Combined Ischemic Preconditioning and Resveratrol Improved Bloodbrain Barrier Breakdown via Hippo/YAP/TAZ Signaling Pathway

2020 ◽  
Vol 18 (9) ◽  
pp. 713-722 ◽  
Author(s):  
Ganji Hong ◽  
Ying Yan ◽  
Yali Zhong ◽  
Jianer Chen ◽  
Fei Tong ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Blood Brain Barrier ◽  
Ischemic Preconditioning ◽  
Infarct Volume ◽  
Ischemia Reperfusion ◽  
Cerebral Infarct ◽  
Brain Barrier ◽  
Binding Motif ◽  
Blood Brain ◽  
Barrier Breakdown

Background: Transient Ischemia/Reperfusion (I/R) is the main reason for brain injury and results in disruption of the Blood-Brain Barrier (BBB). It had been reported that BBB injury is one of the main risk factors for early death in patients with cerebral ischemia. Numerous investigations focus on the study of BBB injury which have been carried out. Objective: The objective of this study was to investigate the treatment function of the activation of the Hippo/Yes-Associated Protein (YAP) signaling pathway by combined Ischemic Preconditioning (IPC) and resveratrol (RES) before brain Ischemia/Reperfusion (BI/R) improves Blood-Brain Barrier (BBB) disruption in rats. Methods: Sprague-Dawley (SD) rats were pretreated with 20 mg/kg RES and IPC and then subjected to 2 h of ischemia and 22 h of reperfusion. The cerebral tissues were collected; the cerebral infarct volume was determined; the Evans Blue (EB) level, the brain Water Content (BWC), and apoptosis were assessed; and the expressions of YAP and TAZ were investigated in cerebral tissues. Results: Both IPC and RES preconditioning reduced the cerebral infarct size, improved BBB permeability, lessened apoptosis, and upregulated expressions of YAP and transcriptional co-activator with PDZ-binding motif (TAZ) compared to the Ischemia/Reperfusion (I/R) group, while combined IPC and RES significantly enhanced this action. Conclusion: combined ischemic preconditioning and resveratrol improved blood-brain barrier breakdown via Hippo/YAP/TAZ signaling pathway.

scholarly journals Detrimental role of pericyte Nox4 in the acute phase of brain ischemia

2015 ◽  
Vol 36 (6) ◽  
pp. 1143-1154 ◽  
Author(s):  
Ataru Nishimura ◽  
Tetsuro Ago ◽  
Junya Kuroda ◽  
Koichi Arimura ◽  
Masaki Tachibana ◽  
...  
Keyword(s):  
Middle Cerebral Artery ◽  
Middle Cerebral Artery Occlusion ◽  
Blood Brain Barrier ◽  
Cerebral Artery ◽  
Infarct Volume ◽  
Artery Occlusion ◽  
Brain Barrier ◽  
Blood Brain ◽  
Barrier Breakdown ◽  
Cerebral Artery Occlusion

Pericytes are mural cells abundantly present in cerebral microvessels and play important roles, including the formation and maintenance of the blood–brain barrier. Nox4 is a major source of reactive oxygen species in cardiovascular cells and modulate cellular functions, particularly under pathological conditions. In the present study, we found that the expression of Nox4 was markedly induced in microvascular cells, including pericytes, in peri-infarct areas after middle cerebral artery occlusion stroke models in mice. The upregulation of Nox4 was greater in a permanent middle cerebral artery occlusion model compared with an ischemia/reperfusion transient middle cerebral artery occlusion model. We performed permanent middle cerebral artery occlusion on mice with Nox4 overexpression in pericytes (Tg-Nox4). Infarct volume was significantly greater with enhanced reactive oxygen species production and blood–brain barrier breakdown in peri-infarct areas in Tg-Nox4, compared with littermate controls. In cultured brain pericytes, Nox4 was significantly upregulated by hypoxia and was promptly downregulated by reoxygenation. Phosphorylation of NFκB and production of matrix metalloproteinase 9 were significantly increased in both cultured pericytes overexpressing Nox4 and in peri-infarct areas in Tg-Nox4. Collectively, Nox4 is upregulated in pericytes in peri-infarct areas after acute brain ischemia and may enhance blood–brain barrier breakdown through activation of NFκB and matrix metalloproteinase 9, thereby causing enlargement of infarct volume.

scholarly journals Dietary Virgin Olive Oil Reduces Blood Brain Barrier Permeability, Brain Edema, and Brain Injury in Rats Subjected to Ischemia-Reperfusion

