Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 9.404
Filtrar
1.
Cells ; 10(9)2021 08 31.
Artigo em Inglês | MEDLINE | ID: mdl-34571912

RESUMO

COVID-19 presents with a wide range of clinical neurological manifestations. It has been recognized that SARS-CoV-2 infection affects both the central and peripheral nervous system, leading to smell and taste disturbances; acute ischemic and hemorrhagic cerebrovascular disease; encephalopathies and seizures; and causes most surviving patients to have long lasting neurological symptoms. Despite this, typical neuropathological features associated with the infection have still not been identified. Studies of post-mortem examinations of the cerebral cortex are obtained with difficulty due to laboratory safety concerns. In addition, they represent cases with different neurological symptoms, age or comorbidities, thus a larger number of brain autoptic data from multiple institutions would be crucial. Histopathological findings described here are aimed to increase the current knowledge on neuropathology of COVID-19 patients. We report post-mortem neuropathological findings of ten COVID-19 patients. A wide range of neuropathological lesions were seen. The cerebral cortex of all patients showed vascular changes, hyperemia of the meninges and perivascular inflammation in the cerebral parenchyma with hypoxic neuronal injury. Perivascular lymphocytic inflammation of predominantly CD8-positive T cells mixed with CD68-positive macrophages, targeting the disrupted vascular wall in the cerebral cortex, cerebellum and pons were seen. Our findings support recent reports highlighting a role of microvascular injury in COVID-19 neurological manifestations.


Assuntos
COVID-19/patologia , Córtex Cerebral/patologia , Idoso , Idoso de 80 Anos ou mais , Autopsia , Encéfalo/patologia , Encéfalo/virologia , Encefalopatias/patologia , Encefalopatias/virologia , Linfócitos T CD8-Positivos/patologia , Córtex Cerebral/virologia , Feminino , Humanos , Inflamação , Macrófagos/patologia , Masculino , Microvasos/patologia , Microvasos/virologia , Pessoa de Meia-Idade , Doenças do Sistema Nervoso/patologia , Doenças do Sistema Nervoso/virologia , SARS-CoV-2/patogenicidade
2.
Int J Mol Sci ; 22(15)2021 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-34361091

RESUMO

Oxidative phosphorylation (OxPhos) is the basic function of mitochondria, although the landscape of mitochondrial functions is continuously growing to include more aspects of cellular homeostasis. Thanks to the application of -omics technologies to the study of the OxPhos system, novel features emerge from the cataloging of novel proteins as mitochondrial thus adding details to the mitochondrial proteome and defining novel metabolic cellular interrelations, especially in the human brain. We focussed on the diversity of bioenergetics demand and different aspects of mitochondrial structure, functions, and dysfunction in the brain. Definition such as 'mitoexome', 'mitoproteome' and 'mitointeractome' have entered the field of 'mitochondrial medicine'. In this context, we reviewed several genetic defects that hamper the last step of aerobic metabolism, mostly involving the nervous tissue as one of the most prominent energy-dependent tissues and, as consequence, as a primary target of mitochondrial dysfunction. The dual genetic origin of the OxPhos complexes is one of the reasons for the complexity of the genotype-phenotype correlation when facing human diseases associated with mitochondrial defects. Such complexity clinically manifests with extremely heterogeneous symptoms, ranging from organ-specific to multisystemic dysfunction with different clinical courses. Finally, we briefly discuss the future directions of the multi-omics study of human brain disorders.


Assuntos
Encefalopatias/patologia , Metabolismo Energético , Mitocôndrias/patologia , Doenças Mitocondriais/patologia , Fosforilação Oxidativa , Animais , Encefalopatias/metabolismo , Humanos , Mitocôndrias/metabolismo , Doenças Mitocondriais/metabolismo
3.
Int J Mol Sci ; 22(16)2021 Aug 18.
Artigo em Inglês | MEDLINE | ID: mdl-34445581

RESUMO

Peroxisome Proliferator-Activated Receptor gamma (PPARγ) is a master regulator of metabolism, adipogenesis, inflammation and cell cycle, and it has been extensively studied in the brain in relation to inflammation or neurodegeneration. Little is known however about its role in viral infections of the brain parenchyma, although they represent the most frequent cause of encephalitis and are a major threat for the developing brain. Specific to viral infections is the ability to subvert signaling pathways of the host cell to ensure virus replication and spreading, as deleterious as the consequences may be for the host. In this respect, the pleiotropic role of PPARγ makes it a critical target of infection. This review aims to provide an update on the role of PPARγ in viral infections of the brain. Recent studies have highlighted the involvement of PPARγ in brain or neural cells infected by immunodeficiency virus 1, Zika virus, or human cytomegalovirus. They have provided a better understanding on PPARγ functions in the infected brain, and revealed that it can be a double-edged sword with respect to inflammation, viral replication, or neuronogenesis. They unraveled new roles of PPARγ in health and disease and could possibly help designing new therapeutic strategies.


Assuntos
Encefalopatias/patologia , Encefalite/patologia , PPAR gama/metabolismo , Infecção por Zika virus/complicações , Zika virus/isolamento & purificação , Animais , Encefalopatias/etiologia , Encefalopatias/metabolismo , Encefalite/etiologia , Encefalite/metabolismo , Humanos , Transdução de Sinais , Infecção por Zika virus/virologia
4.
Molecules ; 26(15)2021 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-34361850

RESUMO

Celastrol, the most abundant compound derived from the root of Tripterygium wilfordii, largely used in traditional Chinese medicine, has shown preclinical and clinical efficacy for a broad range of disorders, acting via numerous mechanisms, including the induction of the expression of several neuroprotective factors, the inhibition of cellular apoptosis, and the decrease of reactive oxygen species (ROS). Given the crucial implication of these pathways in the pathogenesis of Central Nervous System disorders, both in vitro and in vivo studies have focused their attention on the possible use of this compound in these diseases. However, although most of the available studies have reported significant neuroprotective effects of celastrol in cellular and animal models of these pathological conditions, some of these data could not be replicated. This review aims to discuss current in vitro and in vivo lines of evidence on the therapeutic potential of celastrol in neurodegenerative diseases, including Alzheimer's and Parkinson's diseases, amyotrophic lateral sclerosis, Huntington's disease, multiple sclerosis, and cadmium-induced neurodegeneration, as well as in psychiatric disorders, such as psychosis and depression. In vitro and in vivo studies focused on celastrol effects in cerebral ischemia, ischemic stroke, traumatic brain injury, and epilepsy are also described.


Assuntos
Encefalopatias/tratamento farmacológico , Triterpenos Pentacíclicos , Raízes de Plantas/química , Tripterygium/química , Animais , Encefalopatias/metabolismo , Encefalopatias/patologia , Humanos , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/uso terapêutico , Triterpenos Pentacíclicos/química , Triterpenos Pentacíclicos/uso terapêutico
5.
Int J Mol Sci ; 22(13)2021 Jun 23.
Artigo em Inglês | MEDLINE | ID: mdl-34201807

RESUMO

MicroRNAs (miRNAs) are small, non-coding RNAs that function as endogenous gene silencers. Soon after the discovery of miRNAs, a subset of brain-enriched and brain-specific miRNAs were identified and significant advancements were made in delineating miRNA function in brain development. However, understanding the molecular mechanisms that regulate miRNA biogenesis in normal and diseased brains has become a prevailing challenge. Besides transcriptional regulation of miRNA host genes, miRNA processing intermediates are subjected to multifaceted regulation by canonical miRNA processing enzymes, RNA binding proteins (RBPs) and epitranscriptomic modifications. Further still, miRNA activity can be regulated by the sponging activity of other non-coding RNA classes, namely circular RNAs (circRNAs) and long non-coding RNAs (lncRNAs). Differential abundance of these factors in neuronal and glial lineages partly underlies the spatiotemporal expression and function of lineage-specific miRNAs. Here, we review the continuously evolving understanding of the regulation of neuronal and glial miRNA biogenesis at the transcriptional and posttranscriptional levels and the cooperativity of miRNA species in targeting key mRNAs to drive lineage-specific development. In addition, we review dysregulation of neuronal and glial miRNAs and the detrimental impacts which contribute to developmental brain disorders.


Assuntos
Encefalopatias/patologia , Regulação da Expressão Gênica no Desenvolvimento , MicroRNAs/genética , Neuroglia/patologia , Neurônios/patologia , RNA Mensageiro/metabolismo , Animais , Encefalopatias/genética , Encefalopatias/metabolismo , Humanos , Neuroglia/metabolismo , Neurônios/metabolismo , Processamento Pós-Transcricional do RNA , RNA Mensageiro/genética
7.
Postgrad Med ; 133(7): 728-749, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34152933

RESUMO

Multiple sclerosis (MS) is an inflammatory neurodegenerative disorder manifesting as gradual or progressive loss of neurological functions. Most patients present with relapsing-remitting disease courses. Extensive research over recent decades has expounded our insights into the presentations and diagnostic features of MS. Groups of genetic diseases, CADASIL and leukodystrophies, for example, have been frequently misdiagnosed with MS due to some overlapping clinical and radiological features. The delayed identification of these diseases in late adulthood can lead to severe neurological complications. Herein we discuss genetic diseases that have the potential to mimic multiple sclerosis, with highlights on clinical identification and practicing pearls that may aid physicians in recognizing MS-mimics with genetic background in clinical settings.


