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Zhao Y.,Capital Medical University | Zhao Y.,Beijing Geriatric Medical Research Center | Zhao Y.,Key Laboratory of Neurodegenerative Diseases | Zhao Y.,Beijing Key Laboratory of Translational Medicine for Cerebrovascular Diseases | And 24 more authors.
Stroke | Year: 2014

BACKGROUND AND PURPOSE - : Zinc has been reported to possess both neurotoxic and neuroprotective capabilities. The effects of elevated intracellular zinc accumulation following transient focal cerebral ischemia remain to be fully elucidated. Here, we investigated whether removing zinc with the membrane-permeable zinc chelator, N,N,N′,N′-tetrakis(2- pyridylmethyl)ethylenediamine (TPEN), would decrease the intracellular levels of zinc in the ischemic tissue, leading to reduced brain damage and improved neurological outcomes. METHODS - : Rats were pretreated with TPEN or vehicle before or after a 90-minute middle cerebral artery occlusion. Cerebral infarct volume, neurological functions, neuronal apoptosis, poly(ADP-ribose) polymerase activity, and cytosolic labile zinc were assessed after ischemia and reperfusion. RESULTS - : Cerebral ischemia caused a dramatic cytosolic labile zinc accumulation in the ischemic tissue, which was decreased markedly by TPEN (15 mg/kg) pretreatment. Chelating zinc lead to reduced infarct volume compared with vehicle-treated middle cerebral artery occlusion rats, accompanied by much improved neurological assessment and motor function, which were sustained for 14 days after reperfusion. We also determined that reducing zinc accumulation rescued neurons from ischemia-induced apoptotic death by reducing poly(ADP-ribose) polymerase-1 activation. CONCLUSIONS - : Ischemia-induced high accumulation of intracellular zinc significantly contributed to ischemic brain damage through promotion of neuronal apoptotic death. Removing zinc may be an effective and novel approach to reduce ischemic brain injury. © 2014 American Heart Association, Inc.


Zhao H.,Capital Medical University | Zhao H.,Beijing Geriatric Medical Research Center | Zhao H.,Key Laboratory of Neurodegenerative Diseases of Ministry of Education | Zhao H.,Beijing Key Laboratory of Translational Medicine for Cerebrovascular Diseases | And 29 more authors.
Brain Research | Year: 2014

The present study was designed to investigate the potential role of miR-23a-3p in experimental brain ischemia-reperfusion injury. Cerebral ischemia reperfusion was induced by transient middle cerebral artery occlusion (MCAO) for 1 h in C57/BL6 mice. And miR-23a-3p angomir was transfected to upregulate the miR-23a-3p level. Our results showed that miR-23a-3p levels were transiently increased at 4 h after reperfusion in the peri-infarction area, while markedly increased in the infarction core at reperfusion 4 h and 24 h. Importantly, in vivo study demonstrated that miR-23a-3p angomir treatment through intracerebroventricular injection markedly decreased cerebral infarction volume after MCAO. Simultaneously, miR-23a-3p reduced peroxidative production nitric oxide (NO) and 3-nitrotyrosine (3-NT), and increased the expression of manganese superoxide dismutase (MnSOD). In vitro study demonstrated that miR-23a-3p decreased hydrogen peroxide (H2O2)-induced lactate dehydrogenase (LDH) leakage dose-dependently, and reduced protein levels of activated caspase-3 in neuro-2a cells. In addition, miR-23a-3p reduced H2O2-induced production of NO and 3-NT dose-dependently, and reversed the decreased activity of total SOD and MnSOD in neuro-2a cells. Our study indicated that miR-23a-3p suppressed oxidative stress and lessened cerebral ischemia-reperfusion injury. © 2014 Elsevier B.V. All rights reserved.


Tong X.,Capital Medical University | Tong X.,China National Clinical Research Center for Neurological Diseases | Tong X.,Beijing Institute for Brain Disorders | Tong X.,Beijing Key Laboratory of Translational Medicine for Cerebrovascular Diseases | And 40 more authors.
World Neurosurgery | Year: 2016

Objective To identify whether age, sex, and lesion location are associated with initial presentation in patients with brain arteriovenous malformations (AVMs). Methods Collected data of 3299 consecutive patients with AVM treated at Beijing Tiantan Hosptial from January 1980 to January 2015 were analyzed. The variables assessed were age at diagnosis, sex, AVM location, and mode of initial presentation. Results Initial presentation was AVM hemorrhage in 57.9%, seizure in 20.9%, chronic headache in 14.9%, focal neurologic deficit in 5.2%, and incidental in 1.2%. Younger age and female sex were associated with initial hemorrhage (all P < 0.05). Hemorrhage was more likely to occur in patients with AVMs in the basal ganglia, the corpus callosum, the ventricles, the cerebellum, and the brainstem (all P < 0.05). Male sex was associated with initial seizure (P < 0.05). Initial seizure was more likely to occur in patients with AVMs in the frontal, temporal, parietal, frontotemporal, and frontoparietal lobe (all P < 0.05). Compared with frontal AVMs, temporal AVMs were more likely to present with hemorrhage (P < 0.05) and less likely to present with seizure (P < 0.05). AVMs involving the occipital lobe were more likely to present with chronic headaches (P < 0.05). Conclusions Initial AVM presentation varied with patient age, sex, and AVM locations. Younger age, female sex, and deep and infratentorial locations may be associated with initial hemorrhage. Male sex and frontal, temporal, and parietal AVM locations may be predictors of initial seizure. Chronic headache was more likely to occur in patients with AVMs involving the occipital lobe. © 2016 Elsevier Inc.


Gao F.,Capital Medical University | Gao F.,China National Clinical Research Center for Neurological Diseases | Gao F.,Beijing Institute for Brain Disorders | Gao F.,Beijing Key Laboratory of Translational Medicine for Cerebrovascular Diseases | And 20 more authors.
World Neurosurgery | Year: 2016

Objective To investigate long noncoding ribonucleic acid (lncRNA) expression patterns in adult moyamoya disease (MMD) patients and explore their possible roles in the pathophysiology of MMD. Methods A healthy control group (n = 10) and an MMD group (n = 15) were evaluated. RNA was extracted from peripheral blood samples and hybridized to microarray to get lncRNA expression profiles. Then predicted lncRNA target genes were identified, and bioinformatics analysis was performed to investigate their molecular functions. Results In the MMD group, 3649 lncRNAs exhibited more than 2-fold expression than their counterparts in the healthy control group; of these, 1494 were upregulated, while 2155 were downregulated. Principal component analysis and Hclust analysis produced completely different clusters between the 2 groups. Gene ontology and KEGG pathway enrichment analysis suggested that the differentially expressed lncRNAs regulate multiple signaling pathways that were related with inflammation and vascular disease, and mitogen-activated protein kinase (MAPK) signaling pathway was the core regulatory pathway. Conclusions Long noncoding RNA expression profiles were quite different between MMD and control groups. Multiple signaling pathways that were closely associated with immune response, vasculogenesis, and smooth muscle contraction were indicated to participate in lncRNAs regulatory mechanism; of these, MAPK signaling pathway, which has been well studied for the treatment of many other cardiovascular diseases, was the core of this regulatory network. Our findings could help further understand the pathophysiology of MMD and provide new potential therapeutic targets. © 2016 Elsevier Inc. All rights reserved.


Ma X.,Capital Medical University | Ma X.,China National Clinical Research Center For Neurological Diseases | Ma X.,Beijing Institute for Brain Disorders | Ma X.,Beijing Key Laboratory of Translational Medicine for Cerebrovascular Diseases | And 16 more authors.
Child's Nervous System | Year: 2016

Purpose: Seizure outcome after treatment for pediatric patients with arteriovenous malformations (AVMs) has been rarely described in the literature. The aim of this study was to determine the risk factors for seizure presentation in pediatric AVM patients and the predictors for seizure control following treatment. Methods: We searched our characteristics of seizures associated with brain arteriovenous malformations prospectively maintained AVM database at Beijing Tiantan Hospital and identified 198 pediatric patients with brain AVMs between the year 2009 and 2014. Seizure presentation, patient characteristics, AVM features, treatment modalities, and postoperative outcomes, especially post-treatment seizure control were collected. Univariate and multivariate logistic regression analyses were applied to determine the risk factors for seizure presentation as well as the predictors for seizure control. Results: Before initiation of any treatments, 63 (31.8 %) of the overall 198 patients presented with seizure. According to multivariate analyses, larger AVM size, frontal AVM location, and history of prior hemorrhage were significantly associated with seizure presentation (all p < 0.05). For patients with pre-treatment seizure presentation, good seizure outcome was achieved in 73.8 %. AVM obliteration, short-period history of seizure, and short duration for seizure onset were independent predictors of good seizure outcome in the multivariate analysis. For the 135 patients without seizures at presentation, the overall rate of de novo seizures was 4.4 %. Conclusion: In pediatric patients with brain AVMs, prior hemorrhage, larger AVM size, and frontal lobe location may predict subsequent seizures. Highest seizure control can be achieved by complete obliteration of the AVMs with microsurgical resection. © 2016 Springer-Verlag Berlin Heidelberg


Tao Z.,Capital Medical University | Tao Z.,Beijing Geriatric Medical Research Center | Tao Z.,Beijing Key Laboratory of Translational Medicine for Cerebrovascular Diseases | Zhao H.,Capital Medical University | And 21 more authors.
Journal of the Neurological Sciences | Year: 2015

MicroRNA-99a (miR-99a) has been reported to function as a tumor suppressor through regulating cell cycle and apoptosis. But its clinical significance in ischemic stroke and its function in cerebral ischemia-reperfusion (I/R) injury remained unknown. Herein transient middle cerebral artery occlusion was built on C57BL/6 mice, followed by intracerebroventricular injection of miR-99a agomir or antagomir before reperfusion for 24 h. Our clinical analysis indicates that plasma miR-99a level was significantly decreased in ischemic stroke patients as compared to healthy subjects, and a significant correlation was observed between miR-99a and clinical parameters. And miR-99a overexpression mitigated I/R injury in mice, as evidenced by reduced brain infarct volume and neural apoptosis, whereas miR-99a downregulation aggravates brain injury. In vitro, miR-99a protected neuro-2a cells against hydrogen peroxide-induced oxidative stress injury, by improving cell viability, suppressing LDH release and cell apoptosis. In addition, miR-99a overexpression inhibited H2O2 induced G1/S phase transition in neuro-2a cells, accompanied by a significant decrease in cyclin D1 level and a tendency of down-regulation of CDK6. It was further proved in mice that miR-99a inhibited cyclin D1 and CDK6 expressions following cerebral I/R injury. These findings indicate that miR-99a reduces neuronal damage following cerebral I/R through regulating cell cycle progression and preventing apoptosis, suggesting that miR-99a could be used as a new therapeutic agent targeting neuronal cell cycle re-entry following stroke. © 2015 Elsevier B.V. All rights reserved.


Liu X.,Capital Medical University | Liu X.,Key Laboratory of Neurodegenerative Diseases | Liu X.,Beijing Key Laboratory of Translational Medicine for Cerebrovascular Diseases | Zhao S.,Capital Medical University | And 21 more authors.
Translational Stroke Research | Year: 2014

Remote ischemic postconditioning (RIPostC) has been proved to protect the brain from stroke, but the precise mechanism remains not fully understood. In the present study, we aimed to investigate whether RIPostC attenuates cerebral ischemia-reperfusion injury by abating endoplasmic reticulum (ER) stress response. CHOP, a multifunctional transcription factor in ER stress, regulates the expression of genes related to apoptosis, such as Bim and Bcl-2. Male SD rats were subjected to right middle cerebral artery occlusion (MCAO) for 2 h followed by reperfusion, and RIPostC was induced by three cycles of 10 min ischemia and 10 min reperfusion on bilateral femoral arteries immediately after ischemia. CHOP siRNA (CHOPi) and control siRNA (Coni) were injected into the right lateral ventricle 30 min before the beginning of ischemia. RIPostC, CHOPi, or RIPostC + CHOPi application reduced infarct volume, improved the neurological function, and decreased cell apoptosis. RIPostC increased the protein level of glucose-regulated protein 78 (GRP78) and decreased the protein level of phosphorylated-EIF2α, caspase-12, and CHOP. Furthermore, the expression of CHOP, Bim and cleaved-caspase-3 was decreased, while Bcl-2 expression was increased in response to application of RIPostC, CHOPi, or RIPostC + CHOPi. In sum, RIPostC protects against ischemia-reperfusion brain injury in rats by attenuating ER stress response-induced apoptosis. © 2014, Springer Science+Business Media New York.


Liu X.-R.,Capital Medical University | Luo M.,Capital Medical University | Yan F.,Capital Medical University | Zhang C.-C.,Capital Medical University | And 5 more authors.
CNS Neuroscience and Therapeutics | Year: 2012

Aims: Ischemic postconditioning (IPostC) has been proved to have neuroprotective effects for cerebral ischemia, but the underlying mechanism remains elusive. This study aimed at validating the neuroprotective effects of IPostC and investigating whether the neuroprotection of IPostC is associated with matrix metalloproteinase 9 (MMP9) and the extracellular matrix proteins, laminin and fibronectin, following cerebral ischemia/reperfusion in rats. Methods: The rats in middle cerebral artery occlusion (MCAO) group underwent MCAO and reperfusion, and the animals in MCAO + IPostC group were treated by occluding bilateral common carotid arteries for 10 seconds and then reperfusing for 10 seconds for five episodes at the beginning of MCAO. Apoptosis was detected with terminal deoxynucleotidyl transferase dUTP nick end labeling staining. The expression of MMP9, laminin, and fibronectin was measured with immunofluorescence and enzyme-linked immunosorbent assay. Results: IPostC reduced brain edema and infarct volume and improved the neurological function. Furthermore, IPostC decreased cell apoptosis compared with the MCAO group. Compared to the MCAO group, IPostC treatment reduced MMP9 expression. Moreover, the results showed that the expression of laminin and fibronectin significantly increased in the MCAO + IPostC group compared to the MCAO group. Conclusion: These findings indicated that diminishment of MMP9 expression and the attenuation of degradation of laminin and fibronectin may be involved in the protective mechanisms of postconditioning against cerebral ischemia/reperfusion injury. © 2012 Blackwell Publishing Ltd.

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