2010 ◽  
Vol 10 ◽  
pp. 1180-1191 ◽  
Author(s):  
Fatemeh Mohagheghi ◽  
Mohammad Reza Bigdeli ◽  
Bahram Rasoulian ◽  
Ali Asghar Zeinanloo ◽  
Ali Khoshbaten
Keyword(s):  
Brain Edema ◽  
Blood Brain Barrier ◽  
Infarct Volume ◽  
Ischemia Reperfusion ◽  
Virgin Olive Oil ◽  
Brain Barrier ◽  
Barrier Permeability ◽  
Blood Brain Barrier Permeability ◽  
Blood Brain ◽  
Brain Barrier Permeability

Recent studies suggest that dietary virgin olive oil (VOO) reduces hypoxia-reoxygenation injury in rat brain slices. We sought to extend these observations in anin vivostudy of rat cerebral ischemia-reperfusion injury. Four groups, each consisting of 18 Wistar rats, were studied. One group (control) received saline, while three treatment groups received oral VOO (0.25, 0.5, and 0.75 mL/kg/day, respectively). After 30 days, blood lipid profiles were determined, before a 60-min period of middle cerebral artery occlusion (MCAO). After 24-h reperfusion, neurological deficit scores, infarct volume, brain edema, and blood brain barrier permeability were each assessed in subgroups of six animals drawn from each main group. VOO reduced the LDL/HDL ratio in doses of 0.25, 0.5, and 0.75 mL/kg/day in comparison to the control group (p< 0.05), and offered cerebroprotection from ischemia-reperfusion. For controls vs. doses of 0.25 vs. 0.5 vs. 0.75 mL/kg/day, attenuated corrected infarct volumes were 207.82 ± 34.29 vs. 206.41 ± 26.23 vs. 124.21 ± 14.73 vs. 108.46 ± 31.63 mm3; brain water content of the infarcted hemisphere was 82 ±± 0.25 vs. 81.5 ± 0.56 vs. 80.5 ± 0.22 vs. 80.5 ± 0.34%; and blood brain barrier permeability of the infarcted hemisphere was 11.31 ± 2.67 vs. 9.21 ± 2.28 vs. 5.83 ± 1.6 vs. 4.43 ± 0.93 µg/g tissue (p< 0.05 for measures in doses 0.5 and 0.75 mL/kg/day vs. controls). Oral administration of VOO reduces infarct volume, brain edema, blood brain barrier permeability, and improves neurologic deficit scores after transient MCAO in rats.

scholarly journals Interferon-Beta Blocks Infiltration of Inflammatory Cells and Reduces Infarct Volume after Ischemic Stroke in the Rat

2003 ◽  
Vol 23 (9) ◽  
pp. 1029-1039 ◽  
Author(s):  
Wouter B. Veldhuis ◽  
Joris W. Derksen ◽  
Sarah Floris ◽  
Peter H. van der Meide ◽  
Helga E. de Vries ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Interferon Beta ◽  
Infarct Volume ◽  
Ischemia Reperfusion ◽  
Stroke Onset ◽  
Cerebral Injury ◽  
Brain Barrier ◽  
Similar Degree ◽  
Lesion Volume ◽  
Blood Brain

The inflammatory response that exacerbates cerebral injury after ischemia is an attractive therapeutic target: it progresses over days and strongly contributes to worsening of the neurologic outcome. The authors show that, after transient ischemic injury to the rat brain, systemic application of interferon-beta (IFN-β), a cytokine with antiinflammatory properties, attenuated the development of brain infarction. Serial magnetic resonance imaging (MRI) showed that IFN-β treatment reduced lesion volume on diffusion-weighted MRI by 70% ( P < 0.01) at 1 day after stroke. IFN-β attenuated the leakage of contrast agent through the blood–brain barrier ( P < 0.005), indicating a better-preserved blood–brain barrier integrity. Both control and IFN-β-treated animals showed a similar degree of relative hyperperfusion of the lesioned hemisphere, indicating that neuroprotection by IFN-β was not mediated by improved cerebral perfusion as assessed 24 hours after stroke onset. IFN-β treatment resulted in an 85% reduction ( P < 0.0001) in infarct volume 3 weeks later, as determined from T2-weighted MRI and confirmed by histology. This effect was achieved even when treatment was started 6 hours after stroke onset. Quantitative immunohistochemistry at 24 hours after stroke onset showed that IFN-β almost completely prevented the infiltration of neutrophils and monocytes into the brain. Gelatinase zymography showed that this effect was associated with a decrease in matrix metalloproteinase-9 expression. In conclusion, treatment with the antiinflammatory cytokine IFN-β affords significant neuroprotection against ischemia/reperfusion injury, and within a relatively long treatment window. Because IFN-β has been approved for clinical use, it may be rapidly tested in a clinical trial for its efficacy against human stroke.

scholarly journals Oxymatrine Improves the Integrity of the Blood-Brain Barrier after Cerebral Ischemia-Reperfusion Injury through the Caveolin-1/MMP-9 Signaling Pathway