Assuntos
Doenças Genéticas Inatas/diagnóstico , Doenças Genéticas Inatas/patologia , Esclerose Múltipla/diagnóstico , Esclerose Múltipla/patologia , Doenças do Sistema Nervoso/diagnóstico , Doenças do Sistema Nervoso/patologia , Encefalopatias/diagnóstico , Encefalopatias/patologia , Doenças dos Nervos Cranianos/diagnóstico , Doenças dos Nervos Cranianos/patologia , Diagnóstico Tardio , Diagnóstico Diferencial , Erros de Diagnóstico , Doenças Genéticas Inatas/genética , Humanos , Imageamento por Ressonância Magnética
8.
Cochrane Database Syst Rev ; 6: CD000215, 2021 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-34060667

RESUMO

BACKGROUND: Neurocysticercosis is a parasitic infection of the central nervous system by the larval stage of the pork tapeworm and is a common cause of seizures and epilepsy in endemic areas. Anthelmintics (albendazole or praziquantel) may be given alongside supportive treatment (antiepileptics/analgesia) with the aim of killing these larvae (cysticerci), with or without corticosteroid treatment. However, there are potential adverse effects of these drugs, and the cysticerci may eventually die without directed anthelminthic treatment. OBJECTIVES: To assess the effects of anthelmintics on people with neurocysticercosis. SEARCH METHODS: We searched the Cochrane Infectious Diseases Group Specialized Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, LILACS, the WHO ICTRP, and ClinicalTrials.gov, up to 21 October 2020. SELECTION CRITERIA: Randomized controlled trials comparing anthelmintics and supportive treatment (+/- corticosteroids) with supportive treatment alone (+/- corticosteroids) for people with neurocysticercosis. DATA COLLECTION AND ANALYSIS: Two review authors independently screened the title and abstract of all articles identified by the search. We obtained full-text articles to confirm the eligibility of all studies that passed screening. One review author extracted data, which a second review author checked. Two review authors assessed the risk of bias of each trial and performed GRADE assessments. In cases of disagreement at consensus discussion stage between review authors, we consulted a third review author. We calculated risk ratios (RR) for dichotomous variables, with 95% confidence intervals (CIs) for pooled data from studies with similar interventions and outcomes. MAIN RESULTS: We included 16 studies in the review. Only two studies investigated praziquantel and did not report data in a format that could contribute to meta-analysis. Most results in this review are therefore applicable to albendazole versus placebo or no anthelmintic. The aggregate analysis across all participants with neurocysticercosis did not demonstrate a difference between groups in seizure recurrence, but heterogeneity was marked (RR 0.94, 95% CI 0.78 to 1.14; 10 trials, 1054 participants; I2 = 67%; low-certainty evidence). When stratified by participants with a single cyst or multiple cysts, pooled analysis suggests that albendazole probably improves seizure recurrence for participants with a single cyst (RR 0.61, 95% CI 0.4 to 0.91; 5 trials, 396 participants; moderate-certainty evidence). All studies contributing to this analysis recruited participants with non-viable, intraparenchymal cysts only, and most participants were children. We are uncertain whether or not albendazole reduces seizure recurrence in participants with multiple cysts, as the certainty of the evidence is very low, although the direction of effect is towards albendazole causing harm (RR 2.05, 95% CI 1.28 to 3.31; 2 trials, 321 participants; very low-certainty evidence). This analysis included a large study containing a highly heterogeneous population that received an assessment of unclear risk for multiple 'Risk of bias' domains. Regarding radiological outcomes, albendazole probably slightly improves the complete radiological clearance of lesions (RR 1.22, 95% CI 1.07 to 1.39; 13 trials, 1324 participants; moderate-certainty evidence) and the evolution of cysts (RR 1.27, 95% CI 1.10 to 1.47; 6 trials, 434 participants; moderate-certainty evidence). More adverse events appeared to be observed in participants treated with either albendazole or praziquantel compared to those receiving placebo or no anthelmintic. The most commonly reported side effects were headache, abdominal pain, and nausea/vomiting. AUTHORS' CONCLUSIONS: For participants with a single cyst, there was less seizure recurrence in the albendazole group compared to the placebo/no anthelmintic group. The studies contributing to this evidence only recruited participants with a non-viable intraparenchymal cyst. We are uncertain whether albendazole reduces seizure recurrence for participants with multiple cysts. We also found that albendazole probably increases radiological clearance and evolution of lesions. There were very few studies reporting praziquantel outcomes, and these findings apply to albendazole only.


Assuntos
Albendazol/uso terapêutico , Anticestoides/uso terapêutico , Encefalopatias/tratamento farmacológico , Neurocisticercose/tratamento farmacológico , Adulto , Anticestoides/efeitos adversos , Viés , Encefalopatias/parasitologia , Encefalopatias/patologia , Criança , Humanos , Neurocisticercose/complicações , Neurocisticercose/patologia , Placebos/uso terapêutico , Praziquantel/efeitos adversos , Praziquantel/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Convulsões/tratamento farmacológico , Convulsões/etiologia
9.
Brain Dev ; 43(9): 919-930, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34120800

RESUMO

OBJECTIVES: Cytotoxic lesions of the corpus callosum (CLOCCs) are secondary lesions associated with entities like infection manifested by restricted diffusion on diffusion-weighted cranial magnetic resonance imaging. Our objectives are to evaluate the clinic-radiological spectrum of pediatric patients with cytotoxic lesions of the corpus callosum (CC). METHODS: Children (0-18 years) admitted between February 2017 and May 2020 with splenial lesions showing diffusion restriction on MRI, either isolated or within involvement of other parts of the brain, were included retrospectively. The primary lesions of the CC (e.g. acute disseminated encephalomyelitis, acute ischemic infarction, and glioblastoma multiforme) were excluded. CLOCCs were divided into infection-associated, metabolic disorder-associated, and trauma-associated lesions, as well as CLOCCs involving other entities. Data were collected from the medical databases. RESULTS: Forty-one patients were determined to have CLOCCs. Twenty-five (61%) were infection-associated, nine (22%) were trauma-associated, and three (7%) were metabolic disorder-associated cases, including 2 inherited disorders of metabolism. There were four (10%) patients with other entities, three with epilepsy, and one had an apparent life-threatening event. Six patients had a known etiology among the infection-associated group; one had multisystem inflammatory syndrome caused by COVID-19 and one had been infected by COVID-19 without any complications. All the infection-associated patients with isolated splenial lesions recovered totally, although six patients required intensive care hospitalization. Four trauma-associated patients had sequela lesions. CONCLUSIONS: CLOCCs are associated with a spectrum of diseases, including the new coronavirus, COVID-19 infection. Infection-associated CLOCCs has the best prognosis, although severe cases may occur. Sequelae are possible based on the etiology.


Assuntos
Encefalopatias/diagnóstico , Encefalopatias/etiologia , Encefalopatias/patologia , COVID-19/complicações , Infecções do Sistema Nervoso Central/complicações , Corpo Caloso/patologia , Adolescente , Criança , Pré-Escolar , Corpo Caloso/diagnóstico por imagem , Imagem de Difusão por Ressonância Magnética , Feminino , Humanos , Lactente , Masculino , Estudos Retrospectivos , Síndrome de Resposta Inflamatória Sistêmica/complicações
10.
Int J Mol Sci ; 22(10)2021 May 12.
Artigo em Inglês | MEDLINE | ID: mdl-34066051

RESUMO

Sudden cardiac arrest leads to a significantly increased risk of severe neurological impairment and higher mortality rates in survivors due to global brain tissue injury caused by prolonged whole-body ischemia and reperfusion. The brain undergoes various deleterious cascading events. Among these damaging mechanisms, neuroinflammation plays an especially crucial role in the exacerbation of brain damage. Clinical guidelines indicate that 33 °C and 36 °C are both beneficial for targeted temperature management (TTM) after cardiac arrest. To clarify the mechanistic relationship between TTM and inflammation in transient global ischemia (TGI) and determine whether 36 °C produces a neuroprotective effect comparable to 33 °C, we performed an experiment using a rat model. We found that TTM at 36 °C and at 33 °C attenuated neuronal cell death and apoptosis, with significant improvements in behavioral function that lasted for up to 72 h. TTM at 33 °C and 36 °C suppressed the propagation of inflammation including the release of high mobility group box 1 from damaged cells, the activation and polarization of the microglia, and the excessive release of activated microglia-induced inflammatory cytokines. There were equal neuroprotective effects for TTM at 36 °C and 33 °C. In addition, hypothermic complications and should be considered safe and effective after cardiac arrest.


Assuntos
Temperatura Corporal , Encefalopatias/terapia , Isquemia Encefálica/complicações , Hipotermia Induzida/métodos , Inflamação/terapia , Animais , Encefalopatias/etiologia , Encefalopatias/patologia , Inflamação/etiologia , Inflamação/patologia , Masculino , Ratos , Ratos Sprague-Dawley
11.
Commun Biol ; 4(1): 614, 2021 05 21.
Artigo em Inglês | MEDLINE | ID: mdl-34021244

