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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

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. Source

Wu X.,Liaoning Medical University | Wu X.,Capital Medical University | Zhao H.,Capital Medical University | Zhao H.,Beijing Key Laboratory of Translational Medicine for Cerebrovascular Diseases | And 6 more authors.
International Journal of Neuroscience

Objectives: In vivo and in vitro studies have shown that 2-deoxyglucose (2-DG) administration enhances tolerance and exerts neuroprotection against ischemic injury or oxidative stress. In this study, we investigated the effects of 2-DG on ischemic brain injuries in rats and determined whether the effects are related to sublethal endoplasmic reticulum (ER) stress. Methods: 2-DG was administered systemically 7 d before the rats were subjected to focal cerebral ischemia (2 h) followed by reperfusion. Neurological score and infarct volume were evaluated, and protein expression of ER molecular chaperone glucose-regulated protein 78 (GRP78) and X-box protein-1 (XBP-1) was determined at different time points after reperfusion. Results: 2-DG pretreatment significantly decreased neurological scores after reperfusion for 3 h, 6 h, 12 h, and 24 h, reduced infarct volume at 24 h after reperfusion compared to the corresponding control groups. ER molecular chaperone GRP78 and XBP-1 increased in 2-DG pretreatment group as compared to the control. Conclusion: Pretreatment with 2-DG improves the neurological function after cerebral ischemia-reperfusion injury. Increased expression of ER chaperone GRP78 and activation of XBP-1 may contribute to the protective effect of 2-DG against brain injury. © 2014 Informa Healthcare USA, Inc. Source

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

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. Source

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

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. Source

Tong X.,Beijing Tiantan Hospital | Tong X.,Beijing Institute for Brain Disorders | Tong X.,Beijing Key Laboratory of Translational Medicine for Cerebrovascular Diseases | Tong X.,Capital Medical University | And 25 more authors.
World Neurosurgery

Objective To explore outcomes after microsurgery of brain arteriovenous malformations (AVMs) that failed to be obliterated by Gamma Knife radiosurgery (GKRS). Methods From January 2000 to January 2014, 42 consecutive patients underwent surgical resection of persistent AVMs after GKRS. These 42 patients with AVMs who underwent radiosurgery (radiosurgery group) were individually matched with 42 patients with AVMs who did not undergo radiosurgery (no radiosurgery group) based on patient and AVM characteristics. The modified Rankin Scale was used to assess neurologic status of patients. The effects of GKRS on AVM resection and surgical outcomes were analyzed. Results After GKRS, the mean AVM volume was significantly reduced by 76.8% (P < 0.01), the size was reduced by 41% (P < 0.01), and the Spetzler-Martin grade was reduced in 61.9% of the patients (P < 0.01). During the time interval from radiosurgery to surgical resection, subsequent hemorrhages led to significant neurologic deterioration (P = 0.046). Compared with the control group, the frequency of preoperative embolization, operative time, and blood loss were significantly lower in the radiosurgery group (all P < 0.05). The no radiosurgery group had a significantly higher rate of worsening in mRS scores at 6 months after surgery (40.5% vs. 16.7%, P = 0.029). Good neurologic status (mRS score <3) was achieved in 81% of the radiosurgery group and 83% of the no radiosurgery group at the final follow-up evaluation. Conclusions GKRS performed several years before microsurgical resection can facilitate resectability of AVMs and decrease the rate of postoperative neurologic deterioration. For patients with persistent AVMs several years after GKRS, microsurgical resection is recommended to achieve good clinical outcomes. © 2016 Elsevier Inc. All rights reserved. Source

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