2020 ◽  
Author(s):  
Jiaoyan Yu ◽  
Qingqing Liu ◽  
Xi Li ◽  
Mei Zhao ◽  
Ting Sun ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Protective Effect ◽  
Signaling Pathway ◽  
Blood Brain Barrier ◽  
Ischemia Reperfusion ◽  
Neurological Function ◽  
Brain Barrier ◽  
High Morbidity ◽  
Cerebral Ischemia Reperfusion ◽  
Blood Brain

Abstract BackgroundIschemic stroke (IS) is a major neurological disease worldwide and is associated with extremely high morbidity and mortality. Oxymatrine (OMT) has neuroprotective properties and protects against IS. However, whether its protective effect involves the blood-brain barrier (BBB) integrity is unknown.MethodsHere, we used in vivo and in vitro models of IS to evaluate the protective effect of OMT and its mechanism with regard to the BBB. We assayed the role of OMT using neurological function scores and triphenyltetrazolium chloride, Nissl, and terminal deoxynucleotidyl transferase dUTP nick end labeling staining.ResultsOMT significantly improved the neurological function and brain state and reduced BBB permeability in a mouse model of cerebral ischemia-reperfusion. Additionally, OMT improved the tight junction of bEend.3 cells under oxygen-glucose deprivation. Moreover, intracranial lentivirus injection-induced Cav-1 knockdown reduced the neuroprotective effects of OMT.ConclusionsOMT could improve I/R injury-induced damage to the BBB, and its effects may be related to the regulation of the Cav-1/MMP-9 signaling pathway. This suggests that OMT may offer effective protection against BBB injury after I/R.

scholarly journals Calcium-dependent reactive oxygen formation and blood-brain barrier breakdown by NOX5 limits post-reperfusion outcome in stroke

2018 ◽  
Author(s):  
Ana I Casas ◽  
Pamela WM Kleikers ◽  
Eva Geuss ◽  
Friederike Langhauser ◽  
Javier Egea ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Infarct Volume ◽  
Reactive Oxygen ◽  
Brain Barrier ◽  
Dependent Manner ◽  
Calcium Dependent ◽  
Mechanical Removal ◽  
Blood Brain ◽  
Barrier Breakdown ◽  
Blood Brain Barrier Breakdown

AbstractIschemic stroke is a predominant cause of disability worldwide, with thrombolytic or mechanical removal of the occlusion being the only therapeutic options. Reperfusion bears the risk of an acute deleterious calcium-dependent breakdown of the blood-brain-barrier. Its mechanism, however, is unknown. Here we identify type 5 NADPH oxidase (NOX5), a calcium-activated, reactive oxygen species (ROS)-forming enzyme as missing link. Using a humanised knock-in mouse model and in vitro in organotypic cultures, we find re-oxygenation or calcium overload to increase brain ROS levels in a NOX5-dependent manner. In vivo, post-ischemic ROS formation, infarct volume and functional outcomes were worsened in NOX5 knock-in mice. Of clinical and therapeutic relevance, in a human blood-barrier model pharmacological NOX inhibition also prevented acute re-oxygenation induced leakage. Our data therefore identify NOX5 as sufficient to induce acute post-reperfusion calcium-dependent blood-brain-barrier breakdown. We suggest urgent clinical validation by conducting protective post-stroke re-canalisation in the presence of a NOX inhibitor.

scholarly journals Oxymatrine Improves the Integrity of the Blood-brain Barrier After Cerebral Ischemia-reperfusion Injury Through the Caveolin-1/MMP-9 Signaling Pathway

2020 ◽  
Author(s):  
Jiaoyan Yu ◽  
Qingqing Lu ◽  
Xi Li ◽  
Mei Zhao ◽  
Ting Sun ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Protective Effect ◽  
Signaling Pathway ◽  
Blood Brain Barrier ◽  
Ischemia Reperfusion ◽  
Brain Barrier ◽  
Brain State ◽  
High Morbidity ◽  
Cerebral Ischemia Reperfusion ◽  
Blood Brain

Abstract Ischemic stroke (IS) is a major neurological disease worldwide and is associated with extremely high morbidity and mortality. Oxymatrine (OMT) has neuroprotective properties and protects against IS. However, whether its protective effect involves the blood-brain barrier (BBB) integrity is unknown. In this study, we used in vivo and in vitro models of IS to evaluate the protective effect of OMT and its mechanism with regard to the BBB. Our results showed that OMT significantly improved the neurological function and brain state and reduced BBB permeability in a mouse model of cerebral ischemia-reperfusion. Additionally, OMT improved the tight junction of bEend.3 cells under oxygen-glucose deprivation. Moreover, intracranial lentivirus injection-induced Cav-1 knockdown reduced the neuroprotective effects of OMT. Our results indicated that OMT could improve cI/R injury-induced damage to the BBB, and its effects may be related to the regulation of the Cav-1/MMP-9 signaling pathway. This suggests that OMT may offer effective protection against BBB injury after cI/R.

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