RESUMO

Understanding and treating heterogeneous brain disorders requires specialized techniques spanning genetics, proteomics, and neuroimaging. Designed to meet this need, NeuroPM-box is a user-friendly, open-access, multi-tool cross-platform software capable of characterizing multiscale and multifactorial neuropathological mechanisms. Using advanced analytical modeling for molecular, histopathological, brain-imaging and/or clinical evaluations, this framework has multiple applications, validated here with synthetic (N > 2900), in-vivo (N = 911) and post-mortem (N = 736) neurodegenerative data, and including the ability to characterize: (i) the series of sequential states (genetic, histopathological, imaging or clinical alterations) covering decades of disease progression, (ii) concurrent intra-brain spreading of pathological factors (e.g., amyloid, tau and alpha-synuclein proteins), (iii) synergistic interactions between multiple biological factors (e.g., toxic tau effects on brain atrophy), and (iv) biologically-defined patient stratification based on disease heterogeneity and/or therapeutic needs. This freely available toolbox ( neuropm-lab.com/neuropm-box.html ) could contribute significantly to a better understanding of complex brain processes and accelerating the implementation of Precision Medicine in Neurology.


Assuntos
Encefalopatias/patologia , Biologia Computacional/métodos , Proteínas do Tecido Nervoso/metabolismo , Neuroimagem/métodos , Software , Encefalopatias/genética , Encefalopatias/metabolismo , Progressão da Doença , Epigenômica , Humanos , Proteínas do Tecido Nervoso/genética , Proteoma , Transcriptoma
12.
Ann Neurol ; 90(1): 143-158, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33999436

RESUMO

OBJECTIVE: Precursors of peptide hormones undergo posttranslational modifications within the trans-Golgi network (TGN). Dysfunction of proteins involved at different steps of this process cause several complex syndromes affecting the central nervous system (CNS). We aimed to clarify the genetic cause in a group of patients characterized by hypopituitarism in combination with brain atrophy, thin corpus callosum, severe developmental delay, visual impairment, and epilepsy. METHODS: Whole exome sequencing was performed in seven individuals of six unrelated families with these features. Postmortem histopathological and HID1 expression analysis of brain tissue and pituitary gland were conducted in one patient. Functional consequences of the homozygous HID1 variant p.R433W were investigated by Seahorse XF Assay in fibroblasts of two patients. RESULTS: Bi-allelic variants in the gene HID1 domain-containing protein 1 (HID1) were identified in all patients. Postmortem examination confirmed cerebral atrophy with enlarged lateral ventricles. Markedly reduced expression of pituitary hormones was found in pituitary gland tissue. Colocalization of HID1 protein with the TGN was not altered in fibroblasts of patients compared to controls, while the extracellular acidification rate upon stimulation with potassium chloride was significantly reduced in patient fibroblasts compared to controls. INTERPRETATION: Our findings indicate that mutations in HID1 cause an early infantile encephalopathy with hypopituitarism as the leading presentation, and expand the list of syndromic CNS diseases caused by interference of TGN function. ANN NEUROL 2021;90:149-164.


Assuntos
Encefalopatias/genética , Epilepsia/genética , Hipopituitarismo/genética , Alelos , Encefalopatias/patologia , Pré-Escolar , Epilepsia/patologia , Feminino , Humanos , Hipopituitarismo/patologia , Lactente , Masculino , Hipófise/patologia , Sequenciamento Completo do Exoma , Adulto Jovem
13.
Vet Res ; 52(1): 65, 2021 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-33941270

RESUMO

The brain is a complex organ and any model for studying it in its normal and pathological aspects becomes a tool of choice for neuroscientists. The mastering and dissemination of protocols allowing brain organoids development have paved the way for a whole range of new studies in the field of brain development, modeling of neurodegenerative or neurodevelopmental diseases, understanding tumors as well as infectious diseases that affect the brain. While studies are so far limited to the use of human cerebral organoids, there is a growing interest in having similar models in other species. This review presents what is currently developed in this field, with a particular focus on the potential of cerebral organoids for studying neuro-infectious diseases in human and domestic animals.


Assuntos
Animais Domésticos , Encefalopatias , Encéfalo , Organoides , Animais , Encéfalo/patologia , Encéfalo/fisiologia , Encéfalo/fisiopatologia , Encefalopatias/patologia , Encefalopatias/fisiopatologia , Humanos , Organoides/patologia , Organoides/fisiologia , Organoides/fisiopatologia
14.
Biomed Pharmacother ; 139: 111646, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33940509

RESUMO

Out-of-hospital cardiac arrest (CA) is a leading cause of death in the United States. Severe post-resuscitation cerebral dysfunction is a primary cause of poor outcome. Therefore, we investigate the effects of polyethylene glycol-20k (PEG-20k), a cell impermeant, on post-resuscitation cerebral function. Thirty-two male Sprague-Dawley rats were randomized into four groups: 1) Control; 2) PEG-20k; 3) Sham control; 4) Sham with PEG-20k. To investigate blood brain barrier (BBB) permeability, ten additional rats were randomized into two groups: 1) CPR+Evans Blue (EB); 2) Sham+EB. Ventricular fibrillation was induced and untreated for 8 min, followed by 8 min of CPR, and resuscitation was attempted by defibrillation. Cerebral microcirculation was visualized at baseline, 2, 4 and 6 h after return of spontaneous circulation (ROSC). Brain edema was assessed by comparing wet-to-dry weight ratios after 6 h. S-100ß, NSE and EB concentrations were analyzed to determine BBB permeability damage. For results, Post-resuscitation cerebral microcirculation was impaired compared to baseline and sham control (p < 0.05). However, dysfunction was reduced in animals treated with PEG-20k compared to control (p < 0.05). Post-resuscitation cerebral edema as measured by wet-to-dry weight ratio was lower in PEG-20k compared to control (3.23 ±â€¯0.5 vs. 3.36 ±â€¯0.4, p < 0.05). CA and CPR increased BBB permeability and damaged neuronal cell with associated elevation of S-100ß sand NSE serum levels. PEG-20k administered during CPR improved cerebral microcirculation and reducing brain edema and injury.


Assuntos
Encefalopatias/prevenção & controle , Reanimação Cardiopulmonar/efeitos adversos , Parada Cardíaca/terapia , Polietilenoglicóis/farmacologia , Animais , Barreira Hematoencefálica , Encefalopatias/patologia , Edema Encefálico/prevenção & controle , Circulação Cerebrovascular/efeitos dos fármacos , Modelos Animais de Doenças , Cardioversão Elétrica , Eletrocardiografia , Parada Cardíaca/complicações , Masculino , Microcirculação/efeitos dos fármacos , Tamanho do Órgão/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Fibrilação Ventricular
15.
J Cell Mol Med ; 25(12): 5640-5654, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33938133

RESUMO

This study tested the hypothesis that combined therapy with human umbilical cord-derived mesenchymal stem cells (HUCDMSCs) and hyperbaric oxygen (HBO) was superior to either one on preserving neurological function and reducing brain haemorrhagic volume (BHV) in rat after acute intracerebral haemorrhage (ICH) induced by intracranial injection of collagenase. Adult male SD rats (n = 30) were equally divided into group 1 (sham-operated control), group 2 (ICH), group 3 (ICH +HUCDMSCs/1.2 × 106 cells/intravenous injection at 3h and days 1 and 2 after ICH), group 4 (ICH +HBO/at 3 hours and days 1 and 2 after ICH) and group 5 (ICH +HUCDMSCs-HBO), and killed by day 28 after ICH. By day 1, the neurological function was significantly impaired in groups 2-5 than in group 1 (P < .001), but it did not differ among groups 2 to 5. By days 7, 14 and 28, the integrity of neurological function was highest in group 1, lowest in group 2 and significantly progressively improved from groups 3 to 5 (all P < .001). By day 28, the BHV was lowest in group 1, highest in group 2 and significantly lower in group 5 than in groups 3/4 (all P < .0001). The protein expressions of inflammation (HMGB1/TLR-2/TLR-4/MyD88/TRAF6/p-NF-κB/IFN-γ/IL-1ß/TNF-α), oxidative stress/autophagy (NOX-1/NOX-2/oxidized protein/ratio of LC3B-II/LC3B-I) and apoptosis (cleaved-capspase3/PARP), and cellular expressions of inflammation (CD14+, F4/80+) in brain tissues exhibited an identical pattern, whereas cellular levels of angiogenesis (CD31+/vWF+/small-vessel number) and number of neurons (NeuN+) exhibited an opposite pattern of BHV among the groups (all P < .0001). These results indicate that combined HUCDMSC-HBO therapy offered better outcomes after rat ICH.


Assuntos
Encefalopatias/terapia , Oxigenação Hiperbárica/métodos , Inflamação/terapia , Hemorragias Intracranianas/complicações , Transplante de Células-Tronco Mesenquimais/métodos , Células-Tronco Mesenquimais/citologia , Cordão Umbilical/citologia , Animais , Apoptose , Encefalopatias/etiologia , Encefalopatias/patologia , Modelos Animais de Doenças , Inflamação/etiologia , Inflamação/patologia , Masculino , Estresse Oxidativo , Ratos , Ratos Sprague-Dawley
16.
J Alzheimers Dis ; 81(2): 769-785, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33814431

RESUMO

BACKGROUND: Transmissible spongiform encephalopathies (TSEs) are rare neurodegenerative disorders that affect animals and humans. Bovine spongiform encephalopathy (BSE) in cattle, and Creutzfeld-Jakob Disease (CJD) in humans belong to this group. The causative agent of TSEs is called "prion", which corresponds to a pathological form (PrPSc) of a normal cellular protein (PrPC) expressed in nerve cells. PrPSc is resistant to degradation and can induce abnormal folding of PrPC, and TSEs are characterized by extensive spongiosis and gliosis and the presence of PrPSc amyloid plaques. CJD presents initially with clinical symptoms similar to Alzheimer's disease (AD). In AD, tau aggregates and amyloid-ß protein plaques are associated with memory loss and cognitive impairment in patients. OBJECTIVE: In this work, we study the role of tau and its relationship with PrPSc plaques in CJD. METHODS: Multiple immunostainings with specific antibodies were carried out and analyzed by confocal microscopy. RESULTS: We found increased expression of the glial fibrillary acidic protein (GFAP) and matrix metalloproteinase (MMP-9), and an exacerbated apoptosis in the granular layer in cases with prion disease. In these cases, tau protein phosphorylated at Thr-231 was overexpressed in the axons and dendrites of Purkinje cells and the extensions of parallel fibers in the cerebellum. CONCLUSION: We conclude that phosphorylation of tau may be a response to a toxic and inflammatory environment generated by the pathological form of prion.


Assuntos
Cerebelo/metabolismo , Síndrome de Creutzfeldt-Jakob/patologia , Doenças Priônicas/patologia , Proteínas tau/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Encefalopatias/metabolismo , Encefalopatias/patologia , Bovinos , Cerebelo/patologia , Síndrome de Creutzfeldt-Jakob/metabolismo , Encefalopatia Espongiforme Bovina/metabolismo , Encefalopatia Espongiforme Bovina/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doenças Priônicas/metabolismo , Treonina/metabolismo
17.
FASEB J ; 35(5): e21568, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33817875

RESUMO

The neuronal Na+ -activated K+ channel Slack (aka Slo2.2, KNa 1.1, or Kcnt1) has been implicated in setting and maintaining the resting membrane potential and defining excitability and firing patterns, as well as in the generation of the slow afterhyperpolarization following bursts of action potentials. Slack activity increases significantly under conditions of high intracellular Na+ levels, suggesting this channel may exert important pathophysiological functions. To address these putative roles, we studied whether Slack K+ channels contribute to pathological changes and excitotoxic cell death caused by glutamatergic overstimulation of Ca2+ - and Na+ -permeable N-methyl-D-aspartic acid receptors (NMDAR). Slack-deficient (Slack KO) and wild-type (WT) mice were subjected to intrastriatal microinjections of the NMDAR agonist NMDA. NMDA-induced brain lesions were significantly increased in Slack KO vs WT mice, suggesting that the lack of Slack renders neurons particularly susceptible to excitotoxicity. Accordingly, excessive neuronal cell death was seen in Slack-deficient primary cerebellar granule cell (CGC) cultures exposed to glutamate and NMDA. Differences in neuronal survival between WT and Slack KO CGCs were largely abolished by the NMDAR antagonist MK-801, but not by NBQX, a potent and highly selective competitive antagonist of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type ionotropic glutamate receptors. Interestingly, NMDAR-evoked Ca2+ signals did not differ with regard to Slack genotype in CGCs. However, real-time monitoring of K+ following NMDAR activation revealed a significant contribution of this channel to the intracellular drop in K+ . Finally, TrkB and TrkC neurotrophin receptor transcript levels were elevated in NMDA-exposed Slack-proficient CGCs, suggesting a mechanism by which this K+ channel contributes to the activation of the extracellular-signal-regulated kinase (Erk) pathway and thereby to neuroprotection. Combined, our findings suggest that Slack-dependent K+ signals oppose the NMDAR-mediated excitotoxic neuronal injury by promoting pro-survival signaling via the BDNF/TrkB and Erk axis.


Assuntos
Potenciais de Ação , Encefalopatias/prevenção & controle , Morte Celular , N-Metilaspartato/toxicidade , Proteínas do Tecido Nervoso/fisiologia , Neurônios/citologia , Canais de Potássio Ativados por Sódio/fisiologia , Animais , Encefalopatias/induzido quimicamente , Encefalopatias/metabolismo , Encefalopatias/patologia , Células Cultivadas , Agonistas de Aminoácidos Excitatórios/toxicidade , Ácido Glutâmico/metabolismo , Masculino , Potenciais da Membrana , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neurônios/metabolismo , Neurônios/patologia , Transdução de Sinais
18.
Signal Transduct Target Ther ; 6(1): 169, 2021 04 24.
Artigo em Inglês | MEDLINE | ID: mdl-33895780

RESUMO

Neurological manifestations are frequently reported in the COVID-19 patients. Neuromechanism of SARS-CoV-2 remains to be elucidated. In this study, we explored the mechanisms of SARS-CoV-2 neurotropism via our established non-human primate model of COVID-19. In rhesus monkey, SARS-CoV-2 invades the CNS primarily via the olfactory bulb. Thereafter, viruses rapidly spread to functional areas of the central nervous system, such as hippocampus, thalamus, and medulla oblongata. The infection of SARS-CoV-2 induces the inflammation possibly by targeting neurons, microglia, and astrocytes in the CNS. Consistently, SARS-CoV-2 infects neuro-derived SK-N-SH, glial-derived U251, and brain microvascular endothelial cells in vitro. To our knowledge, this is the first experimental evidence of SARS-CoV-2 neuroinvasion in the NHP model, which provides important insights into the CNS-related pathogenesis of SARS-CoV-2.


Assuntos
Encefalopatias/metabolismo , Encéfalo/metabolismo , COVID-19/metabolismo , Bulbo Olfatório/metabolismo , SARS-CoV-2/metabolismo , Animais , Astrócitos/metabolismo , Astrócitos/patologia , Astrócitos/virologia , Encéfalo/patologia , Encéfalo/virologia , Encefalopatias/patologia , Encefalopatias/virologia , COVID-19/patologia , Modelos Animais de Doenças , Humanos , Macaca mulatta , Microglia/metabolismo , Microglia/patologia , Microglia/virologia , Neurônios/metabolismo , Neurônios/patologia , Neurônios/virologia , Bulbo Olfatório/patologia , Bulbo Olfatório/virologia
19.
Int J Mol Sci ; 22(7)2021 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-33916769

RESUMO

The blood-brain barrier (BBB) is a highly selective and restrictive semipermeable network of cells and blood vessel constituents. All components of the neurovascular unit give to the BBB its crucial and protective function, i.e., to regulate homeostasis in the central nervous system (CNS) by removing substances from the endothelial compartment and supplying the brain with nutrients and other endogenous compounds. Many transporters have been identified that play a role in maintaining BBB integrity and homeostasis. As such, the restrictive nature of the BBB provides an obstacle for drug delivery to the CNS. Nevertheless, according to their physicochemical or pharmacological properties, drugs may reach the CNS by passive diffusion or be subjected to putative influx and/or efflux through BBB membrane transporters, allowing or limiting their distribution to the CNS. Drug transporters functionally expressed on various compartments of the BBB involve numerous proteins from either the ATP-binding cassette (ABC) or the solute carrier (SLC) superfamilies. Pathophysiological stressors, age, and age-associated disorders may alter the expression level and functionality of transporter protein elements that modulate drug distribution and accumulation into the brain, namely, drug efficacy and toxicity. This review focuses and sheds light on the influence of inflammatory conditions and diseases such as Alzheimer's disease, epilepsy, and stroke on the expression and functionality of the BBB drug transporters, the consequential modulation of drug distribution to the brain, and their impact on drug efficacy and toxicity.


Assuntos
Transportadores de Cassetes de Ligação de ATP/metabolismo , Barreira Hematoencefálica/metabolismo , Encefalopatias , Sistemas de Liberação de Medicamentos , Endotélio Vascular/metabolismo , Proteínas Carreadoras de Solutos/metabolismo , Barreira Hematoencefálica/patologia , Encefalopatias/tratamento farmacológico , Encefalopatias/metabolismo , Encefalopatias/patologia , Endotélio Vascular/patologia , Humanos
20.
Int J Mol Sci ; 22(6)2021 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-33809675

RESUMO

Microglia are the resident immune cells of the central nervous system (CNS) that have distinct ontogeny from other tissue macrophages and play a pivotal role in health and disease. Microglia rapidly react to the changes in their microenvironment. This plasticity is attributed to the ability of microglia to adapt a context-specific phenotype. Numerous gene expression profiling studies of immunosorted CNS immune cells did not permit a clear dissection of their phenotypes, particularly in diseases when peripheral cells of the immune system come to play. Only recent advances in single-cell technologies allowed studying microglia at high resolution and revealed a spectrum of discrete states both under homeostatic and pathological conditions. Single-cell technologies such as single-cell RNA sequencing (scRNA-seq) and mass cytometry (Cytometry by Time-Of-Flight, CyTOF) enabled determining entire transcriptomes or the simultaneous quantification of >30 cellular parameters of thousands of individual cells. Single-cell omics studies demonstrated the unforeseen heterogeneity of microglia and immune infiltrates in brain pathologies: neurodegenerative disorders, stroke, depression, and brain tumors. We summarize the findings from those studies and the current state of knowledge of functional diversity of microglia under physiological and pathological conditions. A precise definition of microglia functions and phenotypes may be essential to design future immune-modulating therapies.


Assuntos
Encefalopatias/patologia , Encéfalo/patologia , Genômica , Microglia/patologia , Análise de Célula Única , Animais , Encefalopatias/terapia , Humanos , Degeneração Neural/patologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...