Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 18.219
Filtrar
1.
Postgrad Med ; 131(7): 533-538, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31478419

RESUMO

Introduction: Depression in patients with mild cognitive impairment (MCI) and dementia of the Alzheimer's type (AD) is associated with worse prognosis. Indeed, depressed MCI patients have worse cognitive performance and greater loss of gray-matter volume in several brain areas. To date, knowledge of the factors that can mitigate this detrimental effect is still limited. The aim of the present study was to understand in what way cognitive reserve/brain reserve and depression interact and are linked to regional atrophy in early stage AD. Methods: Depression was evaluated with the Patient Health Questionnaire-9 in 90 patients with early AD, and a cutoff of ≥ 5 was used to separate depressed (n = 44) from non-depressed (n = 46) patients. Each group was further stratified into high/low cognitive reserve/brain reserve. Cognitive reserve was calculated using years of education as proxy, while normalized parenchymal volumes were used to estimate brain reserve. Voxel-based morphometry was carried out to extract and analyze gray-matter maps. 2 × 2 ANCOVAs were run to test the effect of the reserve-by-depression interaction on gray matter. Age and hippocampal ratio were used as covariates. Composite indices of major cognitive domains were also analyzed with comparable models. Results: No reserve-by-depression interaction was found in the analytical models of gray matter. Depression was associated with less gray matter volume in the cerebellum and parahippocampal gyrus. The brain reserve-by-depression interaction was a significant predictor of executive functioning. Among those with high brain reserve, depressed patients had poorer executive skills. No significant results were found in association with cognitive reserve. Conclusion: These findings suggest that brain reserve may modulate the association between neurodegeneration and depression in patients with MCI and dementia of the AD type, influencing in particular executive functioning.


Assuntos
Doença de Alzheimer/psicologia , Disfunção Cognitiva/psicologia , Reserva Cognitiva , Depressão/psicologia , Substância Cinzenta/diagnóstico por imagem , Idoso , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/fisiopatologia , Atrofia , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Cerebelo/diagnóstico por imagem , Cerebelo/patologia , Disfunção Cognitiva/diagnóstico por imagem , Disfunção Cognitiva/fisiopatologia , Depressão/diagnóstico por imagem , Depressão/fisiopatologia , Feminino , Substância Cinzenta/patologia , Hipocampo/diagnóstico por imagem , Hipocampo/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Tamanho do Órgão , Giro Para-Hipocampal/diagnóstico por imagem , Giro Para-Hipocampal/patologia , Questionário de Saúde do Paciente
2.
Postgrad Med ; 131(7): 479-485, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31513436

RESUMO

Objectives: To evaluate clinical, electrophysiological, and neuroradiological factors which correlate with the prognosis in patients with mesial temporal lobe epilepsy (MTLE). Methods: This was a single-center prospective outcome study in patients with MTLE. The patients' family history, clinical characteristics, neurophysiological data (electroencephalography - EEG), neuroimaging, antiepileptic therapy, and outcome were collected and analyzed. The population was divided into four groups depending on the frequency of the seizures when they attended their last follow up. All variables and outcome measures were compared between the four groups. Results: In total 83 consecutive patients were included within the four groups. Group 1 (seizure-free) consisted of 7 patients, (9%), Group 2 (rare seizures) consisted of 15 patients (18%), Group 3 (often seizures) consisted of 30 patients (36%), and Group 4 (very often seizures) consisted of 31 patients (37%). The groups did not differ significantly in demographic characteristics. There was a strong positive correlation between resistance to therapy and sleep activation on EEG (p = 0.005), occurrence of focal to bilateral seizures (p = 0.007), automatisms (p = 0.004), and the number of previously used antiepileptic drugs (AEDs) (p = 0.002). There was no association between febrile convulsions (FC), hippocampal sclerosis (HS), and the outcome that was found. Conclusion: MTLE is a heterogeneous syndrome. Establishing the factors responsible for, and associated with, drug resistance is important for optimal management and treatment, as early identification of drug resistance should then ensure a timely referral for surgical treatment is made. This prospective study shows that sleep activation on EEG, ictal automatisms, occurrence of focal to bilateral tonic-clonic seizures, and increased number of tried AEDs are negative prognostic factors.


Assuntos
Automatismo/fisiopatologia , Epilepsia Resistente a Medicamentos/fisiopatologia , Epilepsia do Lobo Temporal/fisiopatologia , Hipocampo/patologia , Convulsões Febris/fisiopatologia , Sono/fisiologia , Adulto , Idoso , Anticonvulsivantes/uso terapêutico , Epilepsia Resistente a Medicamentos/diagnóstico por imagem , Epilepsia Resistente a Medicamentos/tratamento farmacológico , Eletroencefalografia , Epilepsia do Lobo Temporal/diagnóstico por imagem , Epilepsia do Lobo Temporal/tratamento farmacológico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Esclerose , Adulto Jovem
3.
Medicine (Baltimore) ; 98(35): e16841, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31464910

RESUMO

RATIONALE: Multiple primary central nervous system lymphoma (MPCNSL) is a rare disease with differential diagnosis and treatment. As the underlying pathogenesis is not yet clarified, the early-stage clinical manifestations are occult and atypical. Also, the imaging manifestations are not specific, which is challenging for the clinical diagnosis and treatment. Therefore, additional clinical research is essential to understand the etiology of the disease. PATIENT CONCERNS: A 63-year-old male patient suffered from MPCNSLs but without typical clinical manifestations. The findings of the imaging examination were as follows. Magnetic resonance imaging (MRI) showed long T1 and T2 signal shadows in the right frontal lobe, right hippocampus, right cerebellar hemisphere, and the left occipital lobe. In addition, patchy T1-enhanced signal shadows were observed in the right frontal lobe and around the midline. Frontal lesions were detected in the magnetic resonance spectroscopy (MRS), Cho peak increased, and N-acetylaspartate (NAA) peak decreased. On the other hand, in the diffusion weighted imaging (DWI), apparent dispersion coefficient (ADC) showed low-value changes and high signal changes. The positron emission tomography-computed tomography (PET-CT) displayed radioactive accumulation in the right frontal lobe. DIAGNOSIS: Multiple primary central nervous system lymphoma. INTERVENTIONS: The patient received some conservative medical treatment, but his condition continued to worsen. Finally, he received a pathological biopsy, and refused further treatment after the result was reported. OUTCOMES: The patient died 1 week after biopsy, and the course of disease was about 100 days. LESSONS: PCNSL is a primary intracranial malignancy with low incidence and a high degree of malignancy and specificity in clinical manifestations. To facilitate early clinical treatment and improve the long-term survival of patients, it is necessary to master the imaging diagnostic methods and its features. The comprehensive application of multiple imaging examinations, such as CT, MRI, PET/CT, and PET/MRI, as well as, cerebrospinal fluid cytology can greatly improve the diagnosis of PCNSL.


Assuntos
Neoplasias Encefálicas/diagnóstico por imagem , Linfoma não Hodgkin/diagnóstico por imagem , Imagem Multimodal/métodos , Neoplasias Primárias Múltiplas/diagnóstico por imagem , Neoplasias Encefálicas/patologia , Cerebelo/diagnóstico por imagem , Cerebelo/patologia , Imagem de Difusão por Ressonância Magnética , Evolução Fatal , Lobo Frontal/diagnóstico por imagem , Lobo Frontal/patologia , Hipocampo/diagnóstico por imagem , Hipocampo/patologia , Humanos , Linfoma não Hodgkin/patologia , Masculino , Pessoa de Meia-Idade , Neoplasias Primárias Múltiplas/patologia , Lobo Occipital/diagnóstico por imagem , Lobo Occipital/patologia , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons
4.
Life Sci ; 232: 116611, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31260683

RESUMO

PURPOSE: To observe the effect of dexmedetomidine (DEX) on mitochondrial apoptosis of hippocampal neurons in hypoxia/reoxygenation (H/R) brain injury in developing rats, and to investigate its regulatory mechanism on HIF-1α/p53 signaling pathway. METHODS: Hypoxia/reoxygenation model was used in this study. TUNEL assay was performed to detect cell apoptosis. Immunohistochemical analysis and Western-blotting analysis were conducted to detect Cytochrome-C (Cyt-c), APAF-1, Caspase-3, Neuroglobin (Ngb), HIF-1α and p53 expression. After 28 days, Morris water maze (MWM) was performed. RESULTS: 50 µg/kg DEX improved H/R-induced brain injury and inhibited mitochondrial apoptosis in rats. Western-blotting and Immunohistochemical results demonstrated that DEX could up-regulate Ngb through α2 receptor to inhibit H/R-induced mitochondrial apoptosis. In addition, by adding inhibitors yohimbine and 2-methoxyestradiol (2ME2), we found that DEX could activate HIF-1α/p53 signaling pathway. MWM test showed that DEX could enhance long-term learning and memory of H/R brain injury rats. CONCLUSION: DEX alleviates H/R-induced brain injury and mitochondrial apoptosis in developing rats through α2 receptor, which may be related to activation of HIF-1α/p53 signaling pathway to up-regulate the expression of Ngb.


Assuntos
Hipóxia Celular/efeitos dos fármacos , Dexmedetomidina/farmacologia , Hipocampo/efeitos dos fármacos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Neurônios/efeitos dos fármacos , Proteína Supressora de Tumor p53/metabolismo , Animais , Apoptose/efeitos dos fármacos , Apoptose/fisiologia , Hipocampo/metabolismo , Hipocampo/patologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Masculino , Mitocôndrias/metabolismo , Neurônios/metabolismo , Neurônios/patologia , Substâncias Protetoras/farmacologia , Ratos , Ratos Sprague-Dawley , Traumatismo por Reperfusão/metabolismo , Transdução de Sinais/efeitos dos fármacos , Proteína Supressora de Tumor p53/efeitos dos fármacos
5.
Toxicol Lett ; 314: 106-116, 2019 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-31306743

RESUMO

Chronic low-level lead exposure alters cognitive function in young children however the mechanisms mediating these deficits in the brain are not known. Previous studies in our laboratory showed that early lead exposure reduced the number of microglial cells in hippocampus/dentate gyrus of C57BL/6 J mice. In the current study, C-C chemokine receptor 7 (CCR7) and major histocompatibility complex II (MHC II) were examined to investigate whether these neuroimmune factors which are known to trigger cell migration and antigen presentation, were altered by early chronic lead exposure. Thirty-six C57BL/6 J male mice were exposed to 0 ppm (controls, n = 12), 30 ppm (low-dose, n = 12), or 430 ppm (higher-dose, n = 12) of lead acetate via dams' milk from postnatal day (PND) 0 to 28. Flow cytometry was used to quantify cell types and cell surface expression of MHC II and CCR7 in hippocampal and whole brain microglia. Non-parametric independent samples median tests were used to test for statistically significant differences between groups. As compared to controls, CCR7 in hippocampal microglia was decreased in the low-dose group, measured as geometric mean fluorescence intensity (GMFI); in the higher-dose group CCR7+MHC II- hippocampal microglia were decreased. Further analyses revealed that the higher-dose group had decreased percentage of CCR7+MHC II- hippocampal macrophages as compared to controls but increased MHC II levels in CCR7+MHC II+ hippocampal macrophages as compared to controls. It was also noted that lead exposure disrupted the balance of MHC II and/or CCR7 in lead exposed animals. Reduced CCR7 in hippocampal microglia might alter the neuroimmune environment in hippocampi of lead exposed animals. Additional studies are needed to test this possibility.


Assuntos
Hipocampo/efeitos dos fármacos , Intoxicação do Sistema Nervoso por Chumbo na Infância/etiologia , Microglia/efeitos dos fármacos , Compostos Organometálicos/toxicidade , Receptores CCR7/metabolismo , Animais , Animais Recém-Nascidos , Regulação para Baixo , Feminino , Hipocampo/metabolismo , Hipocampo/patologia , Antígenos de Histocompatibilidade Classe II/metabolismo , Lactação , Intoxicação do Sistema Nervoso por Chumbo na Infância/metabolismo , Intoxicação do Sistema Nervoso por Chumbo na Infância/patologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Macrófagos/patologia , Masculino , Camundongos Endogâmicos C57BL , Microglia/metabolismo , Microglia/patologia , Fatores de Tempo
6.
Cancer Radiother ; 23(5): 370-377, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31331843

RESUMO

PUPOSE: Medulloblastoma is the most common primary malignant central nervous system tumor in childhood, accounting for 16-25% of cases (1). New treatment approaches have led to improved survival rates; however toxicities are still a major concern. PATIENTS AND METHODS: Participants were selected from the records of patients who were treated with craniospinal irradiation for medulloblastoma. Between January 2008 and December 2012, 62 patients were diagnosed with medulloblastoma at the national institute of oncology Rabat, 27 patients were still alive at the time of the study, of which n=16 patients were included in the study. The mean age of patients at the time of the study was 9.6 years. All children were treated with radiation therapy and chemotherapy, according to standard protocols. Median follow-up between treatment and evaluation was 4 years. All the children were assessed with the Wechsler Intelligence Scale for Children - fourth Edition (WISC-IV) three to five years after completion of radiotherapy. The test was administered by two well-trained psychologists in a distraction-free environment. The scoring was then reviewed by a psychologist from Brooklyn College. RESULTS: The mean standard score Full-Scale Intelligence Quotient (FSIQ) (M=63, SD=12.6) was found to be in the extremely low range and in the 1st percentile rank (PR), compared to the general population. All the measured primary index scales were below typical performance: verbal comprehension (M=67.7, SD=13.1), perceptual reasoning (M=63.5, SD=13.8) and processing speed (M=62.7, SD=15.5) were all found to be in the extremely low range, while xorking memory (M=75.5, SD=10.8) was found to be in the borderline range compared to the general population. To identify factors influencing the results, we performed both univariate and multivariate analyses. Age at the time of radiotherapy, initial clinical stage, total cranial radiotherapy dose, socioeconomic status, and the time of evaluation were identified as significantly impacting cognitive scores in the univariate analysis. In the multivariate analysis, only age at the time of radiotherapy and initial clinical stage remained factors significantly impacting cognitive outcomes with P=0.001 and P<0.001 respectively. CONCLUSION: Our study is evidence that tremendous efforts are still to be made in low-income countries to correctly measure neurocognitive dysfunction in medulloblastoma survivors and to prepare those patients to a typical life after the completion of treatment.


Assuntos
Neoplasias Cerebelares/radioterapia , Irradiação Craniana/efeitos adversos , Meduloblastoma/radioterapia , Transtornos Neurocognitivos/etiologia , Fatores Etários , Antineoplásicos/uso terapêutico , Neoplasias Cerebelares/tratamento farmacológico , Criança , Pré-Escolar , Terapia Combinada , Seguimentos , Substância Cinzenta/lesões , Substância Cinzenta/patologia , Hipocampo/lesões , Hipocampo/patologia , Humanos , Meduloblastoma/tratamento farmacológico , Transtornos da Memória/etiologia , Transtornos da Memória/patologia , Transtornos Neurocognitivos/patologia , Tamanho do Órgão , Modelos de Riscos Proporcionais , Escalas de Wechsler , Substância Branca/lesões , Substância Branca/patologia
7.
Nat Commun ; 10(1): 3090, 2019 07 12.
Artigo em Inglês | MEDLINE | ID: mdl-31300647

RESUMO

The role of brain somatic mutations in Alzheimer's disease (AD) is not well understood. Here, we perform deep whole-exome sequencing (average read depth 584×) in 111 postmortem hippocampal formation and matched blood samples from 52 patients with AD and 11 individuals not affected by AD. The number of somatic single nucleotide variations (SNVs) in AD brain specimens increases significantly with aging, and the rate of mutation accumulation in the brain is 4.8-fold slower than that in AD blood. The putatively pathogenic brain somatic mutations identified in 26.9% (14 of 52) of AD individuals are enriched in PI3K-AKT, MAPK, and AMPK pathway genes known to contribute to hyperphosphorylation of tau. We show that a pathogenic brain somatic mutation in PIN1 leads to a loss-of-function mutation. In vitro mimicking of haploinsufficiency of PIN1 aberrantly increases tau phosphorylation and aggregation. This study provides new insights into the genetic architecture underlying the pathogenesis of AD.


Assuntos
Doença de Alzheimer/genética , Peptidilprolil Isomerase de Interação com NIMA/genética , Agregação Patológica de Proteínas/genética , Proteínas tau/metabolismo , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Envelhecimento/genética , Doença de Alzheimer/patologia , Animais , Linhagem Celular Tumoral , Feminino , Técnicas de Silenciamento de Genes , Haploinsuficiência , Hipocampo/citologia , Hipocampo/patologia , Humanos , Mutação com Perda de Função , Masculino , Camundongos , Pessoa de Meia-Idade , Taxa de Mutação , Peptidilprolil Isomerase de Interação com NIMA/metabolismo , Neurônios , Fosforilação/genética , Polimorfismo de Nucleotídeo Único , Agregação Patológica de Proteínas/patologia , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Sequenciamento Completo do Exoma
8.
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
9.
Nat Commun ; 10(1): 2394, 2019 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-31160584

RESUMO

To understand the molecular processes that link Aß amyloidosis, tauopathy and neurodegeneration, we screened for tau-interacting proteins by immunoprecipitation/LC-MS. We identified the carboxy-terminal PDZ ligand of nNOS (CAPON) as a novel tau-binding protein. CAPON is an adaptor protein of neuronal nitric oxide synthase (nNOS), and activated by the N-methyl-D-aspartate receptor. We observed accumulation of CAPON in the hippocampal pyramidal cell layer in the AppNL-G-F -knock-in (KI) brain. To investigate the effect of CAPON accumulation on Alzheimer's disease (AD) pathogenesis, CAPON was overexpressed in the brain of AppNL-G-F mice crossbred with MAPT (human tau)-KI mice. This produced significant hippocampal atrophy and caspase3-dependent neuronal cell death in the CAPON-expressing hippocampus, suggesting that CAPON accumulation increases neurodegeneration. CAPON expression also induced significantly higher levels of phosphorylated, oligomerized and insoluble tau. In contrast, CAPON deficiency ameliorated the AD-related pathological phenotypes in tauopathy model. These findings suggest that CAPON could be a druggable AD target.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Doença de Alzheimer/metabolismo , Hipocampo/metabolismo , Agregação Patológica de Proteínas/metabolismo , Células Piramidais/metabolismo , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Precursor de Proteína beta-Amiloide/genética , Animais , Atrofia , Caspase 3/metabolismo , Morte Celular , Cromatografia Líquida , Modelos Animais de Doenças , Técnicas de Introdução de Genes , Hipocampo/patologia , Humanos , Imunoprecipitação , Espectrometria de Massas , Camundongos , Neurônios/metabolismo , Neurônios/patologia , Agregação Patológica de Proteínas/patologia , Células Piramidais/patologia , Tauopatias , Proteínas tau/metabolismo
10.
Pan Afr Med J ; 32: 131, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31223419

RESUMO

We present the case of a 69-year old man who was brought to the hospital after being found unconscious; last seen at baseline 9 hours prior. On admission he was found to be severely hypoglycemic and received prompt glucose administration, with no immediate neurological improvement. Stroke was suspected. A brain MRI revealed abnormal hyperintense signal involving the head and tail of the left hippocampus. After close neurological monitoring and supportive care in the ICU, his condition improved over time, leaving no residual focal deficits. This case highlights the presence of MRI changes in patients with severe hypoglycemia as it happens in hypoglycemic coma.


Assuntos
Coma/etiologia , Hipoglicemia/complicações , Imagem por Ressonância Magnética/métodos , Idoso , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Coma/diagnóstico por imagem , Hipocampo/patologia , Humanos , Hipoglicemia/diagnóstico por imagem , Hipoglicemia/terapia , Unidades de Terapia Intensiva , Masculino , Índice de Gravidade de Doença , Acidente Vascular Cerebral/diagnóstico
11.
Nat Commun ; 10(1): 2572, 2019 06 12.
Artigo em Inglês | MEDLINE | ID: mdl-31189917

RESUMO

Activation of G-protein coupled receptors elevates cAMP levels promoting dissociation of protein kinase A (PKA) holoenzymes and release of catalytic subunits (PKAc). This results in PKAc-mediated phosphorylation of compartmentalized substrates that control central aspects of cell physiology. The mechanism of PKAc activation and signaling have been largely characterized. However, the modes of PKAc inactivation by regulated proteolysis were unknown. Here, we identify a regulatory mechanism that precisely tunes PKAc stability and downstream signaling. Following agonist stimulation, the recruitment of the chaperone-bound E3 ligase CHIP promotes ubiquitylation and proteolysis of PKAc, thus attenuating cAMP signaling. Genetic inactivation of CHIP or pharmacological inhibition of HSP70 enhances PKAc signaling and sustains hippocampal long-term potentiation. Interestingly, primary fibroblasts from autosomal recessive spinocerebellar ataxia 16 (SCAR16) patients carrying germline inactivating mutations of CHIP show a dramatic dysregulation of PKA signaling. This suggests the existence of a negative feedback mechanism for restricting hormonally controlled PKA activities.


Assuntos
Subunidades Catalíticas da Proteína Quinase Dependente de AMP Cíclico/metabolismo , AMP Cíclico/metabolismo , Retroalimentação Fisiológica/fisiologia , Chaperonas Moleculares/metabolismo , Ataxias Espinocerebelares/patologia , Animais , Retroalimentação Fisiológica/efeitos dos fármacos , Fibroblastos , Células HEK293 , Proteínas de Choque Térmico HSP70/antagonistas & inibidores , Hipocampo/patologia , Holoenzimas/metabolismo , Humanos , Leupeptinas/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Fosforilação , Cultura Primária de Células , Ligação Proteica/efeitos dos fármacos , Proteólise/efeitos dos fármacos , Nucleosídeos de Purina/farmacologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Ataxias Espinocerebelares/genética , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitinação/fisiologia
12.
Acta Neurobiol Exp (Wars) ; 79(1): 73-85, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31038486

RESUMO

Preconditioning with lipopolysaccharide (LPS) or opioid antagonists has a neuroprotective effect in ischemic insults. However, the co­preconditioning effect of toll­like receptor ligands and opioid antagonists has not been investigated. In this study we examined the neuroprotective effect of LPS and naltrexone (NTX) preconditioning and co­preconditioning in unilateral selective hippocampal ischemia in rats to assess for possible synergistic protective effects. LPS and NTX were injected unilaterally into the left cerebral ventricle of male rats. Forty­eight hours after LPS and twenty­four hours after NTX injection, ipsilateral selective hippocampal ischemia was induced using a modified version of the photothrombotic method. Protective effects for LPS and NTX were assessed by evaluating infarct volume (using 2,3,5­triphenyltetrazolium chloride staining), and cognitive function (using radial arm water maze and passive avoidance tests). Animals in the ischemic group had an infarct lesion and considerable cognitive impairment, compared with the sham group. LPS or NTX preconditioning significantly reduced the infarct size and improved cognitive function. Moreover, co­preconditioning with LPS and NTX increased the protective effect compared with preconditioning with LPS or NTX alone. Our data showed that LPS and NTX preconditioning resulted in a neuroprotective effect in hippocampal ischemia. Furthermore, co­preconditioning with LPS and NTX resulted in a synergistic protective effect.


Assuntos
Isquemia Encefálica/tratamento farmacológico , Lateralidade Funcional/fisiologia , Hipocampo/patologia , Precondicionamento Isquêmico/métodos , Lipopolissacarídeos/administração & dosagem , Naltrexona/administração & dosagem , Fármacos Neuroprotetores/administração & dosagem , Animais , Aprendizagem da Esquiva/efeitos dos fármacos , Isquemia Encefálica/complicações , Isquemia Encefálica/etiologia , Modelos Animais de Doenças , Hipocampo/irrigação sanguínea , Injeções Intraventriculares , Transtornos de Aprendizagem/etiologia , Transtornos de Aprendizagem/prevenção & controle , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Estimulação Luminosa/efeitos adversos , Distribuição Aleatória , Ratos , Ratos Wistar , Tempo de Reação/efeitos dos fármacos , Resultado do Tratamento
13.
Int J Mol Sci ; 20(9)2019 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-31067671

RESUMO

Effects of fructose 1,6-bisphosphate (F-1,6-P2) towards N-methyl-d-aspartate NMDA excitotoxicity were evaluated in rat organotypic hippocampal brain slice cultures (OHSC) challenged for 3 h with 30 µM NMDA, followed by incubations (24, 48, and 72 h) without (controls) and with F-1,6-P2 (0.5, 1 or 1.5 mM). At each time, cell necrosis was determined by measuring LDH in the medium. Energy metabolism was evaluated by measuring ATP, GTP, ADP, AMP, and ATP catabolites (nucleosides and oxypurines) in deproteinized OHSC extracts. Gene expressions of phosphofructokinase, aldolase, and glyceraldehyde-3-phosphate dehydrogenase were also measured. F-1,6-P2 dose-dependently decreased NMDA excitotoxicity, abolishing cell necrosis at the highest concentration tested (1.5 mM). Additionally, F-1,6-P2 attenuated cell energy imbalance caused by NMDA, ameliorating the mitochondrial phosphorylating capacity (increase in ATP/ADP ratio) Metabolism normalization occurred when using 1.5 mM F-1,6-P2. Remarkable increase in expressions of phosphofructokinase, aldolase and glyceraldehyde-3-phosphate dehydrogenase (up to 25 times over the values of controls) was also observed. Since this phenomenon was recorded even in OHSC treated with F-1,6-P2 with no prior challenge with NMDA, it is highly conceivable that F-1,6-P2 can enter into intact cerebral cells producing significant benefits on energy metabolism. These effects are possibly mediated by changes occurring at the gene level, thus opening new perspectives for F-1,6-P2 application as a useful adjuvant to rescue mitochondrial metabolism of cerebral cells under stressing conditions.


Assuntos
Frutose-Bifosfatase/farmacologia , Hipocampo/efeitos dos fármacos , N-Metilaspartato/toxicidade , Fármacos Neuroprotetores/farmacologia , Animais , Metabolismo Energético , Frutose-Bifosfato Aldolase/metabolismo , Gliceraldeído-3-Fosfato Desidrogenases/metabolismo , Hipocampo/metabolismo , Hipocampo/patologia , Necrose , Fosfofrutoquinases/metabolismo , Nucleosídeos de Purina/metabolismo , Ratos , Ratos Wistar
14.
Wei Sheng Yan Jiu ; 48(2): 269-278, 2019 Mar.
Artigo em Chinês | MEDLINE | ID: mdl-31133106

RESUMO

OBJECTIVE: To investigate the effects of resveratrol(Res) on N-methyl-D-aspartate receptor(NMDAR1)and protein kinase C(PKC)expressions in the hippocampus in Alzheimer's disease(AD) rats. METHODS: The model of AD was induced by ovariectomy combined intraperitoneal injection of D-galactose(100 mg/kg). Thirty-Six female Wistar rats were randomly divided into 6 groups inculding Sham control group, AD model group, Res low dose group(20 mg/kg), Res middle dose group(40 mg/kg), Res high dose group(80 mg/kg group)and estrogen replacement therapy(ERT) group. The genes of NMDAR1 and PKC were detected by real-time PCR. NMDAR1 total protein, p-NMDAR1 protein and PKC protein were checked by Western blot. RESULTS: Compared with the Sham control group, the gene expressions and the protein expressions of NMDAR1 and PKC in the model group were decreased(P<0. 05). Moreover, compared with the model group, genes of NMDAR1 and PKC in the 3 Res dose groups were significantly increased(P<0. 05 or P<0. 01). The elavated levels of genes of NMDAR1 and PKC in ERT group were similar to the Res 80 mg/kg group(P<0. 01). p-NMDAR1/NMDAR1 and the protein expressions of PKC were also significantly increased in Res 40 mg/kg group and Res 80 mg/kg group as well as in ERT group(P<0. 05 or P<0. 01). CONCLUSION: Up-regulating the gene and protein expressions of p-NMDAR1/NMDAR1 and PKC may be one of the mechanisms of improvement of Res on the memory in AD rats.


Assuntos
Doença de Alzheimer , Hipocampo/metabolismo , Proteína Quinase C/efeitos dos fármacos , Receptores de N-Metil-D-Aspartato/efeitos dos fármacos , Resveratrol/farmacologia , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Animais , Anti-Inflamatórios não Esteroides/administração & dosagem , Modelos Animais de Doenças , Feminino , Hipocampo/efeitos dos fármacos , Hipocampo/patologia , Humanos , Proteína Quinase C/metabolismo , Distribuição Aleatória , Ratos , Ratos Wistar , Receptores de N-Metil-D-Aspartato/metabolismo
15.
Biomed Res Int ; 2019: 2649281, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30956976

RESUMO

Centella asiatica ameliorates memory impairment and induces expression of hippocampal brain-derived neurotropic factor (BDNF) in chronically stressed rats. The relationship between the anti-inflammatory effect of Centella asiatica on hippocampal BDNF and the involvement of sirtuin-1, a BDNF expression regulator, in neuroprotective mechanisms of Centella asiatica warrants an investigation. We investigated the effect of Centella asiatica ethanolic extracts (CA) on TNF-α, IL-10, and SIRT1 levels and whether these predicted BDNF expression in rat hippocampus after chronic stress. For the experiments, thirty male rats (Sprague Dawley) were divided into six groups: nonstressed-control, stressed-control, nonstressed +CA 300mg/kg/d, stressed +CA 150 mg/kg/d, stressed +CA 300 mg/kg/d, and stressed +CA 600 mg/kg/d. On day 28, rats were sacrificed and hippocampus was dissected out. Hippocampal TNF-α, IL-10, SIRT1, and BDNF were measured by enzyme-linked immunosorbent assay. Hippocampal TNF-α level was significantly higher in the stressed-control compared to nonstressed-control groups. Across all stress conditions, rats receiving the highest dose of CA had the lowest mean TNF-α and highest mean BDNF. There were no significant differences in IL-10 and SIRT1 levels between groups. Hippocampal TNF-α did not predict hippocampal BDNF in a regression analysis. In conclusion, lower TNF-α and higher BDNF in the hippocampus support the hypothesis that these factors independently contribute to Centella asiatica's neuroprotective effect in chronically stressed rats.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/metabolismo , Centella/química , Hipocampo/metabolismo , Fármacos Neuroprotetores/farmacologia , Estresse Psicológico , Triterpenos/farmacologia , Fator de Necrose Tumoral alfa/metabolismo , Animais , Doença Crônica , Hipocampo/patologia , Masculino , Fármacos Neuroprotetores/química , Ratos , Ratos Sprague-Dawley , Estresse Psicológico/metabolismo , Estresse Psicológico/patologia , Estresse Psicológico/prevenção & controle , Triterpenos/química
16.
Mol Med Rep ; 19(5): 4185-4194, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30942466

RESUMO

Prenatal nicotine exposure (PNE) is closely related to depression in offspring. However, the underlying mechanism is still unclear. We hypothesized that neurosteroid in the hippocampus may mediate PNE­induced depression­like behaviors. Nicotine was subcutaneously administered (1.0 mg/kg) to pregnant rats twice daily from gestational day (GD) 9 to 20. In adolescent offspring, PNE significantly increased immobility time and decreased the sucrose preference in female rats. The numbers of hippocampal neurons declined in the CA3 and DG regions. Steroidogenic acute regulatory protein (StAR) expression was suppressed in female rats. In fetal offspring, the neuronal numbers of CA3 regions in PNE female fetal hippocampal were significantly decreased, accompanied by the enhanced content of corticosterone and StAR expression. These data indicated that PNE induced depression­like behavior in adolescent female rats via the regulation of neurosteroid levels in the hippocampus.


Assuntos
Transtorno Depressivo/etiologia , Hipocampo/metabolismo , Hipocampo/fisiopatologia , Exposição Materna/efeitos adversos , Neurotransmissores/metabolismo , Nicotina/efeitos adversos , Efeitos Tardios da Exposição Pré-Natal , Animais , Comportamento Animal , Biomarcadores , Transtorno Depressivo/psicologia , Modelos Animais de Doenças , Feminino , Expressão Gênica , Hipocampo/patologia , Gravidez , Ratos
17.
Int J Mol Med ; 43(6): 2420-2428, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31017259

RESUMO

Mitochondria are crucial for neuronal cell survival and death through their functions in ATP production and the intrinsic pathway of apoptosis. Mitochondrial dysfunction is considered to play a central role in several serious human diseases, including neurodegenerative diseases, such as Parkinson's and Alzheimer's disease and ischemic neurodegeneration. The aim of the present study was to investigate the impact of transient global brain ischemia on the expression of selected proteins involved in mitochondrial dynamics and mitochondria­associated membranes. The main foci of interest were the proteins mitofusin 2 (Mfn2), dynamin­related protein 1 (DRP1), voltage­dependent anion­selective channel 1 (VDAC1) and glucose­regulated protein 75 (GRP75). Western blot analysis of total cell extracts and mitochondria isolated from either the cerebral cortex or hippocampus of experimental animals was performed. In addition, Mfn2 was localized intracellularly by laser scanning confocal microscopy. It was demonstrated that 15­min ischemia, or 15­min ischemia followed by 1, 3, 24 or 72 h of reperfusion, was associated with a marked decrease of the Mfn2 protein in mitochondria isolated from the cerebral cortex, but not in hippocampal mitochondria. Moreover, a translocation of the Mfn2 protein to the cytoplasm was documented immediately after global brain ischemia in the neurons of the cerebral cortex by laser scanning confocal microscopy. Mfn2 translocation was followed by decreased expression of Mfn2 during reperfusion. Markedly elevated levels of the VDAC1 protein were also documented in total cell extracts isolated from the hippocampus of rats after 15 min of global brain ischemia followed by 3 h of reperfusion, and from the cerebral cortex of rats after 15 min of global brain ischemia followed by 72 h of reperfusion. The mitochondrial Mfn2 release observed during the early stages of reperfusion may thus represent an important mechanism of mitochondrial dysfunction associated with neuronal dysfunction or death induced by global brain ischemia.


Assuntos
Isquemia Encefálica/patologia , Córtex Cerebral/patologia , Hipocampo/patologia , Proteínas de Membrana/análise , Mitocôndrias/patologia , Proteínas Mitocondriais/análise , Animais , Masculino , Ratos , Ratos Wistar
18.
J Vet Intern Med ; 33(3): 1440-1445, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30942925

RESUMO

A 7-year-old neutered female domestic shorthaired cat born in Poland and then moved to Japan presented to the local clinic with recent onset of convulsive cluster seizures and status epilepticus. Magnetic resonance imaging revealed bilateral swelling of the hippocampus with T2 hyperintensity and contrast enhancing image, suggesting hippocampal necrosis. The cat completely recovered after treatment with antiepileptic drugs (AED) and administration of prednisolone (1 mg/kg PO q24h for 4 days and tapered). However, cluster seizures reoccurred and developed into status epilepticus despite increasing doses of AED. Although the convulsions were resolved by other AEDs, stupor and renal failure developed, and the cat was euthanized. Pathological findings were consistent with hippocampal necrosis. Immunological analysis for leucine-rich glioma inactivated 1 (LGI1) autoantibodies was negative, but antibodies against DCC (deleted in colorectal carcinoma) known as netrin-1 receptor were found. This report describes a case of feline autoimmune limbic encephalitis and hippocampal necrosis that were presumably associated with DCC autoantibodies.


Assuntos
Doenças Autoimunes/veterinária , Doenças do Gato/imunologia , Hipocampo/patologia , Encefalite Límbica/veterinária , Necrose/veterinária , Receptores de Netrina/imunologia , Animais , Anti-Inflamatórios/uso terapêutico , Anticonvulsivantes/uso terapêutico , Doenças Autoimunes/tratamento farmacológico , Doenças Autoimunes/imunologia , Gatos , Feminino , Hipocampo/diagnóstico por imagem , Encefalite Límbica/tratamento farmacológico , Encefalite Límbica/imunologia , Imagem por Ressonância Magnética/veterinária , Prednisolona/uso terapêutico , Convulsões/tratamento farmacológico , Estado Epiléptico/tratamento farmacológico
19.
Oxid Med Cell Longev ; 2019: 1327986, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31019649

RESUMO

Epilepsy is a neurological disorder characterized by recurrent spontaneous seizures due to an imbalance between cerebral excitability and inhibition, with a tendency towards uncontrolled excitability. Epilepsy has been associated with oxidative and nitrosative stress due to prolonged neuronal hyperexcitation and loss neurons during seizures. The experimental animal models report level of ATP diminished and increase in lipid peroxidation, catalase, and glutathione altered activity in the brain. We studied the immunohistochemical expression and localization of antioxidant enzymes GPx, SOD, and CAT in the rat brains treated with KA and PTZ. A significant decrease was observed in the number of immunoreactive cells to GPx, without significant changes for SOD and CAT in KA-treated rats, and decrease in the number of immunoreactive cells to SOD, without significant changes for GPx and only CAT in PTZ-treated rats. Evident immunoreactivity of GPx, SOD, and CAT was observed mainly in astrocytes and neurons of the hippocampal brain region in rats exposed at KA; similar results were observed in rats treated with PTZ at the first hours. These results provide evidence supporting the role of activation of the Nrf2 antioxidant system pathway against oxidative stress effects in the experimental models of epileptic seizures.


Assuntos
Imuno-Histoquímica/métodos , Fator 2 Relacionado a NF-E2/metabolismo , Convulsões/enzimologia , Convulsões/patologia , Animais , Antioxidantes/metabolismo , Comportamento Animal , Hipocampo/patologia , Ácido Caínico , Masculino , Modelos Biológicos , Pentilenotetrazol , Ratos Wistar
20.
Magn Reson Imaging ; 60: 52-67, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30940494

RESUMO

To understand multifactorial conditions such as Alzheimer's disease (AD) we need brain signatures that predict the impact of multiple pathologies and their interactions. To help uncover the relationships between pathology affected brain circuits and cognitive markers we have used mouse models that represent, at least in part, the complex interactions altered in AD, while being raised in uniform environments and with known genotype alterations. In particular, we aimed to understand the relationship between vulnerable brain circuits and memory deficits measured in the Morris water maze, and we tested several predictive modeling approaches. We used in vivo manganese enhanced MRI traditional voxel based analyses to reveal regional differences in volume (morphometry), signal intensity (activity), and magnetic susceptibility (iron deposition, demyelination). These regions included hippocampus, olfactory areas, entorhinal cortex and cerebellum, as well as the frontal association area. The properties of these regions, extracted from each of the imaging markers, were used to predict spatial memory. We next used eigenanatomy, which reduces dimensionality to produce sets of regions that explain the variance in the data. For each imaging marker, eigenanatomy revealed networks underpinning a range of cognitive functions including memory, motor function, and associative learning, allowing the detection of associations between context, location, and responses. Finally, the integration of multivariate markers in a supervised sparse canonical correlation approach outperformed single predictor models and had significant correlates to spatial memory. Among a priori selected regions, expected to play a role in memory dysfunction, the fornix also provided good predictors, raising the possibility of investigating how disease propagation within brain networks leads to cognitive deterioration. Our cross-sectional results support that modeling approaches integrating multivariate imaging markers provide sensitive predictors of AD-like behaviors. Such strategies for mapping brain circuits responsible for behaviors may help in the future predict disease progression, or response to interventions.


Assuntos
Doença de Alzheimer/diagnóstico por imagem , Disfunção Cognitiva/diagnóstico por imagem , Modelos Animais de Doenças , Processamento de Imagem Assistida por Computador/métodos , Imagem por Ressonância Magnética , Doença de Alzheimer/patologia , Animais , Comportamento Animal , Biomarcadores , Encéfalo/patologia , Mapeamento Encefálico/métodos , Cognição , Disfunção Cognitiva/patologia , Meios de Contraste , Estudos Transversais , Progressão da Doença , Fórnice/patologia , Genótipo , Hipocampo/patologia , Magnetismo , Aprendizagem em Labirinto , Memória , Transtornos da Memória/patologia , Camundongos , Camundongos Knockout , Doenças Neurodegenerativas/diagnóstico por imagem , Doenças Neurodegenerativas/genética , Neuroimagem , Memória Espacial
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA