with different outcomes. Different patterns between cortical thickness and gyrification networks are probably due to their peculiar developmental trajectories and sensitivity to environmental influences. The role of gyrification network alterations in predicting the outcome suggests a role of early maturational processes in the prognosis of AN.


Assuntos
Anorexia Nervosa/patologia , Córtex Cerebral/patologia , Adulto , Conectoma/métodos , Feminino , Humanos , Processamento de Imagem Assistida por Computador/métodos , Imagem por Ressonância Magnética/métodos , Masculino
19.
Nat Med ; 25(5): 784-791, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31061540

RESUMO

Owing to recent medical and technological advances in neonatal care, infants born extremely premature have increased survival rates1,2. After birth, these infants are at high risk of hypoxic episodes because of lung immaturity, hypotension and lack of cerebral-flow regulation, and can develop a severe condition called encephalopathy of prematurity3. Over 80% of infants born before post-conception week 25 have moderate-to-severe long-term neurodevelopmental impairments4. The susceptible cell types in the cerebral cortex and the molecular mechanisms underlying associated gray-matter defects in premature infants remain unknown. Here we used human three-dimensional brain-region-specific organoids to study the effect of oxygen deprivation on corticogenesis. We identified specific defects in intermediate progenitors, a cortical cell type associated with the expansion of the human cerebral cortex, and showed that these are related to the unfolded protein response and changes. Moreover, we verified these findings in human primary cortical tissue and demonstrated that a small-molecule modulator of the unfolded protein response pathway can prevent the reduction in intermediate progenitors following hypoxia. We anticipate that this human cellular platform will be valuable for studying the environmental and genetic factors underlying injury in the developing human brain.


Assuntos
Lesões Encefálicas/etiologia , Hipóxia Encefálica/etiologia , Modelos Neurológicos , Lesões Encefálicas/metabolismo , Lesões Encefálicas/patologia , Hipóxia Celular/genética , Hipóxia Celular/fisiologia , Córtex Cerebral/metabolismo , Córtex Cerebral/patologia , Humanos , Hipóxia Encefálica/metabolismo , Hipóxia Encefálica/patologia , Lactente Extremamente Prematuro , Recém-Nascido , Células-Tronco Neurais/metabolismo , Células-Tronco Neurais/patologia , Neurogênese/genética , Neurogênese/fisiologia , Organoides/metabolismo , Organoides/patologia , Proteínas com Domínio T/metabolismo , Resposta a Proteínas não Dobradas
20.
Brain Struct Funct ; 224(5): 1871-1884, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31049690

RESUMO

Neonatal brain lesions cause deficits in structure and function of the cerebral cortex that sometimes are not fully expressed until adolescence. To better understand the onset and persistence of changes caused by postnatal day 7 (P7) ethanol treatment, we examined neocortical cell numbers, volume, surface area and thickness from neonatal to post-adolescent ages. In control mice, total neuron number decreased from P8 to reach approximately stable levels at about P30, as expected from normal programmed cell death. Cortical thickness reached adult levels by P14, but cortical volume and surface area continued to increase from juvenile (P20-30) to post-adolescent (P54-93) ages. P7 ethanol caused a reduction of total neurons by P14, but this deficit was transient, with later ages having only small and non-significant reductions. Previous studies also reported transient neuron loss after neonatal lesions that might be partially explained by an acute acceleration of normally occurring programmed cell death. GABAergic neurons expressing parvalbumin, calretinin, or somatostatin were reduced by P14, but unlike total neurons the reductions persisted or increased in later ages. Cortical volume, surface area and thickness were also reduced by P7 ethanol. Cortical volume showed evidence of a transient reduction at P14, and then was reduced again in post-adolescent ages. The results show a developmental sequence of neonatal ethanol effects. By juvenile ages the cortex overcomes the P14 deficit of total neurons, whereas P14 GABA cell deficits persist. Cortical volume reductions were present at P14, and again in post-adolescent ages.


Assuntos
Córtex Cerebral/efeitos dos fármacos , Etanol/farmacologia , Neurogênese/efeitos dos fármacos , Efeitos Tardios da Exposição Pré-Natal/patologia , Animais , Animais Recém-Nascidos , Encéfalo/efeitos dos fármacos , Encéfalo/crescimento & desenvolvimento , Encéfalo/metabolismo , Córtex Cerebral/crescimento & desenvolvimento , Córtex Cerebral/patologia , Feminino , Neurônios GABAérgicos/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Parvalbuminas/metabolismo , Gravidez
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