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1.
Int J Mol Sci ; 22(4)2021 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-33670754

RESUMO

Alzheimer's disease (AD) is the most common neurodegenerative disease worldwide. Histopathologically, AD presents with two hallmarks: neurofibrillary tangles (NFTs), and aggregates of amyloid ß peptide (Aß) both in the brain parenchyma as neuritic plaques, and around blood vessels as cerebral amyloid angiopathy (CAA). According to the vascular hypothesis of AD, vascular risk factors can result in dysregulation of the neurovascular unit (NVU) and hypoxia. Hypoxia may reduce Aß clearance from the brain and increase its production, leading to both parenchymal and vascular accumulation of Aß. An increase in Aß amplifies neuronal dysfunction, NFT formation, and accelerates neurodegeneration, resulting in dementia. In recent decades, therapeutic approaches have attempted to decrease the levels of abnormal Aß or tau levels in the AD brain. However, several of these approaches have either been associated with an inappropriate immune response triggering inflammation, or have failed to improve cognition. Here, we review the pathogenesis and potential therapeutic targets associated with dysfunction of the NVU in AD.


Assuntos
Doença de Alzheimer/fisiopatologia , Encéfalo/irrigação sanguínea , Encéfalo/fisiopatologia , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/patologia , Amiloide/metabolismo , Animais , Barreira Hematoencefálica/patologia , Barreira Hematoencefálica/fisiopatologia , Encéfalo/patologia , Humanos , Terapia de Alvo Molecular
2.
Ann Neurol ; 89(3): 459-473, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33314303

RESUMO

OBJECTIVE: The purpose of this study was to investigate the significance of circulating micro RNAs (miRNAs) in the pathogenesis of reversible cerebral vasoconstriction syndrome (RCVS). METHODS: We prospectively recruited 3 independent cohorts of patients with RCVS and age-matched and sex-matched controls in a single medical center. Next-generation small RNA sequencing followed by quantitative polymerase chain reaction (PCR) was used to identify and validate differentially expressed miRNAs, which was cross-validated in migraine patients in ictal stage or interictal stage. Computational analysis was used to predict the target genes of miRNAs, followed by in vitro functional analysis. RESULTS: We identified a panel of miRNAs including miR-130a-3p, miR-130b-3p, let-7a-5p, let-7b-5p, and let-7f-5p that well differentiated patients with RCVS from controls (area under the receiver operating characteristics curve [AUC] was 0.906, 0.890, and 0.867 in the 3 cohorts, respectively). The abundance of let-7a-5p, let-7b-5p, and let-7f-5p, but not miR-130a-3p nor miR-130b-3p, was significantly higher in patients with ictal migraine compared with that of controls and patients with interictal migraine. Target prediction and pathway enrichment analysis suggested that the transforming growth factor-ß signaling pathway and endothelin-1 responsible for vasomotor control might link these miRNAs to RCVS pathogenesis, which was confirmed in vitro by transfecting miRNAs mimics or incubating the patients' cerebrospinal fluid (CSF) in 3 different vascular endothelial cells. Moreover, miR-130a-3p was associated with imaging-proven disruption of the blood-brain barrier (BBB) in patients with RCVS and its overexpression led to reduced transendothelial electrical resistance (ie, increased permeability) in in vitro human BBB model. INTERPRETATION: We identified the circulating miRNA signatures associated with RCVS, which may be functionally linked to its headache, BBB integrity, and vasomotor function. ANN NEUROL 2021;89:459-473.


Assuntos
Barreira Hematoencefálica/fisiopatologia , Transtornos Cerebrovasculares/genética , MicroRNA Circulante/sangue , Células Endoteliais , MicroRNAs/sangue , Vasoconstrição/genética , Adulto , Permeabilidade Capilar , Estudos de Casos e Controles , Transtornos Cerebrovasculares/sangue , Transtornos Cerebrovasculares/fisiopatologia , MicroRNA Circulante/genética , Simulação por Computador , Impedância Elétrica , Endotelina-1/genética , Endotelina-1/metabolismo , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Células Endoteliais da Veia Umbilical Humana , Humanos , Técnicas In Vitro , Masculino , Pessoa de Meia-Idade , Transtornos de Enxaqueca/sangue , Transtornos de Enxaqueca/genética , Transtornos de Enxaqueca/fisiopatologia , Reprodutibilidade dos Testes , Análise de Sequência de RNA , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta/metabolismo , Sistema Vasomotor/fisiopatologia
3.
Am J Physiol Heart Circ Physiol ; 320(2): H740-H761, 2021 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-33337961

RESUMO

Over two-thirds of individuals aged 65 and older are obese or overweight in the United States. Epidemiological data show an association between the degree of adiposity and cognitive dysfunction in the elderly. In this review, the pathophysiological roles of microvascular mechanisms, including impaired endothelial function and neurovascular coupling responses, microvascular rarefaction, and blood-brain barrier disruption in the genesis of cognitive impairment in geriatric obesity are considered. The potential contribution of adipose-derived factors and fundamental cellular and molecular mechanisms of senescence to exacerbated obesity-induced cerebromicrovascular impairment and cognitive decline in aging are discussed.


Assuntos
Barreira Hematoencefálica/fisiopatologia , Cognição , Disfunção Cognitiva/fisiopatologia , Endotélio Vascular/fisiopatologia , Microvasos/fisiopatologia , Acoplamento Neurovascular , Obesidade/fisiopatologia , Fatores Etários , Idoso , Animais , Barreira Hematoencefálica/metabolismo , Envelhecimento Cognitivo , Disfunção Cognitiva/epidemiologia , Disfunção Cognitiva/prevenção & controle , Disfunção Cognitiva/psicologia , Endotélio Vascular/metabolismo , Feminino , Humanos , Masculino , Microcirculação , Microvasos/metabolismo , Obesidade/epidemiologia , Obesidade/psicologia , Obesidade/terapia , Medição de Risco , Fatores de Risco
4.
Cells ; 9(11)2020 10 27.
Artigo em Inglês | MEDLINE | ID: mdl-33120941

RESUMO

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel human coronavirus that has sparked a global pandemic of the coronavirus disease of 2019 (COVID-19). The virus invades human cells through the angiotensin-converting enzyme 2 (ACE2) receptor-driven pathway, primarily targeting the human respiratory tract. However, emerging reports of neurological manifestations demonstrate the neuroinvasive potential of SARS-CoV-2. This review highlights the possible routes by which SARS-CoV-2 may invade the central nervous system (CNS) and provides insight into recent case reports of COVID-19-associated neurological disorders, namely ischaemic stroke, encephalitis, encephalopathy, epilepsy, neurodegenerative diseases, and inflammatory-mediated neurological disorders. We hypothesize that SARS-CoV-2 neuroinvasion, neuroinflammation, and blood-brain barrier (BBB) dysfunction may be implicated in the development of the observed disorders; however, further research is critical to understand the detailed mechanisms and pathway of infectivity behind CNS pathogenesis.


Assuntos
Betacoronavirus/metabolismo , Barreira Hematoencefálica/fisiopatologia , Barreira Hematoencefálica/virologia , Infecções por Coronavirus/complicações , Doenças do Sistema Nervoso/complicações , Pneumonia Viral/complicações , Internalização do Vírus , Betacoronavirus/imunologia , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/virologia , Citocinas/metabolismo , Humanos , Pandemias , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/imunologia , Pneumonia Viral/virologia
5.
Fluids Barriers CNS ; 17(1): 55, 2020 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-32912226

RESUMO

Human coronaviruses are highly pathogenic viruses that pose a serious threat to human health. Examples include the severe acute respiratory syndrome outbreak of 2003 (SARS-CoV-1), the Middle East Respiratory Syndrome (MERS-CoV) outbreak of 2012, and the current SARS-CoV-2 (COVID-19) pandemic. Herein, we review the neurological manifestations of coronaviruses and discuss the potential pathogenic role of blood-brain barrier dysfunction. We present the hypothesis that pre-existing vascular damage (due to aging, cardiovascular disease, diabetes, hypertension or other conditions) facilitates infiltration of the virus into the central nervous system (CNS), increasing neuro-inflammation and the likelihood of neurological symptoms. We also discuss the role of a neuroinflammatory cytokine profile in both blood-brain barrier dysfunction and macrovascular disease (e.g. ischemic stroke and thromboembolism). Future studies are needed to better understand the involvement of the microvasculature in coronavirus neuropathology, and to test the diagnostic potential of minimally-invasive screening tools (e.g. serum biomarkers, fluorescein retinal angiography and dynamic-contrast MRI).


Assuntos
Barreira Hematoencefálica/fisiopatologia , Infecções por Coronavirus/fisiopatologia , Inflamação/fisiopatologia , Microvasos/fisiopatologia , Doenças do Sistema Nervoso/fisiopatologia , Pneumonia Viral/fisiopatologia , Betacoronavirus , Barreira Hematoencefálica/imunologia , Barreira Hematoencefálica/virologia , Doenças Cardiovasculares/fisiopatologia , Infecções por Coronavirus/imunologia , Citocinas/imunologia , Diabetes Mellitus/fisiopatologia , Encefalite/imunologia , Encefalite/fisiopatologia , Humanos , Inflamação/imunologia , Microvasos/imunologia , Doenças do Sistema Nervoso/imunologia , Pandemias , Pneumonia Viral/imunologia , Convulsões/imunologia , Convulsões/fisiopatologia , Acidente Vascular Cerebral/imunologia , Acidente Vascular Cerebral/fisiopatologia , Tromboembolia/imunologia , Tromboembolia/fisiopatologia
6.
Nat Commun ; 11(1): 4413, 2020 09 04.
Artigo em Inglês | MEDLINE | ID: mdl-32887883

RESUMO

The molecular signatures of cells in the brain have been revealed in unprecedented detail, yet the ageing-associated genome-wide expression changes that may contribute to neurovascular dysfunction in neurodegenerative diseases remain elusive. Here, we report zonation-dependent transcriptomic changes in aged mouse brain endothelial cells (ECs), which prominently implicate altered immune/cytokine signaling in ECs of all vascular segments, and functional changes impacting the blood-brain barrier (BBB) and glucose/energy metabolism especially in capillary ECs (capECs). An overrepresentation of Alzheimer disease (AD) GWAS genes is evident among the human orthologs of the differentially expressed genes of aged capECs, while comparative analysis revealed a subset of concordantly downregulated, functionally important genes in human AD brains. Treatment with exenatide, a glucagon-like peptide-1 receptor agonist, strongly reverses aged mouse brain EC transcriptomic changes and BBB leakage, with associated attenuation of microglial priming. We thus revealed transcriptomic alterations underlying brain EC ageing that are complex yet pharmacologically reversible.


Assuntos
Envelhecimento/patologia , Barreira Hematoencefálica , Encéfalo/fisiopatologia , Células Endoteliais/metabolismo , Exenatida/farmacologia , Doença de Alzheimer/fisiopatologia , Animais , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/fisiopatologia , Capilares/metabolismo , Células Cultivadas , Humanos , Camundongos , Microglia/efeitos dos fármacos , Doenças Neurodegenerativas/fisiopatologia , Transcriptoma/efeitos dos fármacos
7.
J Stroke Cerebrovasc Dis ; 29(10): 105029, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32912542

RESUMO

BACKGROUND: We investigated whether exogenous lysophosphatidic acid (LPA), a phospholipid extracellular signaling molecule, would increase infarct size and blood-brain barrier (BBB) disruption during the early stage of cerebral ischemia-reperfusion, and whether it works through Akt-mTOR-S6K1 intracellular signaling. MATERIAL AND METHODS: Rats were given either vehicle or LPA 1 mg/kg iv three times during reperfusion after one hour of middle cerebral artery (MCA) occlusion. In another group, prior to administration of LPA, 30 mg/kg of PF-4708671, an S6K1 inhibitor, was injected. After one hour of MCA occlusion and two hours of reperfusion the transfer coefficient (Ki) of 14C-α-aminoisobutyric acid and the volume of 3H-dextran distribution were determined to measure the degree of BBB disruption. At the same time, the size of infarct was determined and western blot analysis was performed to determine the levels of phosphorylated Akt (p-Akt) and phosphorylated S6 (pS6). RESULTS: LPA increased the Ki in the ischemic-reperfused cortex (+43%) when compared with Control rats and PF-4708671 pretreatment prevented the increase of Ki by LPA. LPA increased the percentage of cortical infarct out of total cortical area (+36%) and PF-4708671 pretreatment prevented the increase of the infarct size. Exogenous LPA did not significantly change the levels of p-Akt as well as pS6 in the ischemic-reperfused cortex. CONCLUSION: Our data demonstrate that the increase in BBB disruption could be one of the reasons of the increased infarct size by LPA. S6K1 may not be the major target of LPA. A decrease of LPA during early cerebral ischemia-reperfusion might be beneficial for neuronal survival.


Assuntos
Barreira Hematoencefálica/efeitos dos fármacos , Permeabilidade Capilar/efeitos dos fármacos , Córtex Cerebral/efeitos dos fármacos , Infarto da Artéria Cerebral Média/terapia , Lisofosfolipídeos/toxicidade , Traumatismo por Reperfusão/induzido quimicamente , Reperfusão , Animais , Barreira Hematoencefálica/fisiopatologia , Córtex Cerebral/enzimologia , Córtex Cerebral/patologia , Modelos Animais de Doenças , Infarto da Artéria Cerebral Média/enzimologia , Infarto da Artéria Cerebral Média/patologia , Infarto da Artéria Cerebral Média/fisiopatologia , Masculino , Fosforilação , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos Endogâmicos F344 , Traumatismo por Reperfusão/enzimologia , Traumatismo por Reperfusão/patologia , Traumatismo por Reperfusão/fisiopatologia , Proteínas Quinases S6 Ribossômicas/metabolismo
8.
J Stroke Cerebrovasc Dis ; 29(9): 105071, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32807473

RESUMO

BACKGROUND: Chinese medicine Tongxinluo capsule (TXL) has been extensively used to treat ischemic stroke in China, and one of its mechanisms is to protect against blood brain barrier (BBB) disruption after stroke. However, the underlying protective mechanisms are not fully illuminated. It is reported that the low-density lipoprotein receptor-related protein 1 (LRP-1) is involved in BBB disruption after brain ischemia. In this study, we explored whether TXL could downregulate LRP-1 expression and subsequently protect against BBB disruption after stroke using permanent middle cerebral artery occlusion (pMCAO) in mice. METHODS: The animal model of ischemic stroke was induced by pMCAO in male adult C57BL/6J mice. The mice were orally administered TXL (3.0 g/kg) at 1, 3 and 21 h after pMCAO. Meanwhile, the LRP-1 antagonist receptor associated protein (RAP) was intracerebroventricularly injected at 1 and 21 h after stroke. We measured the following parameters at 6 and 24 h: LRP-1 protein level, BBB leakage, and the expression of tight junction (TJ) proteins including occludin, claudin-5 and zonula occludens-1 (ZO-1). RESULTS: Our results showed that TXL downregulated LRP-1 level, upregulated these TJ proteins level, and reduced BBB leakage in peri-infarct regions after pMCAO. Further study found that the inhibitor RAP played the same role as did TXL in upregulating these TJ proteins level and reducing BBB leakage after stroke. CONCLUSION: Our study demonstrates that TXL protects against BBB disruption after stroke via inhibiting the LRP-1 pathway.


Assuntos
Barreira Hematoencefálica/efeitos dos fármacos , Permeabilidade Capilar/efeitos dos fármacos , Medicamentos de Ervas Chinesas/administração & dosagem , Infarto da Artéria Cerebral Média/tratamento farmacológico , Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo , Administração Oral , Animais , Barreira Hematoencefálica/metabolismo , Barreira Hematoencefálica/patologia , Barreira Hematoencefálica/fisiopatologia , Cápsulas , Modelos Animais de Doenças , Infarto da Artéria Cerebral Média/metabolismo , Infarto da Artéria Cerebral Média/patologia , Infarto da Artéria Cerebral Média/fisiopatologia , Masculino , Camundongos Endogâmicos C57BL , Transdução de Sinais , Proteínas de Junções Íntimas/metabolismo , Junções Íntimas/efeitos dos fármacos , Junções Íntimas/metabolismo , Junções Íntimas/patologia
9.
Sci Rep ; 10(1): 9420, 2020 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-32523011

RESUMO

We investigated the role of nitric oxide synthase (NOS) in mediating blood-brain barrier (BBB) disruption and peripheral immune cell infiltration in the cerebellum following blast exposure. Repetitive, but not single blast exposure, induced delayed-onset BBB disruption (72 hours post-blast) in cerebellum. The NOS inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME) administered after blast blocked BBB disruption and prevented CD4+ T-cell infiltration into cerebellum. L-NAME also blocked blast-induced increases in intercellular adhesion molecule-1 (ICAM-1), a molecule that plays a critical role in regulating blood-to-brain immune cell trafficking. Blocking NOS-mediated BBB dysfunction during this acute/subacute post-blast interval (24-71 hours after the last blast) also prevented sensorimotor impairment on a rotarod task 30 days later, long after L-NAME cleared the body. In postmortem brains from Veterans/military Servicemembers with blast-related TBI, we found marked Purkinje cell dendritic arbor structural abnormalities, which were comparable to neuropathologic findings in the blast-exposed mice. Taken collectively, these results indicate that blast provokes delayed-onset of NOS-dependent pathogenic cascades that can later emerge as behavioral dysfunction. These results also further implicate the cerebellum as a brain region vulnerable to blast-induced mTBI.


Assuntos
Traumatismos por Explosões/metabolismo , Traumatismos por Explosões/fisiopatologia , Concussão Encefálica/fisiopatologia , Doenças Cerebelares/metabolismo , Doenças Cerebelares/fisiopatologia , Cerebelo/fisiopatologia , Óxido Nítrico Sintase/metabolismo , Animais , Traumatismos por Explosões/tratamento farmacológico , Barreira Hematoencefálica/metabolismo , Barreira Hematoencefálica/fisiopatologia , Concussão Encefálica/tratamento farmacológico , Concussão Encefálica/metabolismo , Doenças Cerebelares/tratamento farmacológico , Cerebelo/efeitos dos fármacos , Cerebelo/metabolismo , Modelos Animais de Doenças , Molécula 1 de Adesão Intercelular/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , NG-Nitroarginina Metil Éster/farmacologia , Células de Purkinje/efeitos dos fármacos , Células de Purkinje/metabolismo , Células de Purkinje/patologia
10.
PLoS Negl Trop Dis ; 14(6): e0008290, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32479527

RESUMO

Angiostrongyliasis is induced by the nematode Angiostrongylus cantonensis and leads to eosinophilic meningitis and meningoencephalitis in humans. Excretory-secretory products (ESPs) are important investigation targets for studying the relationship between hosts and nematodes. These products assist worms in penetrating the blood-brain barrier and avoiding the host immune response. Autophagy is a catabolic process that is responsible for digesting cytoplasmic organelles, proteins, and lipids and removing them through lysosomes. This process is essential to cell survival and homeostasis during nutritional deficiency, cell injury and stress. In this study, we investigated autophagy induction upon treatment with the ESPs of the fifth-stage larvae (L5) of A. cantonensis and observed the relationship between autophagy and the Shh pathway. First, the results showed that A. cantonensis infection induced blood-brain barrier dysfunction and pathological changes in the brain. Moreover, A. cantonensis L5 ESPs stimulated autophagosome formation and the expression of autophagy molecules, such as LC3B, Beclin, and p62. The data showed that upon ESPs treatment, rapamycin elevated cell viability through the activation of the autophagy mechanism in astrocytes. Finally, we found that ESPs induced the activation of the Sonic hedgehog (Shh) signaling pathway and that the expression of autophagy molecules was increased through the Shh signaling pathway. Collectively, these results suggest that A. cantonensis L5 ESPs stimulate autophagy through the Shh signaling pathway and that autophagy has a protective effect in astrocytes.


Assuntos
Angiostrongylus cantonensis/metabolismo , Astrócitos/parasitologia , Autofagia , Encéfalo/patologia , Proteínas Hedgehog/metabolismo , Transdução de Sinais , Angiostrongylus cantonensis/imunologia , Animais , Astrócitos/citologia , Barreira Hematoencefálica/fisiopatologia , Encéfalo/parasitologia , Interações Hospedeiro-Parasita , Larva/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Ratos , Ratos Sprague-Dawley , Caramujos
11.
J Stroke Cerebrovasc Dis ; 29(5): 104748, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32160957

RESUMO

OBJECTIVE: Intracerebral hemorrhage (ICH) is a disease that threatens human health due to its high morbidity and mortality. On behalf of finding the better methods in the treatment of ICH, researchers pay more attention to a new technology which is finding effective genes to modify stem cells. METHODS: In this study, we isolated, cultured and identified bone marrow mesenchymal stem cells (MSCs) in vitro. Further, the MSCs (transfected with lentivirus expressing microRNA-126a-3p (miR-126)) were injected into the type Ⅶ collagenase-induced ICH rats to investigate the recovery effects of blood-brain barrier (BBB) and nerve damage in vivo. RESULTS: The MSCs surface marker molecules (CD29: 98.5%; CD90: 96.5%) were highly expressed, and the blood cell surface molecule was negatively expressed (CD45: 2%). Meanwhile, it was verified that miR-126 facilitated the differentiation of MSCs into vascular endothelial cells, owing to the rise of markers (CD31 and VE-cadherin). The modified neurological severity score, modified limb placing test score, brain water content and evans blue content were reduced after transplanted miR-126-modified MSCs. It was found that miR-126 accelerated the differentiation of MSCs into vascular endothelial cells via immunohistochemical staining in vivo. HE staining indicated the area of edema was obviously decreased compared with that in ICH + vector-MSCs group. MiR-126-modified MSCs alleviated the cell apoptosis in brain tissues by TUNEL assay. In addition, the mRNA and protein expression of protease activated receptor-1 and matrix metalloproteinase-9 were diminished, whilst the expression of zonula occludens-1 (ZO-1) and claudin-5 were enhanced in ICH+miR-126-MSCs group. Immunofluorescence assay revealed that miR-126-modified MSCs decreased the disruption of tight junction (ZO-1 and claudin-5). CONCLUSIONS: All data illustrate that miR-126-modified MSCs repair BBB and nerve injury after ICH.


Assuntos
Barreira Hematoencefálica/metabolismo , Permeabilidade Capilar , Hemorragia Cerebral/cirurgia , Células Progenitoras Endoteliais/transplante , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais , MicroRNAs/metabolismo , Regeneração Nervosa , Células-Tronco Neurais/transplante , Animais , Apoptose , Barreira Hematoencefálica/patologia , Barreira Hematoencefálica/fisiopatologia , Diferenciação Celular , Células Cultivadas , Hemorragia Cerebral/metabolismo , Hemorragia Cerebral/patologia , Hemorragia Cerebral/fisiopatologia , Modelos Animais de Doenças , Células Progenitoras Endoteliais/metabolismo , Regulação da Expressão Gênica , Masculino , Células-Tronco Mesenquimais/metabolismo , MicroRNAs/genética , Atividade Motora , Células-Tronco Neurais/metabolismo , Ratos Sprague-Dawley , Reflexo , Sensação , Transdução de Sinais , Junções Íntimas/metabolismo , Junções Íntimas/patologia
12.
Fluids Barriers CNS ; 17(1): 14, 2020 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-32024544

RESUMO

BACKGROUND: The cerebrospinal fluid (CSF)/serum quotient of albumin (QAlb) is the most used biomarker for the evaluation of blood-cerebrospinal fluid barrier (B-CSF-B) permeability. For years QAlb was considered only as an age-related parameter but recently it has also been associated to sex. The aim of the present study was to explore the impact of sex in the determination of B-CSF-B dysfunction. METHODS: The analysis was retrospectively conducted on subjects consecutively admitted to the neurological ward. CSF and serum albumin levels were measured by immunonephelometry and pathological QAlb thresholds were considered: 6.5 under 40 years, 8.0 in the age 40-60 and 9.0 over 60 years. RESULTS: 1209 subjects were included in the study. 718 females and 491 males (age: 15-88 years): 24.6% of patients had a diagnosis of multiple sclerosis, 23.2% suffered from other inflammatory neurological diseases, 24.6% were affected by non-inflammatory neurological diseases, and for 27.6% of patients the final neurological diagnosis could not be traced. Dysfunctional B-CSF-B was detected more frequently (44 vs. 20.1%, p < 0.0001) and median QAlb value were higher (7.18 vs. 4.87, p < 0.0001) in males than in females in the overall study population and in all disease subgroups. QAlb and age were positively correlated both in female (p < 0.0001) and male (p < 0.0001) patients, however the slopes of the two regression lines were not significantly different (p = 0.7149), while the difference between the elevations was extremely significant (p < 0.0001) with a gap of 2.2 units between the two sexes. Finally, in a multivariable linear regression analysis increased age and male sex were independently associated with higher QAlb in the overall study population (both p < 0.001) and after stratification by age and disease group. CONCLUSIONS: Accordingly, identification and validation of sex-targeted QAlb thresholds should be considered as a novel tool in an effort to achieve more precision in the medical approach.


Assuntos
Fatores Etários , Barreira Hematoencefálica/patologia , Esclerose Múltipla/patologia , Permeabilidade , Fatores Sexuais , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/líquido cefalorraquidiano , Barreira Hematoencefálica/fisiopatologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Albumina Sérica/metabolismo , Adulto Jovem
13.
PLoS One ; 15(2): e0228679, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32017808

RESUMO

BACKGROUND: Chronic autoimmune demyelinating polyneuropathies (CADP) result in impaired sensorimotor function. However, anecdotal clinical observations suggest the development of cognitive deficits during the course of disease. METHODS: We tested 16 patients with CADP (11 patients with chronic inflammatory demyelinating polyneuropathy, 4 patients with multifocal motor neuropathy and 1 patient with multifocal acquired demyelinating sensory and motor neuropathy) and 40 healthy controls (HC) with a neuropsychological test battery. Blood-brain-barrier dysfunction (BBBd) in patients was assessed retrospectively by analysing the cerebral spinal fluid (CSF) status at the time the diagnosis of CAPD was established. RESULTS: CADP patients failed on average in 1.7 out of 9 neuropsychological tests (SD ± 1.25, min. 0, max. 5). 50% of the CADP patients failed in at least two neuropsychological tests and 44.3% of the patients failed in at least two different cognitive domains. CADP patients exhibiting BBBd at the time of first diagnosis failed in more neuropsychological tests than patients with intact integrity of the BBB (p < 0.05). When compared directly with the HC group, CADP patients performed worse than HC in tests measuring information processing ability and speed as well as phonemic verbal fluency after adjusting for confounding covariates. CONCLUSIONS: Our results suggest that mild to moderate cognitive deficits might be present in patients with CAPD. One possible tentative explanation, albeit strong evidence is still lacking for this pathophysiological mechanism, refers to the effect of autoimmune antibodies entering the CNS via the dysfunctional blood-brain barrier typically seen in some of the CADP patients.


Assuntos
Disfunção Cognitiva/etiologia , Polineuropatias/fisiopatologia , Adulto , Idoso , Autoanticorpos , Doenças Autoimunes do Sistema Nervoso , Barreira Hematoencefálica/fisiopatologia , Estudos de Casos e Controles , Disfunção Cognitiva/líquido cefalorraquidiano , Disfunção Cognitiva/diagnóstico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Polineuropatias/líquido cefalorraquidiano , Polineuropatias/complicações , Polineuropatias/patologia , Polirradiculoneuropatia Desmielinizante Inflamatória Crônica/complicações , Polirradiculoneuropatia Desmielinizante Inflamatória Crônica/fisiopatologia , Estudos Retrospectivos
14.
Exp Neurol ; 326: 113203, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31954682

RESUMO

INTRODUCTION: Disruption of the blood brain barrier (BBB) and subsequent cerebral edema formation is one of the major adverse effects of brain surgery, leading to postoperative neurological dysfunction. Recently, Mfsd2a has been shown to have a crucial role for the maintenance of BBB functions. In this study, we aimed to evaluate the role of Mfsd2a on BBB disruption following surgical brain injury (SBI) in rats. MATERIALS AND METHODS: Rats were subjected to SBI by partial resection of the right frontal lobe. To evaluate the effect of Mfsd2a on BBB permeability and neurobehavior outcome following SBI, Mfsd2a was either overexpressed or downregulated in the brain by administering Mfsd2a CRISPR activation or knockout plasmids, respectively. The potential mechanism of Mfsd2a-mediated BBB protection through the cav-1/Nrf-2/HO-1 signaling pathway was evaluated. RESULTS: Mfsd2a levels were significantly decreased while cav-1, Nrf-2 and HO-1 levels were increased in the right frontal perisurgical area following SBI. When overexpressed, Mfsd2a attenuated brain edema and abolished neurologic impairment caused by SBI while downregulation of Mfsd2a expression further deteriorated BBB functions and worsened neurologic performance following SBI. The beneficial effect of Mfsd2a overexpression on BBB functions was associated with diminished expression of cav-1, increased Keap-1/Nrf-2 dissociation and further augmented levels of Nrf-2 and HO-1 in the right frontal perisurgical area, leading to enhanced levels of tight junction proteins following SBI. The BBB protective effect of Mfsd2a was blocked by selective inhibitors of Nrf-2 and HO-1. CONCLUSIONS: Mfsd2a attenuates BBB disruption through cav-1/Nrf-2/HO-1 signaling pathway in rats subjected to experimental SBI.


Assuntos
Barreira Hematoencefálica/fisiopatologia , Lesões Encefálicas/fisiopatologia , Transdução de Sinais/genética , Animais , Comportamento Animal , Água Corporal/metabolismo , Lesões Encefálicas/genética , Lesões Encefálicas/terapia , Caveolina 1/genética , Lobo Frontal/lesões , Terapia Genética , Heme Oxigenase (Desciclizante)/genética , Proteína 1 Associada a ECH Semelhante a Kelch/genética , Masculino , Fator 2 Relacionado a NF-E2/genética , Ratos , Ratos Sprague-Dawley , Resultado do Tratamento
15.
Epilepsy Behav ; 102: 106682, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31846897

RESUMO

PURPOSE: Investigating immune cells in autoimmune limbic encephalitis (LE) will contribute to our understanding of its pathophysiology and may help to develop appropriate therapies. The aim of the present study was to analyze immune cells to reveal underlying immune signatures in patients with temporal lobe epilepsy (TLE) with LE. METHODS: We investigated 68 patients with TLE with LE compared with 7 control patients with TLE with no signs of LE screened from 154 patients with suspected LE. From the patients with TLE-LE, we differentiated early seizure onset (<20 years, n = 9) and late seizure onset group (≥20 years, n = 59) of patients. Patients underwent neuropsychological assessment, electroencephalography (EEG), brain magnetic resonance imaging (MRI), and peripheral blood (PB) and cerebrospinal fluid (CSF) analysis including flow cytometry. RESULTS: We identified a higher CD4/8+ T-cell ratio in the PB in all patients with TLE-LE and in patients with late-onset TLE-LE each compared with controls (Kruskal-Wallis one-way ANOVA (analysis of variance) with Dunn's test, p < 0.05). Moreover, a lower CD4/CD8+ T-cell ratio is detected in all patients with TLE-LE with blood-CSF barrier dysfunction, unlike in those with none (Kruskal-Wallis one-way ANOVA with Dunn's test, p < 0.05). CONCLUSIONS: These findings suggest that the proportion of CD4+ and CD8+ T-cells in the CSF of patients with LE associated with blood-CSF barrier dysfunction plays a potential role in CNS (central nervous system) inflammation in these patients. Thus, flow cytometry as a methodology reveals novel insights into LE's genesis and symptomatology. The CD4/8+ T-cell ratio in PB as a biomarker for LE requires further investigation.


Assuntos
Doenças Autoimunes/líquido cefalorraquidiano , Doenças Autoimunes/diagnóstico por imagem , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Epilepsia do Lobo Temporal/líquido cefalorraquidiano , Epilepsia do Lobo Temporal/diagnóstico por imagem , Encefalite Límbica/líquido cefalorraquidiano , Encefalite Límbica/diagnóstico por imagem , Adulto , Doenças Autoimunes/fisiopatologia , Biomarcadores/líquido cefalorraquidiano , Barreira Hematoencefálica/diagnóstico por imagem , Barreira Hematoencefálica/fisiopatologia , Eletroencefalografia/métodos , Epilepsia do Lobo Temporal/fisiopatologia , Feminino , Humanos , Encefalite Límbica/fisiopatologia , Imagem por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Adulto Jovem
16.
Am J Physiol Renal Physiol ; 318(2): F354-F362, 2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-31869244

RESUMO

Recent breakthroughs demonstrate that peripheral diseases can trigger inflammation in the brain, causing psychosocial maladies, including depression. While few direct studies have been made, anecdotal reports associate urological disorders with mental dysfunction. Thus, we investigated if insults targeted at the bladder might elicit behavioral alterations. Moreover, the mechanism of neuroinflammation elicited by other peripheral diseases involves the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome, which is present in microglia in the brain and cleaves and activates proinflammatory cytokines such as IL-1ß. Thus, we further explored the importance of NLRP3 in behavioral and neuroinflammatory changes. Here, we used the well-studied cyclophosphamide (CP)-treated rat model. Importantly, CP and its metabolites do not cross the blood-brain barrier or trigger inflammation in the gut, so that any neuroinflammation is likely secondary to bladder injury. We found that CP triggered an increase in inflammasome activity (caspase-1 activity) in the hippocampus but not in the pons. Evans blue extravasation demonstrated breakdown of the blood-brain barrier in the hippocampal region and activated microglia were present in the fascia dentata. Both changes were dependent on NLRP3 activation and prevented with 2-mercaptoethane sulfonate sodium (Mesna), which masks the effects of the CP metabolite acrolein in the urine. Finally, CP-treated rats displayed depressive symptoms that were prevented by NLRP3 inhibition or treatment with Mesna or an antidepressant. Thus, we conclude that CP-induced cystitis causes NLRP3-dependent hippocampal inflammation leading to depression symptoms in rats. This study proposes the first-ever causative explanation of the previously anecdotal link between benign bladder disorders and mood disorders.


Assuntos
Afeto , Comportamento Animal , Ciclofosfamida , Cistite/induzido quimicamente , Depressão/etiologia , Encefalite/etiologia , Hipocampo/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Afeto/efeitos dos fármacos , Animais , Antidepressivos/farmacologia , Comportamento Animal/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Barreira Hematoencefálica/fisiopatologia , Caspase 1/metabolismo , Cistite/metabolismo , Cistite/fisiopatologia , Depressão/tratamento farmacológico , Depressão/metabolismo , Depressão/psicologia , Modelos Animais de Doenças , Encefalite/tratamento farmacológico , Encefalite/metabolismo , Encefalite/fisiopatologia , Feminino , Fluoxetina/farmacologia , Glibureto/farmacologia , Hipocampo/efeitos dos fármacos , Hipocampo/fisiopatologia , Mesna/farmacologia , Microglia/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Ratos Sprague-Dawley , Transdução de Sinais
17.
Neurobiol Aging ; 85: 113-122, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31718926

RESUMO

Blood-brain barrier (BBB) leakage is considered an important underlying process in both cerebral small vessel disease (cSVD) and Alzheimer's disease (AD). The objective of this study was to examine associations between BBB leakage, cSVD, neurodegeneration, and cognitive performance across the spectrum from normal cognition to dementia. Leakage was measured with dynamic contrast-enhanced magnetic resonance imaging in 80 older participants (normal cognition, n = 32; mild cognitive impairment, n = 34; clinical AD-type dementia, n = 14). Associations between leakage and white matter hyperintensity (WMH) volume, hippocampal volume, and cognition (information processing speed and memory performance) were examined with multivariable linear regression and mediation analyses. Leakage within the gray and white matter was positively associated with WMH volume (gray matter, p = 0.03; white matter, p = 0.01). A negative association was found between white matter BBB leakage and information processing speed performance, which was mediated by WMH volume. Leakage was not associated with hippocampal volume. WMH pathology is suggested to form a link between leakage and decline of information processing speed in older individuals with and without cognitive impairment.


Assuntos
Barreira Hematoencefálica/patologia , Barreira Hematoencefálica/fisiopatologia , Processos Mentais/fisiologia , Tempo de Reação , Substância Branca/patologia , Idoso , Idoso de 80 Anos ou mais , Barreira Hematoencefálica/diagnóstico por imagem , Disfunção Cognitiva/etiologia , Demência/etiologia , Feminino , Hipocampo/diagnóstico por imagem , Hipocampo/patologia , Humanos , Imagem por Ressonância Magnética , Masculino , Substância Branca/diagnóstico por imagem
18.
Microvasc Res ; 128: 103956, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31733304

RESUMO

Blood brain barrier (BBB) permeability and oxidative stress have been reported to be important mechanisms for brain damage following ischemic stroke and stanniocalcin-1 (STC-1), a neuroprotective protein, has anti-inflammatory and anti-oxidative stress properties. Herein, we report the effect of STC-1 on BBB permeability and brain oxidative stress after stroke in an animal model. Male Wistar received an intracerebroventricularly injection of human recombinant STC-1 (100 ng/kg) or saline and were subjected to sham procedure or global cerebral ischemia/reperfusion (I/R) model. Six and 24 h after I/R, neurological evaluation was performed; at 24 h brain water content was evaluated in the total brain, and BBB permeability, nitrite/nitrate (N/N) concentration, lipid peroxidation, protein carbonyls formation, superoxide dismutase (SOD) and catalase (CAT) activity were determined in the hippocampus, cortex, prefrontal cortex, striatum and cerebellum. Rats exhibited neurological deficit at 6 and 24 h after I/R and STC-1 reduction at 24 h. After I/R there were an increase of brain water content, BBB permeability in the hippocampus, cortex and pre-frontal cortex and N/N in the hippocampus, and STC-1 decreased this level only in the hippocampus. STC-1 decreased lipid peroxidation in the hippocampus, cortex and prefrontal cortex and protein oxidative damage in the hippocampus and cortex. SOD activity decreased in the hippocampus, cortex and prefrontal cortex after I/R and STC-1 reestablished these levels in the hippocampus and cortex. CAT activity decreased only in the hippocampus and cortex and STC-1 increased the CAT activity in the hippocampus. Our data provide the first experimental demonstration that STC-1 reduced brain dysfunction associated with cerebral I/R in rats, by decreasing BBB permeability and oxidative stress parameters.


Assuntos
Antioxidantes/administração & dosagem , Isquemia Encefálica/prevenção & controle , Encéfalo/efeitos dos fármacos , Permeabilidade Capilar/efeitos dos fármacos , Glicoproteínas/administração & dosagem , Fármacos Neuroprotetores/administração & dosagem , Estresse Oxidativo/efeitos dos fármacos , Traumatismo por Reperfusão/prevenção & controle , Animais , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Barreira Hematoencefálica/fisiopatologia , Encéfalo/metabolismo , Encéfalo/fisiopatologia , Edema Encefálico/metabolismo , Edema Encefálico/fisiopatologia , Edema Encefálico/prevenção & controle , Isquemia Encefálica/metabolismo , Isquemia Encefálica/fisiopatologia , Modelos Animais de Doenças , Injeções Intraventriculares , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Carbonilação Proteica/efeitos dos fármacos , Ratos Wistar , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/fisiopatologia , Transdução de Sinais
19.
Neurobiol Aging ; 85: 96-103, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31733942

RESUMO

The APOE-ε4 genotype is a risk factor for late-onset Alzheimer's disease (AD) as well as vascular pathology. Given the increased risk of blood-brain barrier (BBB) dysfunction and inflammation among APOE-ε4 carriers, we aimed to examine whether BBB dysfunction and inflammation contribute to the relationship between APOE and AD key pathologies, as measured in the cerebrospinal fluid (CSF). We applied bootstrapped regression and path analyses involving Q-albumin CSF/plasma ratio (a BBB/blood-CSF barrier function marker), interleukins (IL-1ß, IL-6, and IL-12p70; inflammation markers), and CSF p-Tau181 and amyloid-ß1-42 (AD pathology markers) of 97 participants (aged 38-83 years) from a university memory clinic. Our results showed that relationship between BBB dysfunction and AD pathology is modulated by IL-6 and these associations appear to be driven by the APOE-ε4 genotype. This suggests that APOE-ε4-related vascular factors are also part of the pathway to AD pathology, in synergy with an elevated immune response, and could become targets for trials focused on delaying AD.


Assuntos
Doença de Alzheimer/patologia , Apolipoproteínas E/genética , Barreira Hematoencefálica/fisiopatologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/genética , Ciclofosfamida/análogos & derivados , Feminino , Humanos , Inflamação , Interleucina-6/líquido cefalorraquidiano , Masculino , Pessoa de Meia-Idade , Risco
20.
Drug Alcohol Depend ; 206: 107637, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31734036

RESUMO

BACKGROUND: Cocaine has a variety of negative effects on the central nervous system, including reports of decreased barrier function of brain microvascular endothelial cells. However, few studies have directly shown the effects of cocaine on blood-brain barrier (BBB) function in vivo. The miniature integrated fluorescence microscope (i.e., miniscope) technology was used to visualize cocaine-induced changes in BBB permeability in awake, freely-moving rats. METHODS: The miniscope was implanted in the prefrontal cortex of adult male rats. After recovery and acclimation, rats received an injection of cocaine (5-20 mg/kg ip) 15 minutes following iv infusion of sodium fluorescein, a low molecular weight tracer. Fluorescence intensity was recordedin vivo via the miniscope for 30 minutes or 24 hours post cocaine administration and served as an indicator of BBB permeability. RESULTS: Results demonstrate that cocaine increased the sodium fluorescein extravasation in brain microcirculation in a dose-dependent manner 30 minutes, but not 24 hours after administration. CONCLUSION: We report for the first time using direct visualization of brain microcirculation with the miniscope technology in awake, freely-moving rats, that acute cocaine administration produced a transient increase in the BBB permeability.


Assuntos
Barreira Hematoencefálica/efeitos dos fármacos , Permeabilidade Capilar/efeitos dos fármacos , Cocaína/farmacocinética , Microscopia de Fluorescência , Animais , Barreira Hematoencefálica/fisiopatologia , Encéfalo/irrigação sanguínea , Encéfalo/diagnóstico por imagem , Células Endoteliais/efeitos dos fármacos , Fluoresceína , Masculino , Ratos
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