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1.
Medicine (Baltimore) ; 99(40): e22353, 2020 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-33019412

RESUMO

INTRODUCTION: Increasing evidences showed differential expression of circulating microRNAs (miRNAs) in patients with acute ischemic stroke (AIS), indicating that miRNAs might serve as promising biomakers in the diagnosis of AIS. However, their accuracy has not been systematically evaluated, so it is necessary to conducted a meta-analysis to evaluate the diagnostic value of miRNAs in AIS patients. METHODS: PubMed, EMBASE, Cochrane Library, Web of Science, Medline, China National Knowledge Infrastructure (CNKI) will be searched for the relevant studies that explored the potential diagnostic values of miRNAs in AIS patients from inception to August 2020. Data will be extracted by two researchers independently; risk of bias of the meta-analysis will be evaluated by the Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2). Data will be synthesised and heterogeneity will be evaluated. All of the above statistical analysis will be performed using Stata V.15.0 and Meta-disc V.1.4. RESULTS: This study will assess the pooled diagnostic performance of circulating miRNAs in AIS. CONCLUSION: This study will clarify confusions about the specificity and sensitivity of circulating miRNAs in diagnosing AIS, which could further guide the promotion and application of them.Open Science Framework (OSF) registration number: 2020, August 19. https://osf.io/6tjf3.


Assuntos
Isquemia Encefálica/sangue , Isquemia Encefálica/diagnóstico , MicroRNA Circulante/sangue , Acidente Vascular Cerebral/sangue , Acidente Vascular Cerebral/diagnóstico , Isquemia Encefálica/patologia , Humanos , Projetos de Pesquisa , Sensibilidade e Especificidade , Acidente Vascular Cerebral/patologia
2.
Korean J Parasitol ; 58(4): 461-466, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32871641

RESUMO

Toxoplasma gondii is an obligate intracellular protozoan parasite that can invade various organs in the host body, including the central nervous system. Chronic intracranial T. gondii is known to be associated with neuroprotection against neurodegenerative diseases through interaction with host brain cells in various ways. The present study investigated the neuroprotective effects of chronic T. gondii infection in mice with cerebral ischemia experimentally produced by middle cerebral artery occlusion (MCAO) surgery. The neurobehavioral effects of cerebral ischemia were assessed by measurement of Garcia score and Rotarod behavior tests. The volume of brain ischemia was measured by triphenyltetrazolium chloride staining. The expression levels of related genes and proteins were determined. After cerebral ischemia, corrected infarction volume was significantly reduced in T. gondii infected mice, and their neurobehavioral function was significantly better than that of the uninfection control group. Chronic T. gondii infection induced the expression of hypoxia-inducible factor 1-alpha (HIF-1α) in the brain before MCAO. T. gondii infection also increased the expression of vascular endothelial growth factor after the cerebral ischemia. It is suggested that chronic intracerebral infection of T. gondii may be a potential preconditioning strategy to reduce neural deficits associated with cerebral ischemia and induce brain ischemic tolerance through the regulation of HIF-1α expression.


Assuntos
Isquemia Encefálica/prevenção & controle , Encéfalo/parasitologia , Interações Hospedeiro-Parasita , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Neuroproteção , Toxoplasma/fisiologia , Toxoplasmose/fisiopatologia , Animais , Encéfalo/citologia , Encéfalo/metabolismo , Encéfalo/patologia , Isquemia Encefálica/parasitologia , Isquemia Encefálica/patologia , Modelos Animais de Doenças , Expressão Gênica , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Camundongos Endogâmicos ICR , Tamanho do Órgão , Toxoplasmose/metabolismo , Toxoplasmose/patologia
3.
Medicine (Baltimore) ; 99(36): e22054, 2020 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-32899067

RESUMO

BACKGROUND: Anticoagulant therapy is used for stroke prevention and proved to be effective and safe in the long term. The study aims to analyse the cost-effectiveness relationship of using of direct-acting oral anticoagulants vs vitamin K antagonists to prevent ischaemic stroke in patients with nonvalvular atrial fibrillation, including all the active ingredients marketed in Spain, prescribed for 2 years in the Primary Care service of the Institut Català de la Salut. METHODS: Population-based cohort study, in which the cost of the 2 treatment groups will be evaluated. Direct costs (pharmacy, primary care, emergency and hospitalization) and indirect costs (lost productivity) will be included from a social perspective. Effectiveness (assessed as the occurrence of a health event, the 1 of primary interest being stroke) will be determined, with a 2-year time horizon and a 3% discount rate. The average cost of the 2 groups of drugs will be compared using a regression model to determine the factors with the greatest influence on determining costs. We will carry out a univariate ('one-way') deterministic sensitivity analysis. DISCUSSION: We hope to provide relevant information about direct and indirect costs of oral anticoagulants, which, together with aspects of effectiveness and safety, could help shape the consensual decision-making of evaluating bodies.


Assuntos
Acenocumarol/economia , Anticoagulantes/economia , Fibrilação Atrial/tratamento farmacológico , Isquemia Encefálica/patologia , Ensaios Clínicos Pragmáticos como Assunto/métodos , Varfarina/economia , Acenocumarol/administração & dosagem , Acenocumarol/uso terapêutico , Administração Oral , Anticoagulantes/administração & dosagem , Anticoagulantes/uso terapêutico , Fibrilação Atrial/complicações , Fibrilação Atrial/epidemiologia , Isquemia Encefálica/prevenção & controle , Análise Custo-Benefício , Inibidores do Fator Xa , Humanos , Atenção Primária à Saúde/organização & administração , Segurança , Espanha/epidemiologia , Acidente Vascular Cerebral/prevenção & controle , Resultado do Tratamento , Vitamina K/antagonistas & inibidores , Varfarina/administração & dosagem , Varfarina/uso terapêutico
4.
Am J Chin Med ; 48(6): 1331-1351, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32907361

RESUMO

Panax notoginseng is the most widely used Chinese medicinal herb for the prevention and treatment of ischemic diseases. Its main active ingredients are saponins, including ginsenoside Rb1, ginsenoside Rg1, and notoginsenoside R1, among others. This review provides an up-to-date overview on the pharmacological roles of P. notoginseng constituents in cerebral ischemia. The saponins of P. notoginseng induce a variety of pharmacological effects in the multiscale mechanisms of cerebral ischemic pathophysiology, including anti-inflammatory activity, reduction of oxidative stress, anti-apoptosis, inhibition of amino acid excitotoxicity, reduction of intracellular calcium overload, protection of mitochondria, repairing the blood-brain barrier, and facilitation of cell regeneration. Regarding cell regeneration, P. notoginseng not only promotes the proliferation and differentiation of neural stem cells, but also protects neurons, endothelial cells and astrocytes in cerebral ischemia. In conclusion, P. notoginseng may treat cerebrovascular diseases through multiple pharmacological effects, and the most critical ones need further investigation.


Assuntos
Isquemia Encefálica/tratamento farmacológico , Ginsenosídeos/farmacologia , Ginsenosídeos/uso terapêutico , Panax notoginseng/química , Fitoterapia , Saponinas/farmacologia , Saponinas/uso terapêutico , Aminoácidos/toxicidade , Animais , Anti-Inflamatórios , Antioxidantes , Apoptose/efeitos dos fármacos , Barreira Hematoencefálica/patologia , Isquemia Encefálica/etiologia , Isquemia Encefálica/patologia , Isquemia Encefálica/prevenção & controle , Cálcio/metabolismo , Autorrenovação Celular/efeitos dos fármacos , Depuradores de Radicais Livres , Ginsenosídeos/isolamento & purificação , Humanos , Fármacos Neuroprotetores , Estresse Oxidativo/efeitos dos fármacos , Saponinas/isolamento & purificação
5.
Nat Commun ; 11(1): 4078, 2020 08 25.
Artigo em Inglês | MEDLINE | ID: mdl-32843630

RESUMO

Acute stroke causes complex, pathological, and systemic responses that have not been treatable by any single medication. In this study, using a murine transient middle cerebral artery occlusion stroke model, a novel therapeutic strategy is proposed, where blood replacement (BR) robustly reduces infarctions and improves neurological deficits in mice. Our analyses of immune cell subsets suggest that BR therapy substantially decreases neutrophils in blood following a stroke. Electrochemiluminescence detection demonstrates that BR therapy reduces cytokine storm in plasma and ELISA demonstrates reduced levels of matrix metalloproteinase-9 (MMP-9) in the plasma and brains at different time points post-stroke. Further, we have demonstrated that the addition of MMP-9 to the blood diminishes the protective effect of the BR therapy. Our study is the first to show that BR therapy leads to profoundly improved stroke outcomes in mice and that the improved outcomes are mediated via MMP-9. These results offer new insights into the mechanisms of stroke damage.


Assuntos
Substitutos Sanguíneos/uso terapêutico , Isquemia Encefálica/tratamento farmacológico , Encéfalo/metabolismo , Animais , Encéfalo/patologia , Infarto Encefálico/tratamento farmacológico , Isquemia Encefálica/patologia , Morte Celular , Citocinas/metabolismo , Modelos Animais de Doenças , Infarto da Artéria Cerebral Média/complicações , Masculino , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Neutrófilos/metabolismo , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/patologia
6.
Nature ; 585(7823): 91-95, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32788726

RESUMO

Signalling between cells of the neurovascular unit, or neurovascular coupling, is essential to match local blood flow with neuronal activity. Pericytes interact with endothelial cells and extend processes that wrap capillaries, covering up to 90% of their surface area1,2. Pericytes are candidates to regulate microcirculatory blood flow because they are strategically positioned along capillaries, contain contractile proteins and respond rapidly to neuronal stimulation3,4, but whether they synchronize microvascular dynamics and neurovascular coupling within a capillary network was unknown. Here we identify nanotube-like processes that connect two bona fide pericytes on separate capillary systems, forming a functional network in the mouse retina, which we named interpericyte tunnelling nanotubes (IP-TNTs). We provide evidence that these (i) have an open-ended proximal side and a closed-ended terminal (end-foot) that connects with distal pericyte processes via gap junctions, (ii) carry organelles including mitochondria, which can travel along these processes, and (iii) serve as a conduit for intercellular Ca2+ waves, thus mediating communication between pericytes. Using two-photon microscope live imaging, we demonstrate that retinal pericytes rely on IP-TNTs to control local neurovascular coupling and coordinate light-evoked responses between adjacent capillaries. IP-TNT damage following ablation or ischaemia disrupts intercellular Ca2+ waves, impairing blood flow regulation and neurovascular coupling. Notably, pharmacological blockade of Ca2+ influx preserves IP-TNTs, rescues light-evoked capillary responses and restores blood flow after reperfusion. Our study thus defines IP-TNTs and characterizes their critical role in regulating neurovascular coupling in the living retina under both physiological and pathological conditions.


Assuntos
Nanotubos , Acoplamento Neurovascular , Pericitos/metabolismo , Animais , Isquemia Encefálica/metabolismo , Isquemia Encefálica/patologia , Cálcio/metabolismo , Sinalização do Cálcio , Capilares/fisiopatologia , Capilares/efeitos da radiação , Comunicação Celular , Feminino , Junções Comunicantes/metabolismo , Hemodinâmica , Masculino , Camundongos , Mitocôndrias/metabolismo , Acoplamento Neurovascular/fisiologia , Pericitos/citologia , Pericitos/patologia , Retina/citologia , Retina/patologia
8.
Stroke ; 51(9): e223-e226, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32684144

RESUMO

BACKGROUND AND PURPOSE: Ischemic infarction of the corpus callosum is rare and infarction isolated to the corpus callosum alone rarer still, accounting for much <1% of ischemic stroke in most stroke registries. About half of callosal infarctions affect the splenium. METHODS: During a 2-week period, at the height of the coronavirus disease 2019 (COVID-19) pandemic in New York City, 4 patients at Montefiore Medical Center in the Bronx were found to have ischemic lesions of the splenium of the corpus callosum, 2 with infarction isolated to the corpus callosum. RESULTS: All patients tested positive for COVID-19 and 3 had prolonged periods of intubation. All had cardiovascular risk factors. Clinically, all presented with encephalopathy and had evidence of coagulopathy and raised inflammatory markers. CONCLUSIONS: Infarction of the splenium of the corpus callosum is exceedingly rare and a cluster of such cases suggests COVID-19 as an inciting agent, with the mechanisms to be elucidated.


Assuntos
Infarto Cerebral/complicações , Infarto Cerebral/patologia , Infecções por Coronavirus/complicações , Corpo Caloso/patologia , Pneumonia Viral/complicações , Idoso , Idoso de 80 Anos ou mais , Isquemia Encefálica/complicações , Isquemia Encefálica/patologia , Complicações do Diabetes/complicações , Evolução Fatal , Feminino , Humanos , Hipertensão/complicações , Hipotireoidismo/complicações , Inflamação/sangue , Intubação Intratraqueal , Pessoa de Meia-Idade , Pandemias , Fatores de Risco , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/patologia , Reabilitação do Acidente Vascular Cerebral
9.
Int. j. morphol ; 38(3): 523-529, June 2020. graf
Artigo em Inglês | LILACS | ID: biblio-1098282

RESUMO

This study aimed to investigate the morphometric and the pattern of protein and gene expression related to the extrinsic apoptotic pathway in experimental focal cerebral ischemia and the hole of neuroprotection with hypothermia and ketoprofen. For this analysis, 120 rats were randomly divided into 3 groups (20 animals each): control - no surgery (20 animals); sham - simulation of surgery (20 animals); ischemic - focal ischemia for 1 hour, without reperfusion (80 animals) and divided into four subgroups with 20 animals each: ischemic + intraischemic hypothermia; ischemic + previous intravenous ketoprofen, and ischemic + hypothermia and ketoprofen. The infarct volume was measured using morphometric analysis of infarct areas defined by triphenyl tetrazolium chloride and the patterns of expression of the apoptosis genes (Fas, c-Flip, caspase-8 and caspase-3) and the apoptosis protein caspase-3 were evaluated by quantitative real-time PCR and immunohistochemistry, respectively. Hypo expression of genes of extrinsic pathway of apoptosis was observed: Fas receptor, c-Flip and caspase-8 in the ischemics areas. Increases in the gene and protein caspase-3 in the ischemic areas were also observed, and these increases were reduced by hypothermia and ketoprofen, also noted in the morphometric study. The caspases-3 increase suggests that this gene plays an important role in apoptosis, probably culminating in cell death and that the neuroprotective effect of hypothermia and ketoprofen is involved.


Este estudio tuvo como objetivo investigar la morfometría y el patrón de expresión de proteínas y genes relacionados con la vía apoptótica extrínseca en la isquemia cerebral focal experimental y el agujero de neuroprotección con hipotermia y ketoprofeno. Se dividieron aleatoriamente 120 ratas en 3 grupos (20 animales cada uno): control - sin cirugía (20 animales); simulación - simulación de cirugía (20 animales); isquemia isquemia focal durante 1 hora, sin reperfusión (80 animales) y dividida en cuatro subgrupos con 20 animales cada uno: isquemia + hipotermia intraisquémica; isquemia + ketoprofeno intravenoso previo, e isquemia + hipotermia y ketoprofeno. El volumen del infarto se midió utilizando un análisis morfométrico de áreas de infarto definidas por cloruro de trifenil tetrazolio y los patrones de expresión de los genes de apoptosis (Fas, c-Flip, caspase-8 y caspase-3) y la proteína de apoptosis caspase-3 fueron evaluados por PCR cuantitativa en tiempo real e inmunohistoquímica, respectivamente. Se observó hipoexpresión de genes de la vía extrínseca de la apoptosis: receptor Fas, c-Flip y caspasa-8 en las áreas isquémicas. También se observaron aumentos en el gen y la proteína caspasa-3 en las áreas isquémicas y estos aumentos se redujeron por hipotermia y ketoprofeno, también observado por estudio morfométrico. El aumento de caspasas-3 sugiere que este gen tiene un papel importante en la apoptosis, y probable causa de muerte celular, involucrando el efecto neuroprotector de la hipotermia y el ketoprofeno.


Assuntos
Animais , Ratos , Isquemia Encefálica/genética , Isquemia Encefálica/metabolismo , Imuno-Histoquímica , Isquemia Encefálica/patologia , Isquemia Encefálica/terapia , Cetoprofeno/farmacologia , Apoptose/genética , Fármacos Neuroprotetores/farmacologia , Modelos Animais de Doenças , Caspase 3/genética , Caspase 8/genética , Reação em Cadeia da Polimerase em Tempo Real , Hipotermia Induzida
10.
Medicine (Baltimore) ; 99(24): e20351, 2020 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-32541457

RESUMO

BACKGROUND: This study will systematically synthesize the evidence on the potential association between non-alcoholic fatty liver (NAFL) and acute cerebral infarction (ACI). METHODS: We will propose literature search in electronic databases (MEDLINE, EMBASE, Cochrane Library, Scopus, Web of Science, WANGFANG, and China National Knowledge Infrastructure) from the source to March 1, 2020. There are no restrictions related to the language and publication status. Two review authors will separately carry out records selection, data extraction and study quality assessment. Any divisions will be solved by discussion with consulting a third review author. We will use RevMan 5.3 software to perform data analysis. RESULTS: The present study will afford additional insight into the investigation the association between NAFL and ACI. CONCLUSION: The results of this study will provide helpful evidence to explore the association between NAFL and ACI.Study registration number: INPLASY202040102.


Assuntos
Isquemia Encefálica/patologia , Infarto Cerebral/complicações , Hepatopatia Gordurosa não Alcoólica/complicações , Doença Aguda , Infarto Cerebral/epidemiologia , China/epidemiologia , Feminino , Humanos , Masculino , Hepatopatia Gordurosa não Alcoólica/epidemiologia , Avaliação de Resultados em Cuidados de Saúde
11.
J Clin Neurosci ; 78: 418-419, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32522486

RESUMO

A6-year-oldgirl presented with acute-onset headache andfluctuating right-sided weakness.HerPedNIHSSwas13. Brain MRI/MRA showed acute pontine arterial ischemic stroke(AIS)and remote right cerebellar and thalamic infarcts.No antecedent trauma or other stroke risk factors were identified. Clinical suspicion of bow hunter syndromewas raised. CTshowed congenital C2-C3 fusion and dynamic angiogramconfirmed the diagnosis. The management challenges of this rare condition are discussed below.


Assuntos
Mucopolissacaridose II/complicações , Acidente Vascular Cerebral/etiologia , Isquemia Encefálica/etiologia , Isquemia Encefálica/patologia , Criança , Gerenciamento Clínico , Feminino , Humanos , Angiografia por Ressonância Magnética , Imagem por Ressonância Magnética/efeitos adversos , Acidente Vascular Cerebral/patologia , Artéria Vertebral/patologia , Insuficiência Vertebrobasilar/complicações
12.
Neurology ; 95(1): e79-e88, 2020 07 07.
Artigo em Inglês | MEDLINE | ID: mdl-32493718

RESUMO

OBJECTIVE: To examine etiologic stroke subtypes and vascular risk factor profiles and their association with white matter hyperintensity (WMH) burden in patients hospitalized for acute ischemic stroke (AIS). METHODS: For the MRI Genetics Interface Exploration (MRI-GENIE) study, we systematically assembled brain imaging and phenotypic data for 3,301 patients with AIS. All cases underwent standardized web tool-based stroke subtyping with the Causative Classification of Ischemic Stroke (CCS). WMH volume (WMHv) was measured on T2 brain MRI scans of 2,529 patients with a fully automated deep-learning trained algorithm. Univariable and multivariable linear mixed-effects modeling was carried out to investigate the relationship of vascular risk factors with WMHv and CCS subtypes. RESULTS: Patients with AIS with large artery atherosclerosis, major cardioembolic stroke, small artery occlusion (SAO), other, and undetermined causes of AIS differed significantly in their vascular risk factor profile (all p < 0.001). Median WMHv in all patients with AIS was 5.86 cm3 (interquartile range 2.18-14.61 cm3) and differed significantly across CCS subtypes (p < 0.0001). In multivariable analysis, age, hypertension, prior stroke, smoking (all p < 0.001), and diabetes mellitus (p = 0.041) were independent predictors of WMHv. When adjusted for confounders, patients with SAO had significantly higher WMHv compared to those with all other stroke subtypes (p < 0.001). CONCLUSION: In this international multicenter, hospital-based cohort of patients with AIS, we demonstrate that vascular risk factor profiles and extent of WMH burden differ by CCS subtype, with the highest lesion burden detected in patients with SAO. These findings further support the small vessel hypothesis of WMH lesions detected on brain MRI of patients with ischemic stroke.


Assuntos
Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/patologia , Substância Branca/patologia , Idoso , Idoso de 80 Anos ou mais , Arteriopatias Oclusivas/complicações , Isquemia Encefálica/diagnóstico por imagem , Isquemia Encefálica/etiologia , Isquemia Encefálica/patologia , Aprendizado Profundo , Feminino , Humanos , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco , Acidente Vascular Cerebral/diagnóstico por imagem , Substância Branca/diagnóstico por imagem
13.
Am J Physiol Cell Physiol ; 319(2): C381-C391, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32491927

RESUMO

Several microRNAs (miRNAs or miRs) regulate cerebral ischemic injury outcomes; however, little is known about the role of miR-539-5p during cerebral ischemic injury or the postischemic state. Cerebral ischemic injury was modeled in vitro by exposing human cortical neurons to oxygen-glucose deprivation (OGD) and in vivo by occluding the middle cerebral artery (MCAO) in a rat model. The effects of miR-539-5p, histone deacetylase 1 (HDAC1), and early growth response 2 (EGR2) on cerebral ischemia were investigated using gain- and loss-of-function experiments. We identified changes in miR-539-5p, HDAC1, EGR2, and phosphorylated c-Jun NH2-terminal kinase (JNK). The interaction among miR-539-5p, HDAC1, and EGR2 was determined by dual luciferase reporter gene assay, chromatin immunoprecipitation, and coimmunoprecipitation. We also investigated the effects on cell viability and apoptosis and changes in inflammatory cytokine expression and spatial memory on MCAO rats. miR-539-5p and EGR2 were poorly expressed, while HDAC1 was highly expressed in OGD-treated HCN-2 cells. miR-539-5p targeted HDAC1, while HDAC1 prevented acetylation of EGR2 resulting in its downregulation and subsequent activation of the JNK pathway. Overexpression of miR-539-5p or EGR2 or silencing HDAC1 improved viability and reduced apoptosis of OGD-treated HCN-2 cells in vitro. Furthermore, overexpression of miR-539-5p improved spatial memory, while decreasing cell apoptosis and inflammation in MCAO rats. Collectively, these data suggest that miR-539-5p targets HDAC1 to upregulate EGR2, thus blocking the JNK signaling pathway, by which cerebral ischemic injury is alleviated.


Assuntos
Isquemia Encefálica/genética , Histona Desacetilase 1/genética , MicroRNAs/genética , Animais , Apoptose/genética , Isquemia Encefálica/patologia , Citocinas/metabolismo , Progressão da Doença , Proteína 2 de Resposta de Crescimento Precoce/genética , Regulação da Expressão Gênica/genética , Glucose/metabolismo , Humanos , Inflamação/genética , Artéria Cerebral Média/lesões , Artéria Cerebral Média/patologia , Neurônios/metabolismo , Neurônios/patologia , Ratos
14.
Nature ; 582(7812): 395-398, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32494010

RESUMO

Neuroprotectant strategies that have worked in rodent models of stroke have failed to provide protection in clinical trials. Here we show that the opposite circadian cycles in nocturnal rodents versus diurnal humans1,2 may contribute to this failure in translation. We tested three independent neuroprotective approaches-normobaric hyperoxia, the free radical scavenger α-phenyl-butyl-tert-nitrone (αPBN), and the N-methyl-D-aspartic acid (NMDA) antagonist MK801-in mouse and rat models of focal cerebral ischaemia. All three treatments reduced infarction in day-time (inactive phase) rodent models of stroke, but not in night-time (active phase) rodent models of stroke, which match the phase (active, day-time) during which most strokes occur in clinical trials. Laser-speckle imaging showed that the penumbra of cerebral ischaemia was narrower in the active-phase mouse model than in the inactive-phase model. The smaller penumbra was associated with a lower density of terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL)-positive dying cells and reduced infarct growth from 12 to 72 h. When we induced circadian-like cycles in primary mouse neurons, deprivation of oxygen and glucose triggered a smaller release of glutamate and reactive oxygen species, as well as lower activation of apoptotic and necroptotic mediators, in 'active-phase' than in 'inactive-phase' rodent neurons. αPBN and MK801 reduced neuronal death only in 'inactive-phase' neurons. These findings suggest that the influence of circadian rhythm on neuroprotection must be considered for translational studies in stroke and central nervous system diseases.


Assuntos
Relógios Circadianos/fisiologia , Ritmo Circadiano/fisiologia , Modelos Animais de Doenças , Neurônios/patologia , Neuroproteção , Acidente Vascular Cerebral/patologia , Acidente Vascular Cerebral/prevenção & controle , Animais , Isquemia Encefálica/patologia , Isquemia Encefálica/fisiopatologia , Isquemia Encefálica/prevenção & controle , Glucose/deficiência , Humanos , Infarto da Artéria Cerebral Média/patologia , Infarto da Artéria Cerebral Média/fisiopatologia , Infarto da Artéria Cerebral Média/prevenção & controle , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Oxigênio , Ratos , Ratos Sprague-Dawley , Reprodutibilidade dos Testes , Acidente Vascular Cerebral/fisiopatologia , Pesquisa Médica Translacional , Falha de Tratamento
15.
Medicine (Baltimore) ; 99(20): e20178, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32443336

RESUMO

BACKGROUND: The objective of this study is to examine the association between serum lipoprotein levels (SLL) and cognitive impairment (CI) in patients with acute cerebral infarction (ACI). METHODS: All published studies will be searched from the following electronic databases: PubMed, EMBASE, Cochrane Library, PsycINFO, Web of Science, WANGFANG, and China National Knowledge Infrastructure from inauguration of each electronic database up to March 1, 2020. In addition, we will also search other sources, such as dissertations, Google scholar, conference proceedings, and reference lists of relevant reviews. We will not apply any language restrictions to the electronic databases. Two researchers will independently carry out literature selection, data collection, and methodological quality. A third researcher will help to solve any divergences by discussion. The RevMan 5.3 software will be employed to pool the collected data and to analyze the outcome data. RESULTS: This study will scrutinize the association between SLL and CI in patients with ACI. CONCLUSIONS: The results of this study will present helpful evidence of the association between SLL and CI in patients with ACI.Registration number: INPLASY202040018.


Assuntos
Isquemia Encefálica/patologia , Infarto Cerebral/complicações , Disfunção Cognitiva/etiologia , Lipoproteínas/sangue , Doença Aguda , Infarto Cerebral/epidemiologia , China/epidemiologia , Disfunção Cognitiva/sangue , Feminino , Humanos , Masculino , Sensibilidade e Especificidade
16.
Stroke ; 51(6): 1835-1843, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32397936

RESUMO

Background and Purpose- oxLDL (oxidized low-density lipoprotein) has been known for its potential to induce endothelial dysfunction and used as a major serological marker of oxidative stress. Recently, LOX-1 (lectin-like oxidized low-density lipoprotein receptor-1), a lectin-like receptor for oxLDL, has attracted attention in studies of neuronal apoptosis and stroke. We aim to investigate the impact of LOX-1-deficiency on spontaneous hypertension-related brain damage in the present study. Methods- We generated a LOX-1 deficient strain on the genetic background of stroke-prone spontaneously hypertensive rat (SHRSP), an animal model of severe hypertension and spontaneous stroke. In this new disease model with stroke-proneness, we monitored the occurrence of brain abnormalities with and without salt loading by multiple procedures including T2 weighted magnetic resonance imaging and also explored circulatory miRNAs as diagnostic biomarkers for cerebral ischemic injury by microarray analysis. Results- Both T2 weighted magnetic resonance imaging abnormalities and physiological parameter changes could be detected at significantly delayed timing in LOX-1 knockout rats compared with wild-type SHRSP, in either case of normal rat chow and salt loading (P<0.005 in all instances; n=11-20 for SHRSP and n=13-23 for LOX-1 knockout rats). There were no significant differences in the form of magnetic resonance imaging findings between the strains. A number of miRNAs expressed in the normal rat plasma, including rno-miR-150-5p and rno-miR-320-3p, showed significant changes after spontaneous brain damage in SHRSP, whereas the corresponding changes were modest or almost unnoticeable in LOX-1 knockout rats. There appeared to be the lessening of correlation of postischemic miRNA alterations between the injured brain tissue and plasma in LOX-1 knockout rats. Conclusions- Our data show that deficiency of LOX-1 has a protective effect on spontaneous brain damage in a newly generated LOX-1-deficient strain of SHRSP. Further, our analysis of miRNAs as biomarkers for ischemic brain damage supports a potential involvement of LOX-1 in blood brain barrier disruption after cerebral ischemia. Visual Overview- An online visual overview is available for this article.


Assuntos
Barreira Hematoencefálica , Isquemia Encefálica , Deleção de Genes , Hipertensão , Receptores Depuradores Classe E/deficiência , Acidente Vascular Cerebral , Animais , Barreira Hematoencefálica/lesões , Barreira Hematoencefálica/metabolismo , Barreira Hematoencefálica/patologia , Isquemia Encefálica/sangue , Isquemia Encefálica/genética , Isquemia Encefálica/patologia , MicroRNA Circulante , Hipertensão/sangue , Hipertensão/genética , Hipertensão/patologia , MicroRNAs/sangue , MicroRNAs/genética , Ratos , Ratos Endogâmicos SHR , Ratos Transgênicos , Receptores Depuradores Classe E/metabolismo , Acidente Vascular Cerebral/sangue , Acidente Vascular Cerebral/genética , Acidente Vascular Cerebral/patologia
17.
Arch Biochem Biophys ; 689: 108411, 2020 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-32450066

RESUMO

The process of ischemia/reperfusion (IR) in ischemic stroke often leads to significant cell death and permanent neuronal damage. Safe and effective treatments are urgently needed to mitigate the damage caused by IR injury. The naturally occurring pleiotropic peptide phoenixin 14 (PNX-14) has recently come to light as a potential treatment for IR injury. In the present study, we examined the effects of PNX-14 on several key processes involved in ischemic injury, such as pro-inflammatory cytokine expression, oxidative stress, and the related cascade mediated through the toll-like receptor 4 (TLR4) pathway, using BV2 microglia exposed to oxygen-glucose deprivation and reoxygenation (OGD/R). Our results demonstrate an acute ability of PNX-14 to regulate the expression levels of proinflammatory cytokines including tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), and interleukin-6 (IL-6). PNX-14 also prevented oxidative stress by reducing the generation of reactive oxygen species (ROS) and increasing the level of the antioxidant glutathione (GSH). Importantly, PNX-14 inhibited high-mobility group box 1 (HMGB1)/TLR4/myeloid differentiation primary response 88 (MyD88)/nuclear factor-κB (NF-κB) signaling pathway, by inhibiting the activation of TLR4 and preventing the nuclear translocation of p65 protein. We further confirmed the cerebroprotective effects of PNX-14 in an MCAO rat model, which resulted in reduced infarct volume and decreased microglia activation. Together, the results of this study implicate a possible protective role of PNX-14 against various aspects of IR injury in vitro.


Assuntos
Isquemia Encefálica/tratamento farmacológico , Hormônios Hipotalâmicos/uso terapêutico , Microglia/efeitos dos fármacos , Fármacos Neuroprotetores/uso terapêutico , Hormônios Peptídicos/uso terapêutico , Traumatismo por Reperfusão/tratamento farmacológico , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Isquemia Encefálica/patologia , Linhagem Celular , Masculino , Microglia/patologia , Ratos Sprague-Dawley , Traumatismo por Reperfusão/patologia
18.
Zh Nevrol Psikhiatr Im S S Korsakova ; 120(3. Vyp. 2): 29-32, 2020.
Artigo em Russo | MEDLINE | ID: mdl-32307427

RESUMO

INTRODUCTION: Ischemic stroke is one of the most severe neurological pathologies with high mortality and disability. In this connection, the development and study of new drugs for the prevention and treatment of stroke is an extremely important task. A new approach to neuroprotection is the use of lithium salts with antioxidant activity. AIM: To study the cerebroprotective effect of lithium ascorbate on a rat model of ischemic stroke. MATERIAL AND METHODS: Test samples of lithium ascorbate were synthesized ex tempore for an experiment using reagents of ACS qualification (Sigma-Aldrich). The ischemic stroke model was realized using the filament occlusion of the middle cerebral artery in rats of the Sprague Dawley line according to standardized procedure. Neurological examination of the animals, histological study of brain tissue with staining of brain sections, and calculating the volume of cerebral infarction were performed. RESULTS AND CONCLUSION: There is a significant cerebroprotective effect of lithium ascorbate expressed in a multiple decrease in the volume of the zone of cerebral infarction (by 75% of the control group indicator) and the absence of mortality in the experimental group of animals. Newly discovered distinct anti-stroke effect of lithium ascorbate in combination with low toxicity could be considered promising for further clinical studies and practical application in neurology.


Assuntos
Isquemia Encefálica/tratamento farmacológico , Isquemia Encefálica/prevenção & controle , Modelos Animais de Doenças , Compostos de Lítio/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Acidente Vascular Cerebral/tratamento farmacológico , Acidente Vascular Cerebral/prevenção & controle , Animais , Isquemia Encefálica/patologia , Infarto Cerebral/tratamento farmacológico , Infarto Cerebral/patologia , Compostos de Lítio/farmacologia , Fármacos Neuroprotetores/farmacologia , Ratos , Ratos Sprague-Dawley , Acidente Vascular Cerebral/patologia
19.
Life Sci ; 252: 117665, 2020 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-32305521

RESUMO

AIMS: Thrombin formation is increased in patients with acute cerebral ischemic stroke, and augments coagulation and inflammation in the brain. Administration of antithrombin (AT) was previously reported to be protective against renal and myocardial ischemic injury. Thus, we hypothesized that treatment with AT would be neuroprotective against cerebral ischemic injury. This study evaluated the effects of AT treatment on ischemic inflammation and brain damage in mice subjected to middle cerebral artery occlusion (MCAO). MAIN METHODS: A mouse model of 4-hour MCAO was used to induce ischemic brain injury. Recombinant AT gamma was administered intravenously immediately after reperfusion at 4 h after MCAO. Infarct volume, neurological deficit, and regional cerebral blood flow (rCBF) were measured at 24 h after MCAO. To evaluate the effect of AT gamma on ischemic inflammation, we measured the number of Iba1-positive cells (marker of macrophage/microglial activation) and levels of proinflammatory cytokines. Further, we investigated the direct anti-inflammatory effects of rAT in the J774.1 cell line. KEY FINDINGS: Treatment with AT gamma (480 U/kg) reduced infarct volume and neurological deficit, and improved rCBF, in MCAO mice. Moreover, AT gamma treatment decreased the number of Iba1-positive cells and levels of proinflammatory cytokines. In vitro, treatment with thrombin significantly increased proinflammatory cytokine levels, which was significantly reduced by pretreatment with AT gamma. SIGNIFICANCE: Treatment with AT showed neuroprotective effects via anticoagulation actions, as well as direct anti-inflammatory effects on macrophage/microglial activation. These data suggest that AT may be a useful new therapeutic option for cerebral ischemia.


Assuntos
Antitrombinas/farmacologia , Isquemia Encefálica/tratamento farmacológico , Fármacos Neuroprotetores/farmacologia , Acidente Vascular Cerebral/tratamento farmacológico , Animais , Antitrombinas/administração & dosagem , Isquemia Encefálica/patologia , Linhagem Celular , Citocinas/metabolismo , Modelos Animais de Doenças , Infarto da Artéria Cerebral Média , Inflamação/tratamento farmacológico , Inflamação/patologia , Ativação de Macrófagos/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Microglia/efeitos dos fármacos , Microglia/metabolismo , Fármacos Neuroprotetores/administração & dosagem , Proteínas Recombinantes , Acidente Vascular Cerebral/patologia
20.
PLoS One ; 15(4): e0231448, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32330144

RESUMO

BACKGROUND AND PURPOSE: Patients with acute stroke and mild or rapidly improving symptoms frequently show progression. The role of reperfusion treatment in such patients is not clear. We hypothesized that progression was most likely in patients with cortical localization and such patients may benefit from thrombolysis. MATERIAL AND METHODS: We interrogated Hamad Stroke Database to evaluate 90-days outcome in patients with acute ischemic stroke admitted within 4 hours and a NIHSS score of ≤6. Evaluation was based on localization (lacunar or cortical), multi-model imaging abnormalities and whether they received rt-PA. The 90-day mRS was used to determine outcome. RESULTS: During study period 6381 patients were admitted with acute stroke. Mild stroke within 4 hours was diagnosed in 506 [no thrombolysis: 381(lacunar: 213; cortical: 168), thrombolysis: 125 (lacunar: 45; cortical: 80)]. The rt-PA treated patients had significantly higher NIHSS (2.94±3.9 versus 1.28±2.46, p<0.0001), increased rates of complications (16.0% versus 3.9%, p<0.0001) and longer hospital stay (6.05±8.1 versus 3.78±3.6 days; p<0.001). In patients with cortical stroke, intracranial arterial occlusions (11.6% vs 3.9%, p<0.0001) and CTP mismatch (22.2% vs 4.4%, p<0.0001) were more frequent in rt-PA treated patients. Discharge mRS (33.6% versus 13.9%, p<0.001) and 90-days mRS (23.2% versus 11.8%, p = 0.002) was significantly worse in patients with cortical stroke (rt-PA-treated and untreated patients). CONCLUSIONS: The outcome in patients with mild stroke depends on lesion location (lacunar versus cortical) and severity of symptoms. Patients who receive rt-PA have significantly larger deficits, increased imaging abnormalities and higher rates of hospital complication, explaining the poor outcome in such subjects.


Assuntos
Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/patologia , Isquemia Encefálica/etiologia , Isquemia Encefálica/patologia , Progressão da Doença , Feminino , Fibrinolíticos/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Terapia Trombolítica/métodos , Fatores de Tempo , Ativador de Plasminogênio Tecidual/metabolismo , Resultado do Tratamento
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