Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 9.189
Filtrar
1.
Life Sci ; 265: 118806, 2021 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-33249098

RESUMO

AIMS: Neuronal apoptosis acts as the pivotal pathogenesis of cerebral ischemia/reperfusion (I/R) injury after ischemic stroke. PAQR3 (progestin and adipoQ receptor family member 3) is a crucial player who participates in the regulation of cell death. We aim to explore the specific function and the underlying mechanism of PAQR3 in cerebral I/R induced neuronal injury. MAIN METHODS: We established a mouse middle cerebral artery occlusion/reperfusion (MCAO/R) model and rat adrenal pheochromocytoma (PC12) cell oxygen-glucose deprivation/reperfusion (OGD/R) model to detect the expression and of PAQR3 after I/R treatment in vivo and in vitro. We used lentivirus to knockdown PAQR3 and investigated the function of PAQR3 in I/R induced neuronal apoptosis. KEY FINDINGS: PAQR3 expression is markedly increased in the ischemic hemisphere of C57BL/6 mice and PC12 cells after I/R stimulation. Knockdown PAQR3 can attenuate neuronal apoptosis induced by I/R in PC12 cells and exerts neuroprotective effects. PAQR3 deficiency can significantly raise cell viability and suppress LDH leakage under I/R treatment. Silencing PAQR3 attenuates neuronal apoptosis remarkably with fewer TUNEL-positive cells and lower apoptosis rate under I/R treatment. Mechanistically, knockdown of PAQR3 can inhibit the apoptosis pathway through inducing anti-apoptotic proteins and inhibiting pro-apoptotic proteins. Besides, PI3K/AKT signaling suppression with LY294002 abolished the neuroprotective functions induced by silencing PAQR3. SIGNIFICANCE: Our results elucidate that silencing PAQR3 can protect PC12 from OGD/R injury via activating PI3K/AKT pathway. And therefore, provide a novel therapeutic target for the prevention of cerebral I/R injury.


Assuntos
Isquemia Encefálica/metabolismo , Glucose/deficiência , Peptídeos e Proteínas de Sinalização Intracelular/biossíntese , Proteínas de Membrana/biossíntese , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Traumatismo por Reperfusão/metabolismo , Animais , Apoptose/fisiologia , Isquemia Encefálica/genética , Isquemia Encefálica/prevenção & controle , Hipóxia Celular/fisiologia , Inativação Gênica/fisiologia , Peptídeos e Proteínas de Sinalização Intracelular/deficiência , Peptídeos e Proteínas de Sinalização Intracelular/genética , Masculino , Proteínas de Membrana/deficiência , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/metabolismo , Células PC12 , Ratos , Traumatismo por Reperfusão/genética , Traumatismo por Reperfusão/prevenção & controle
2.
PLoS One ; 15(12): e0233073, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33275615

RESUMO

There is unmet need for effective stroke therapies. Numerous neuroprotection attempts for acute cerebral ischemia have failed and as a result there is growing interest in developing therapies to promote functional recovery through increasing synaptic plasticity. For this research study, we hypothesized that in addition to its previously reported role in mediating cell death during the acute phase, the alpha isoform of p38 mitogen-activated protein kinase, p38α, may also contribute to interleukin-1ß-mediated impairment of functional recovery during the subacute phase after acute ischemic stroke. Accordingly, an oral, brain-penetrant, small molecule p38α inhibitor, neflamapimod, was evaluated as a subacute phase stroke treatment to promote functional recovery. Neflamapimod administration to rats after transient middle cerebral artery occlusion at two dose levels was initiated outside of the previously characterized therapeutic window for neuroprotection of less than 24 hours for p38α inhibitors. Six-week administration of neflamapimod, starting at 48 hours after reperfusion, significantly improved behavioral outcomes assessed by the modified neurological severity score at Week 4 and at Week 6 post stroke in a dose-dependent manner. Neflamapimod demonstrated beneficial effects on additional measures of sensory and motor function. It also resulted in a dose-related increase in brain-derived neurotrophic factor (BDNF) protein levels, a previously reported potential marker of synaptic plasticity that was measured in brain homogenates at sacrifice. Taken together with literature evidence on the role of p38α-dependent suppression by interleukin-1ß of BDNF-mediated synaptic plasticity and BDNF production, our findings support a mechanistic model in which inhibition of p38α promotes functional recovery after ischemic stroke by blocking the deleterious effects of interleukin-1ß on synaptic plasticity. The dose-related in vivo efficacy of neflamapimod offers the possibility of having a therapy for stroke that could be initiated outside the short time window for neuroprotection and for improving recovery after a completed stroke.


Assuntos
Isquemia Encefálica/tratamento farmacológico , Piridazinas/farmacologia , Pirimidinas/farmacologia , Acidente Vascular Cerebral/tratamento farmacológico , Animais , Encéfalo/metabolismo , Isquemia Encefálica/complicações , Isquemia Encefálica/metabolismo , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Infarto da Artéria Cerebral Média/complicações , Isquemia/complicações , Masculino , Proteína Quinase 14 Ativada por Mitógeno/antagonistas & inibidores , Proteína Quinase 14 Ativada por Mitógeno/metabolismo , Piridazinas/metabolismo , Pirimidinas/metabolismo , Ratos , Ratos Sprague-Dawley , Recuperação de Função Fisiológica/efeitos dos fármacos , Recuperação de Função Fisiológica/fisiologia , Acidente Vascular Cerebral/complicações , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
3.
Sci Rep ; 10(1): 19658, 2020 11 12.
Artigo em Inglês | MEDLINE | ID: mdl-33184298

RESUMO

Acute cerebral ischaemia may lead to serious consequences, including brain injury caused by uncontrolled reperfusion, which occurs when circulation is re-established. The long non-coding RNA (lncRNA) nuclear enriched abundant transcript 1 (NEAT1) plays an important role in the immune system. However, the potential roles and underlying molecular mechanisms of NEAT1 in cerebral ischaemia/reperfusion (I/R) injury remain unclear. The aim of the present study was to investigate the function of the lncRNA NEAT1 in cerebral I/R injury and its potential beneficial effects on neurons. In our study, oxygen-glucose deprivation (OGD)/reoxygenation (OGD/R) was induced in vitro to mimic cerebral I/R injury. Cholecystokinin-octopeptide (CCK-8) was used to measure cell viability, and flow cytometry was used to measure cell apoptosis. Real-time quantitative PCR (qRT-PCR) was used to measure the expression of phenotypic markers of classically activated (M1) and alternatively activated (M2) microglia, and western blotting was performed to detect the levels of proteins related to the AKT/STAT3 pathway. The expression of the lncRNA NEAT1 was significantly upregulated in patients with ischaemic stroke, and knockdown of the lncRNA NEAT1 alleviated OGD/R-induced apoptosis and increased neuronal viability. Furthermore, the lncRNA NEAT1 may inhibit microglial polarization towards the M1 phenotype to reduce the damage caused by OGD/R and reduce the activity of the AKT/STAT3 pathway. In conclusion, the lncRNA NEAT1 may be a potential target for new therapeutic interventions for cerebral I/R.


Assuntos
Isquemia Encefálica/metabolismo , Microglia/metabolismo , Neurônios/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Longo não Codificante/metabolismo , Apoptose/genética , Polaridade Celular , Células Cultivadas , Sistemas de Liberação de Medicamentos , Citometria de Fluxo , Glucose/metabolismo , Humanos , Inflamação , Oxigênio/metabolismo , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais , Regulação para Cima
4.
Sci Rep ; 10(1): 17193, 2020 10 14.
Artigo em Inglês | MEDLINE | ID: mdl-33057165

RESUMO

Extracellular acidification in the brain has been observed in ischemia; however, the physiological and pathophysiological implications of the pH reduction remain largely unknown. Here, we analyzed the roles of proton-sensing G protein-coupled receptors, including T-cell death-associated gene 8 (TDAG8), ovarian cancer G protein-coupled receptor 1 (OGR1), and G protein-coupled receptor 4 (GPR4) in a mouse ischemia reperfusion model. Cerebral infarction and dysfunctional behavior with transient middle cerebral artery occlusion (tMCAO) and subsequent reperfusion were exacerbated by the deficiency of TDAG8, whereas no significant effect was observed with the deficiency of OGR1 or GPR4. We confirmed that the pH of the predicted infarction region was 6.5. TDAG8 mRNA was observed in Iba1-positive microglia in the mouse brain. The tMCAO increased the mRNA expression of tumor necrosis factor-α in the ipsilateral cerebral hemisphere and evoked morphological changes in microglia in an evolving cerebral injury. These tMCAO-induced actions were significantly enhanced by the TDAG8 deficiency. Administration of minocycline, which is known to inhibit microglial activation, improved the cerebral infarction and dysfunctional behavior induced by tMCAO in the TDAG8-deficient mouse. Thus, acidic pH/TDAG8 protects against cerebral infarction caused by tMCAO, at least due to the mechanism involving the inhibition of microglial functions.


Assuntos
Lesões Encefálicas/metabolismo , Isquemia Encefálica/metabolismo , Substâncias Protetoras/metabolismo , Animais , Modelos Animais de Doenças , Concentração de Íons de Hidrogênio , Infarto da Artéria Cerebral Média/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microglia/metabolismo , Prótons , Receptores Acoplados a Proteínas-G/metabolismo , Reperfusão/métodos , Transdução de Sinais/fisiologia
5.
Arch Biochem Biophys ; 695: 108629, 2020 11 30.
Artigo em Inglês | MEDLINE | ID: mdl-33068524

RESUMO

Cell death is a process consequential to cerebral ischemia and cerebral ischemia/reperfusion (I/R) injury. Recent evidence suggest that necroptosis has been involved in the pathogenesis of ischemic brain injury. The mechanism of necroptosis is initiated by an activation of inflammatory receptors including tumor necrosis factor, toll like receptor, and fas ligands. The signals activate the receptor-interacting protein kinase (RIPK) 1, 3, and a mixed-lineage kinase domain-like pseudokinase (MLKL) to instigate necroptosis. RIPK1 inhibitor, necrostatin-1, was developed, and dramatically reduced brain injury following cerebral ischemia in mice. Consequently, necroptosis could be a novel therapeutic target for stroke, which aims to reduce long-term adverse outcomes after cerebral ischemia. Several studies have been conducted to test the roles of necroptosis on cerebral ischemia and cerebral I/R injury, and the efficacy of necrostatin-1 has been tested in those models. Evidence regarding the roles of necroptosis and the effects of necrostatin-1, from in vitro and in vivo studies, has been summarized and discussed. In addition, other therapeutic managements, involving in necroptosis, are also included in this review. We believe that the insights from this review might clarify the clinical perspective and challenges involved in future stroke treatment by targeting the necroptosis pathway.


Assuntos
Isquemia Encefálica/metabolismo , Necroptose , Traumatismo por Reperfusão/metabolismo , Transdução de Sinais , Animais , Isquemia Encefálica/patologia , Humanos , Imidazóis/metabolismo , Indóis/metabolismo , Camundongos , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Traumatismo por Reperfusão/patologia
6.
Nat Commun ; 11(1): 5196, 2020 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-33060592

RESUMO

Pericytes play essential roles in blood-brain barrier (BBB) integrity and dysfunction or degeneration of pericytes is implicated in a set of neurological disorders although the underlying mechanism remains largely unknown. However, the scarcity of material sources hinders the application of BBB models in vitro for pathophysiological studies. Additionally, whether pericytes can be used to treat neurological disorders remains to be elucidated. Here, we generate pericyte-like cells (PCs) from human pluripotent stem cells (hPSCs) through the intermediate stage of the cranial neural crest (CNC) and reveal that the cranial neural crest-derived pericyte-like cells (hPSC-CNC PCs) express typical pericyte markers including PDGFRß, CD146, NG2, CD13, Caldesmon, and Vimentin, and display distinct contractile properties, vasculogenic potential and endothelial barrier function. More importantly, when transplanted into a murine model of transient middle cerebral artery occlusion (tMCAO) with BBB disruption, hPSC-CNC PCs efficiently promote neurological functional recovery in tMCAO mice by reconstructing the BBB integrity and preventing of neuronal apoptosis. Our results indicate that hPSC-CNC PCs may represent an ideal cell source for the treatment of BBB dysfunction-related disorders and help to model the human BBB in vitro for the study of the pathogenesis of such neurological diseases.


Assuntos
Isquemia Encefálica/metabolismo , Pericitos/metabolismo , Recuperação de Função Fisiológica/fisiologia , Acidente Vascular Cerebral/metabolismo , Animais , Barreira Hematoencefálica/metabolismo , Isquemia Encefálica/patologia , Diferenciação Celular/genética , Infarto da Artéria Cerebral Média , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Crista Neural/metabolismo , Células-Tronco Pluripotentes/metabolismo , Receptor beta de Fator de Crescimento Derivado de Plaquetas/metabolismo , Recuperação de Função Fisiológica/genética , Acidente Vascular Cerebral/patologia , Transcriptoma
8.
Sci Rep ; 10(1): 15999, 2020 09 29.
Artigo em Inglês | MEDLINE | ID: mdl-32994510

RESUMO

During chronic cerebral hypoperfusion (CCH), the cerebral blood flow gradually decreases, leading to cognitive impairments and neurodegenerative disorders, such as vascular dementia. The reduced oxygenation, energy supply induced metabolic changes, and insufficient neuroplasticity could be reflected in the synaptic proteome. We performed stepwise bilateral common carotid occlusions on rats and studied the synaptic proteome changes of the hippocampus, occipital and frontal cortices. Samples were prepared and separated by 2-D DIGE and significantly altered protein spots were identified by HPLC-MS/MS. We revealed an outstanding amount of protein changes in the occipital cortex compared to the frontal cortex and the hippocampus with 94, 33, and 17 proteins, respectively. The high alterations in the occipital cortex are probably due to the hypoxia-induced retrograde degeneration of the primary visual cortex, which was demonstrated by electrophysiological experiments. Altered proteins have functions related to cytoskeletal organization and energy metabolism. As CCH could also be an important risk factor for Alzheimer's disease (AD), we investigated whether our altered proteins overlap with AD protein databases. We revealed a significant amount of altered proteins associated with AD in the two neocortical areas, suggesting a prominent overlap with the AD pathomechanism.


Assuntos
Isquemia Encefálica/diagnóstico por imagem , Redes Reguladoras de Genes , Proteômica/métodos , Sinapses/metabolismo , Animais , Isquemia Encefálica/etiologia , Isquemia Encefálica/metabolismo , Artéria Carótida Primitiva/diagnóstico por imagem , Cromatografia Líquida de Alta Pressão , Modelos Animais de Doenças , Lobo Frontal/metabolismo , Hipocampo/metabolismo , Angiografia por Ressonância Magnética , Masculino , Lobo Occipital/metabolismo , Ratos , Espectrometria de Massas em Tandem
9.
Biomed Khim ; 66(4): 339-344, 2020 Jul.
Artigo em Russo | MEDLINE | ID: mdl-32893824

RESUMO

The level of erythropoietin (EPO) and vascular endothelial growth factor (VEGF-A) was investigated in blood serum and brain of Wistar rats by the enzyme immunoassay with specific rat antibodies. These growth factors are actively studied as biomarkers of ischemia or cytoprotection, as well as targets for agents initiating preconditioning (PreC). Pharmacological (amtizol administration), hypoxic (hypobaric hypoxia), and combined PreC (amtizol+hypobaric hypoxia) were used as neuroprotective approaches in this experimental work. In normoxia groups blood and brain tissue were collected 1 h (early period) or 48 h (delayed period) after the PreC. In addition we studied groups of animals with cerebral ischemia (induced by bilateral ligation of the common carotid arteries) 1 h and 48 h after the combined PreC: the levels of EPO and VEGF-A in the blood serum and the brain supernatant were determined in one day after the ligation. Experiments have shown that amtizol (3,5-diamino-1,2,4-thiadiazole) in normoxia increased the EPO level in the brain, and did not change EPO in blood serum and VEGF-A levels in both serum and the brain. A three-day (60 min exposure with 48 h intervals) hypobaric hypoxia (410 mm Hg) increased EPO and VEGF-A in the blood serum and brain tissues, but in most experimental groups differences did not reach the level of statistical significance versus intact control. The combined PreC was accompanied by a significant increase of EPO and VEGF-A in normoxia conditions both in early and delayed period of PreC. In cerebral ischemia the EPO level in the blood serum and brain tissues was higher than in intact control. The serum level of VEGF-A of the ischemia control group tended to increase while the brain level of VEGF-A remained basically unchanged versus the intact control group. In combined PreC before ischemia, the EPO level was lower in serum as compared with the ischemia control in the delayed PreC period, but did not differ significantly from the ischemia control in serum in early period and in brain tissues in both PreC periods. The VEGF-A level in the groups of combined PreC was significantly lower in serum as compared with the ischemia control in both the early and delayed PreC; in brain tissues it did not differ from the level of both the intact and ishemia control in early PreC period and was higher than in both control groups in the delayed PreC period.


Assuntos
Isquemia Encefálica , Eritropoetina , Fator A de Crescimento do Endotélio Vascular , Animais , Isquemia Encefálica/tratamento farmacológico , Isquemia Encefálica/metabolismo , Eritropoetina/metabolismo , Hipóxia , Ratos , Ratos Wistar , Fator A de Crescimento do Endotélio Vascular/metabolismo
10.
Life Sci ; 260: 118403, 2020 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-32926923

RESUMO

AIMS: To explore the therapeutic effect and possible mechanism of exosomes from MSCs overexpressing miR-223 on cerebral ischemia and microglia polarization mediated inflammation. MAIN METHODS: Rats after middle cerebral artery occlusion and reperfusion (MCAO/R) surgery and microglia BV-2 exposed to oxygen and glucose deprivation (OGD) and cysteinyl leukotrienes (CysLTs) stimulation were subject to exosomes from miR-223-3p transfected MSCs treatment, respectively. Behavioral tests were applied to assess the rats' neurological function. FACS was used to analyze M1/M2 microglia BV-2. production of cytokines in the ischemic hemisphere and BV-2 was detected by ELISA or qRT-PCR. Western blotting and qRT-PCR were also used to examine the expression of cysteinyl leukotriene receptor 2 (CysLT2R) in vivo and in vitro. KEY FINDINGS: Exosomes from MSCs over expressing miR-223-3p decreased MCAO/R induced cerebral infarct volume, improved neurological deficits, promoted learning and memorizing abilities. They suppressed pro-inflammatory factors expression and promoted anti-inflammatory factors secretion in the ischemic cortex and hippocampus. In vitro, exosomal miR-223-3p exhibited a more evident impact on modulating mRNA expression and protein production of cytokines. It promoted M2 microglia transformation of M1 microglia induced by NMLTC4 with a concentration-dependent manner. Western blot and qRT-PCR also revealed exosomal miR-223-3p decreased mRNA and protein expression of CysLT2R in vitro and in vivo. SIGNIFICANCE: Exosomal miR-223-3p from MSCs attenuated cerebral ischemia/reperfusion injury through inhibiting microglial M1 polarization mediated pro-inflammatory response, which may be related with inhibitory effect of exosomal miR-223-3p on CysLT2R.


Assuntos
Isquemia Encefálica/prevenção & controle , Exossomos/genética , Inflamação/prevenção & controle , MicroRNAs/genética , Microglia/metabolismo , Traumatismo por Reperfusão/prevenção & controle , Animais , Isquemia Encefálica/etiologia , Isquemia Encefálica/metabolismo , Isquemia Encefálica/patologia , Infarto da Artéria Cerebral Média/complicações , Inflamação/etiologia , Inflamação/metabolismo , Inflamação/patologia , Masculino , Microglia/imunologia , Microglia/patologia , Ratos , Ratos Sprague-Dawley , Traumatismo por Reperfusão/etiologia , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologia
11.
Life Sci ; 260: 118418, 2020 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-32931799

RESUMO

AIMS: Stroke is a devastating event with a limited choice of intervention. Benzoinum is frequently used to treat stroke in traditional Chinese medicine. Our team has found that the neuroprotection of benzoinum may related to angiogenesis, but the exact biological mechanism is unclear. The objective of this study was to explore its biological mechanism of angiogenesis in cerebral ischemia model rats. MAIN METHODS: First, network pharmacology and molecular docking were performed to predict the possible targets and mechanisms of benzoinum in treating ischemic stroke. The best dose was then selected according to pharmacodynamic indexes such as those for neurological deficit, cerebral infarction rate, and brain histopathology in middle cerebral artery occlusion (MCAO) model rats. Finally, RT-PCR, Western Blot and immunohistochemical analysis were applied to verify the prediction results from molecular docking. KEY FINDINGS: Network pharmacology and molecular docking demonstrated that the targets of treating cerebral ischemia were PDE4D, ACE and TTR, and the mechanism may be related to the ACE-AngI-VEGF signaling pathway. Experimental verification results suggested that 0.50 g/kg and 1.00 g/kg benzoinum could significantly protect against neurological deficit and reduce cerebral infarction rate in the cerebral cortex and hippocampus in MCAO model rats. At an optimal dose, benzoinum could significantly up-regulate VEGF, SHH and ANG-1, yet down-regulate ACE expression in MCAO model rats. SIGNIFICANCE: Balsamic acid is the active ingredient of benzoinum that protects against ischemic stroke and the possible mechanism is related to the promotion of angiogenesis via regulating ACE-AngI-VEGF pathway.


Assuntos
Isquemia Encefálica/tratamento farmacológico , Modelos Animais de Doenças , Regulação da Expressão Gênica/efeitos dos fármacos , Infarto da Artéria Cerebral Média/complicações , Fármacos Neuroprotetores/farmacologia , Bibliotecas de Moléculas Pequenas/farmacologia , Acidente Vascular Cerebral/tratamento farmacológico , Animais , Isquemia Encefálica/etiologia , Isquemia Encefálica/metabolismo , Isquemia Encefálica/patologia , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/patologia , Masculino , Simulação de Acoplamento Molecular , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/metabolismo , Neovascularização Patológica/patologia , Peptidil Dipeptidase A/genética , Peptidil Dipeptidase A/metabolismo , Ratos , Ratos Sprague-Dawley , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/etiologia , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologia , Ribonuclease Pancreático/genética , Ribonuclease Pancreático/metabolismo , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/metabolismo , Acidente Vascular Cerebral/patologia , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo
12.
J Neurosci ; 40(38): 7355-7374, 2020 09 16.
Artigo em Inglês | MEDLINE | ID: mdl-32817249

RESUMO

17ß-Estradiol (E2) is produced from androgens via the action of the enzyme aromatase. E2 is known to be made in neurons in the brain, but the functions of neuron-derived E2 in the ischemic brain are unclear. Here, we used a forebrain neuron-specific aromatase KO (FBN-ARO-KO) mouse model to deplete neuron-derived E2 in the forebrain and determine its roles after global cerebral ischemia. We demonstrated that ovariectomized female FBN-ARO-KO mice exhibited significantly attenuated astrocyte activation, astrocytic aromatization, and decreased hippocampal E2 levels compared with FLOX mice. Furthermore, FBN-ARO-KO mice had exacerbated neuronal damage and worse cognitive dysfunction after global cerebral ischemia. Similar results were observed in intact male mice. RNA-seq analysis revealed alterations in pathways and genes associated with astrocyte activation, neuroinflammation, and oxidative stress in FBN-ARO-KO mice. The compromised astrocyte activation in FBN-ARO-KO mice was associated with robust downregulation of the astrocyte-derived neurotrophic factors, BDNF and IGF-1, as well as the astrocytic glutamate transporter, GLT-1. Νeuronal FGF2, which acts in a paracrine manner to suppress astrocyte activation, was increased in FBN-ARO-KO neurons. Interestingly, blocking FGF2 signaling by central injection of FGFR3-neutralizing antibody was able to reverse the diminishment in neuroprotective astrocyte reactivity, and attenuate neuronal damage in FBN-ARO-KO mice. Moreover, in vivo E2 replacement suppressed FGF2 signaling and rescued the compromised reactive astrogliosis and cognitive deficits. Collectively, our data provide novel genetic evidence for a beneficial role of neuron-derived E2 in astrocyte activation, neuroprotection, and cognitive preservation following ischemic injury to the brain.SIGNIFICANCE STATEMENT Following cerebral ischemia, astrocytes become highly reactive and can exert neuroprotection through the release of neurotrophic factors and clearance of neurotoxic glutamate. The current study advances our understanding of this process by demonstrating that neuron-derived 17ß-estradiol (E2) is neuroprotective and critical for induction of reactive astrocytes and their ability to produce astrocyte-derived neurotrophic factors, BDNF and IGF-1, and the glutamate transporter, GLT-1 after ischemic brain damage. These beneficial effects of neuron-derived E2 appear to be due, at least in part, to suppression of neuronal FGF2 signaling, which is a known suppressor of astrocyte activation. These findings suggest that neuron-derived E2 is neuroprotective after ischemic brain injury via a mechanism that involves suppression of neuronal FGF2 signaling, thereby facilitating astrocyte activation.


Assuntos
Astrócitos/metabolismo , Isquemia Encefálica/metabolismo , Estrogênios/metabolismo , Gliose/metabolismo , Neurônios/metabolismo , Comunicação Parácrina , Animais , Aromatase/genética , Aromatase/metabolismo , Isquemia Encefálica/patologia , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Região CA1 Hipocampal/citologia , Região CA1 Hipocampal/metabolismo , Células Cultivadas , Córtex Cerebral/metabolismo , Córtex Cerebral/patologia , Transportador 2 de Aminoácido Excitatório/metabolismo , Feminino , Fator 2 de Crescimento de Fibroblastos/metabolismo , Fator de Crescimento Insulin-Like I/metabolismo , Masculino , Camundongos , Estresse Oxidativo
13.
Clin Interv Aging ; 15: 1295-1303, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32821090

RESUMO

Purpose: We evaluated the relationship between pretreatment IL-6 and hsCRP levels, symptom severity and functional outcome of patients with acute ischemic stroke (AIS) treated with IV-thrombolysis. Patients and Methods: IL-6 and hsCRP samples were obtained from 83 consecutively treated Caucasian patients with AIS prior to initiation of IV-thrombolysis. Severity of stroke symptoms was assessed using the National Institutes of Health Stroke Scale (NIHSS), whereas functional outcome was assessed with modified Rankin Scale (mRS). The commercially available sets of enzymatic immune tests were used to estimate the concentrations of inflammatory markers in serum. Results: Medians of IL-6 serum concentrations prior to IV-thrombolysis were lower in patients with favorable (mRS 0-2 pts) functional outcome than in those with unfavorable (mRS 3-6 pts) functional outcome, both at hospital dismission (5.92: 2.30-7.71 vs 9.46: 3.79-17.29 pg/mL; p<0.01) and on the ninetieth day from stroke onset (5.87: 2.30-10.58 vs 10.9: 5.94-17.28 pg/mL; p<0.01). There were no existing differences regarding hsCRP levels between groups (2.49: 0.11-9.82 vs 4.44: 0.32-9.87 mg/dL; p=0.30 and 2.57: 0.11-2.57 vs 2.83: 0.32-9.32 mg/dL; p=0.75, respectively). Patients with lacunar strokes were characterized by lower median of IL-6 (5.96: 2.87-13.0% vs 7.29: 2.30-17.28; p=<0.02) and hsCRP (2.25: 0.11-9.82 vs 4.84: 0.35-9.87; p=0.01) than those with nonlacunar infarctions. Multivariate analysis showed an impact of IL-6 on mRS measured on hospital dismission and after three months, regardless of their initial NIHSS, presence of hemorrhagic transformation and type 2 diabetes. No impact of hsCRP, lacunar etiology and patients' age on functional outcome existed. Conclusion: Regardless of the stroke etiology, pretreatment of IL-6, but not of hsCRP levels, may help to predict functional outcome after IV-thrombolysis independently of symptom severity and stroke complications.


Assuntos
Isquemia Encefálica/metabolismo , Isquemia Encefálica/terapia , Proteína C-Reativa/metabolismo , Interleucina-6/metabolismo , Acidente Vascular Cerebral/metabolismo , Idoso , Isquemia Encefálica/complicações , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Acidente Vascular Cerebral/complicações , Terapia Trombolítica , Ativador de Plasminogênio Tecidual/uso terapêutico , Resultado do Tratamento
14.
Acta Biochim Biophys Sin (Shanghai) ; 52(9): 1016-1029, 2020 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-32845287

RESUMO

Recent studies have reported an increasing incidence of ischemic stroke, particularly in younger age groups. Dental pulp stem cells (DPSCs) and periodontal ligament stem cells (PDLSCs) are the most common stem cells acquired from the teeth of adults, even elderly people. However, there are no detailed reports on whether DPSCs or PDLSCs are suitable for the treatment of ischemic stroke. In this study, the in vitro differentiation of DPSCs and PDLSCs into neuron-like cells was evaluated. Then, we established a rat model of cerebral ischemia. DPSCs or PDLSCs were administered to animals, and the therapeutic effects of these two types of cells were investigated. The results showed that PDLSCs had a higher differentiation rate than DPSCs. Immunofluorescence studies showed that the expression of the neuronal differentiation marker Thy-1 was higher in PDLSCs than in DPSCs, and other gene markers of neuronal differentiation showed corresponding trends, which were confirmed by western blot analysis. In this process, the Notch and Wnt signaling pathways were inhibited and activated, respectively. Finally, rats with transient occlusion of the right middle cerebral artery were used as a model to assess the therapeutic effect of PDLSCs and DPSCs on ischemia. The results showed that rats in the PDLSC-treated group emitted significantly greater red fluorescence signal than the DPSC-treated group. PDLSC transplantation promoted the recovery of neurological function more effectively than DPSC transplantation. Hence, PDLSCs represent an autogenous source of adult mesenchymal stem cells with desirable biological properties and may be an ideal candidate for clinical applications.


Assuntos
Isquemia Encefálica , Diferenciação Celular , Polpa Dentária/metabolismo , Neurônios/metabolismo , Ligamento Periodontal/metabolismo , Transplante de Células-Tronco , Células-Tronco/metabolismo , Animais , Isquemia Encefálica/metabolismo , Isquemia Encefálica/patologia , Isquemia Encefálica/terapia , Polpa Dentária/patologia , Modelos Animais de Doenças , Xenoenxertos , Humanos , Masculino , Neurônios/patologia , Ligamento Periodontal/patologia , Ratos , Ratos Sprague-Dawley , Células-Tronco/patologia
15.
Neuroepidemiology ; 54(5): 370-374, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32791504

RESUMO

The severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2) causes the coronavirus disease 2019 (COVID-19). It quickly became pandemic, and so did a new concern about COVID-19 infections increasing the risk for cerebrovascular diseases. There is an association between COVID-19 illness in people and acute stroke. Several chemical, mechanical, and/or inflammatory central nervous system pathologies are proposed to explain how this viral infection might induce acute cerebrovascular disease. Timely available evaluation and/or intervention is imperative for patients with concerns about acute cerebrovascular issues.


Assuntos
Betacoronavirus , Encéfalo/virologia , Circulação Cerebrovascular/fisiologia , Infecções por Coronavirus/complicações , Pneumonia Viral/complicações , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/virologia , Betacoronavirus/metabolismo , Encéfalo/metabolismo , Isquemia Encefálica/etiologia , Isquemia Encefálica/metabolismo , Isquemia Encefálica/virologia , Infecções por Coronavirus/metabolismo , Humanos , Pandemias , Pneumonia Viral/metabolismo , Acidente Vascular Cerebral/metabolismo
16.
Biochim Biophys Acta Mol Basis Dis ; 1866(12): 165934, 2020 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-32827650

RESUMO

Cerebral ischemia-induced hyperglycemia has been reported to accentuate neurological damage following focal or global cerebral ischemia. Hyperglycemia found in rats following focal brain ischemia occurs in the first 24 h and has been claimed to be caused by increased liver gluconeogenesis and insulin resistance. However, liver gluconeogenesis and the mechanisms leading to hyperglycemia after global cerebral ischemia remain uncertain. This study investigated the glycemic homeostasis and hepatic metabolism in rats after transient four-vessel occlusion (4-VO)-induced global cerebral ischemia, an event that mimics to a certain degree the situation during cardiac arrest. Several metabolic fluxes were measured in perfused livers. Activities and mRNA expressions of hepatic glycolysis and glyconeogenesis rate-limiting enzymes were assessed as well as respiratory activity of hepatic isolated mitochondria. Global cerebral ischemia was associated with hyperglycemia and hyperinsulinemia 24 h after ischemia. Insulin resistance developed later and was prominent after the 5th day. Hepatic anabolism and catabolism were both modified in a complex and time-dependent way. Gluconeogenesis, ß-oxidation, ketogenesis and glycolysis were diminished at 24 h after ischemia. At 5 days after ischemia glycolysis had normalized, but gluconeogenesis, ketogenesis and ß-oxidation were accelerated. The overall metabolic modifications suggest that a condition of depressed metabolism was established in response to the new conditions generated by the cerebral global ischemia. Whether the modifications in the liver metabolism found in rats after the ischemic insult can be translated to individuals following global brain ischemia remains uncertain, but the results of this study are hoped to encourage further investigations.


Assuntos
Glicemia/metabolismo , Isquemia Encefálica/metabolismo , Homeostase , Fígado/metabolismo , Animais , Masculino , Ratos , Ratos Wistar
17.
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
18.
Medicine (Baltimore) ; 99(28): e20921, 2020 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-32664088

RESUMO

Inflammation is an important pathophysiological process after an acute stroke (AS). Pro- and anti-inflammatory molecules (cytokines and interleukins) are the key players during this mechanism. Emerging evidence indicate that these molecules can serve as biomarkers of stroke progression and outcome and as novel therapeutics agents. The aim of this study is to explore the temporal changes in these molecules and validate them as biomarker of AS progression and neurological outcome.The "Cytokine Registry In Stroke Patients (CRISP)" is a prospective cohort study of 600 AS patients presenting to the tertiary hospital with-in 24 h of the onset of symptoms. Plasma cytokines and interleukins will be collected at admission and 24 h after and will be measured using enzyme-linked immunosorbent assay (ELISA) to evaluate the difference in their variation among different gender, race and ethnicity and their association with various neurological outcomes. The primary exposures are biological sex (male, female) and race/ethnicity. Confounding variables include age, vascular risk factors, infarct size, stroke onset to presentation time, and identified stroke etiologies. Matched controls will be used for the comparison and evaluation of the difference among gender and race/ethnicities.CRISP is a prospective observational study that investigates the role and relationship of molecular biomarkers identifying specific and relevant targets pertinent for monitoring the progression and outcome in AS patients.Trial Registration: The study is registered on ClinicalTrial.gov: https://clinicaltrials.gov/ (NCT03297827).


Assuntos
Isquemia Encefálica/metabolismo , Citocinas/sangue , Interleucinas/sangue , Acidente Vascular Cerebral/metabolismo , Doença Aguda , Biomarcadores/sangue , Isquemia Encefálica/fisiopatologia , Protocolos Clínicos/normas , Progressão da Doença , Ensaio de Imunoadsorção Enzimática/métodos , Grupos Étnicos/estatística & dados numéricos , Feminino , Humanos , Inflamação/metabolismo , Masculino , Estudos Prospectivos , Sistema de Registros , Fatores de Risco , Acidente Vascular Cerebral/fisiopatologia , Fatores de Tempo
19.
Turk Neurosurg ; 30(4): 483-490, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32672342

RESUMO

AIM: To study miR-24 effects on cerebral infarction in rats. MATERIAL AND METHODS: A rat middle cerebral artery occlusion model (MCAO) was constructed. Intracerebroventricular stereotactic injection of miR-24 agomir/antagomir was performed in the rat MCAO model. According to different experiences, rats were divided into normal, sham, MCAO, miR-24 agomir and miR-24 antagomir groups. Serum TCH, HDL and TG levels were detected. RESULTS: Comparingthe normal and sham groups, we observed decreased relative miR-24 expression (p < 0.05) and increased cerebral infarction area percentage, apoptotic cells and relative caspase-3 protein expression (p < 0.05) in theMCAO, miR-24 agomirand miR-24 antagomir groups. TC, TG and HDL-C levels of the MCAO and miR-24 antagomir groups were higher than those of normal and sham groups (p < 0.05).Compared with the MCAO group, increased relative miR-24 expression (p < 0.05) and decreased TC, TG and HDL-C levels,cerebral infarction area percentage, number of apoptotic cells and caspase-3 expression (p < 0.05) were found in themiR-24 agomir group, contrasting with theobservations from the miR-24 antagomir group. CONCLUSION: miR-24 reduced serum TCH, HDL and TG levels and inhibited brain tissue cell apoptosis in rats with cerebral infarction.


Assuntos
Infarto da Artéria Cerebral Média/patologia , MicroRNAs/metabolismo , Animais , Apoptose/fisiologia , Encéfalo/metabolismo , Isquemia Encefálica/metabolismo , Caspase 3/metabolismo , Colesterol/sangue , HDL-Colesterol/sangue , Infarto da Artéria Cerebral Média/metabolismo , Masculino , Ratos , Ratos Sprague-Dawley , Triglicerídeos/sangue
20.
Sci Rep ; 10(1): 12369, 2020 07 23.
Artigo em Inglês | MEDLINE | ID: mdl-32703986

RESUMO

Cranial irradiation (IR) is commonly used to treat primary brain tumors and metastatic diseases. However, cranial IR-treated patients often develop vascular abnormalities later in life that increase their risk for cerebral ischemia. Studies in rodents have demonstrated that IR impairs maintenance of the neural stem/precursor cell (NSPC) pool and depletes neurogenesis. We and others have previously shown that stroke triggers NSPC proliferation in the subventricular zone and migration towards the stroke-injured neocortex. Whether this response is sustained in the irradiated brain remains unknown. Here, we demonstrate that cranial IR in mice at an early postnatal age significantly reduced the number to neuronal progenitors responding to cortical stroke in adults. This was accompanied by a reduced number of microglia/macrophages in the peri-infarct cortex; however, the astrocytic response was not altered. Our findings indicate that IR impairs the endogenous repair capacity in the brain in response to stroke, hence pointing to another side effect of cranial radiotherapy which requires further attention.


Assuntos
Envelhecimento , Isquemia Encefálica , Córtex Cerebral , Irradiação Craniana/efeitos adversos , Células-Tronco Neurais/metabolismo , Lesões Experimentais por Radiação , Acidente Vascular Cerebral , Animais , Animais Recém-Nascidos , Isquemia Encefálica/etiologia , Isquemia Encefálica/metabolismo , Isquemia Encefálica/patologia , Córtex Cerebral/metabolismo , Córtex Cerebral/patologia , Feminino , Camundongos , Células-Tronco Neurais/patologia , Lesões Experimentais por Radiação/etiologia , Lesões Experimentais por Radiação/metabolismo , Lesões Experimentais por Radiação/patologia , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/metabolismo , Acidente Vascular Cerebral/patologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA