scholarly journals Blood–Brain Barrier Disruption and Hemorrhagic Transformation in Acute Ischemic Stroke: Systematic Review and Meta-Analysis

2021 ◽  
Vol 11 ◽  
Author(s):  
Francesco Arba ◽  
Chiara Rinaldi ◽  
Danilo Caimano ◽  
Federica Vit ◽  
Giorgio Busto ◽  
...  
Keyword(s):  
Systematic Review ◽  
Ischemic Stroke ◽  
Acute Ischemic Stroke ◽  
Blood Brain Barrier ◽  
Meta Analysis ◽  
Hemorrhagic Transformation ◽  
Mr Studies ◽  
Brain Barrier ◽  
Blood Brain ◽  
Ct Studies

Introduction: Hemorrhagic transformation (HT) is a complication of reperfusion therapy for acute ischemic stroke. Blood–brain barrier (BBB) disruption is a crucial step toward HT; however, in clinical studies, there is still uncertainty about this relation. Hence, we conducted a systematic review and meta-analysis to summarize the current evidence.Methods: We performed systematic review and meta-analysis of observational studies from January 1990 to March 2020 about the relation between BBB disruption and HT in patients with acute ischemic stroke with both computed tomography (CT) and magnetic resonance (MR) assessment of BBB. The outcome of interest was HT at follow-up imaging evaluation (within 48 h from symptom onset). We pooled data from available univariate odds ratios (ORs) in random-effects models with DerSimonian–Laird weights and extracted cumulative ORs.Results: We included 30 eligible studies (14 with CT and 16 with MR), N = 2,609 patients, with 88% and 70% of patients included in CT and MR studies treated with acute stroke therapy, respectively. The majority of studies were retrospective and had high or unclear risk of bias. BBB disruption was measured with consistent methodology in CT studies, whereas in MR studies, there was more variability. All CT studies provided a BBB disruption cutoff predictive of HT. Four CT and 10 MR studies were included in the quantitative analysis. We found that BBB disruption was associated with HT with both CT (OR = 3.42; 95%CI = 1.62–7.23) and MR (OR = 9.34; 95%CI = 3.16–27.59). There was a likely publication bias particularly for MR studies.Conclusion: Our results confirm that BBB disruption is associated with HT in both CT and MR studies. Compared with MR, CT has been more uniformly applied in the literature and has resulted in more consistent results. However, more efforts are needed for harmonization of protocols and methodology for implementation of BBB disruption as a neuroradiological marker in clinical practice.

scholarly journals Blood-brain barrier, reperfusion injury, and hemorrhagic transformation in acute ischemic stroke

Neurology ◽  
2012 ◽  
Vol 79 (Issue 13, Supplement 1) ◽  
pp. S52-S57 ◽  
Author(s):  
R. Khatri ◽  
A. M. McKinney ◽  
B. Swenson ◽  
V. Janardhan
Keyword(s):  
Ischemic Stroke ◽  
Acute Ischemic Stroke ◽  
Reperfusion Injury ◽  
Blood Brain Barrier ◽  
Hemorrhagic Transformation ◽  
Brain Barrier ◽  
Blood Brain

Abstract 2792: Bone Marrow Mononuclear Cells Improve Blood-Brain Barrier Permeability And Decrease Hemorrhagic Transformation After Treatment With Tissue Plasminogen Activator In An Embolic Stroke Model

Stroke ◽  
2012 ◽  
Vol 43 (suppl_1) ◽  
Author(s):  
Bing Yang ◽  
Xiaopei Xi ◽  
Sean.I Savitz
Keyword(s):  
Bone Marrow ◽  
Ischemic Stroke ◽  
Acute Ischemic Stroke ◽  
Blood Brain Barrier ◽  
Hemorrhagic Transformation ◽  
Brain Barrier ◽  
Barrier Permeability ◽  
Blood Brain Barrier Permeability ◽  
Blood Brain ◽  
Brain Barrier Permeability

Background: Tissue plasminogen activator (t-PA) is the only treatment approved in the US for acute ischemic stroke. Cell-based therapies are being studied as a new investigational treatment approach for stroke but few studies have assessed the interaction of cell therapies with IV t-PA in an embolic model. Our laboratory has been investigating the therapeutic potential of bone marrow mononuclear cells (MNCs), which have been shown to enhance recovery after acute ischemic stroke and are currently being studied in safety clinical trials. Methods: An embolic ischemic stroke model was established by deposition of an autologous blood clot into the internal carotid artery in adult Long Evans rats. IV t-PA (10 mg/kg) was administered at 1 hour after occlusion. Two hours later, 10 million allogeneic MNCs per kilogram or saline were given intravenously (N=12 per group). Hemorrhagic transformation (HT) and blood-brain barrier permeability using Evans Blue were quantified at 3 days after stroke. In an in vitro study, astrocytes were isolated from postnatal P1 rats, pre-conditioned by oxygen-glucose deprivation (OGD) for 45 min, and then cultured with MNCs derived from the mother’s bone marrow. MMP-3 was assayed in the media. Results: Over 40% (42%) of animals treated with t-PA had HT at 3 days after stroke. The incidence of HT did not differ in the MNC and saline treated groups. However, the ICH scores were significantly reduced in the MNC group (2±1.2) compared to saline controls (3.8±0.8) ( Fig A, p =0.027). BBB permeability was also reduced in the MNC group (0.28±0.07) compared to saline controls (0.6±0.12) ( Fig B, p =0.033). In the in vitro study, MMP-3 levels in the medium of cultured pre-conditioned astrocytes (30.6±3.7 ng/ml) were reduced when co-cultured directly with MNCs (23.1±2.0 ng/ml, p =0.047) but MMP-3 levels were unchanged when astrocytes and MNCs were co-cultured in transwell (32.8±3.2 ng/ml) ( Fig C&D). Conclusion: We have found for the first time that bone marrow derived MNCs reduce hemorrhagic transformation and blood brain barrier permeability after treatment with IV t-PA for acute ischemic stroke. Our results suggest a novel mechanism in which MNCs may attenuate hemorrhagic risk from t-PA by reducing the release of MMP-3 from astrocytes.

scholarly journals Effects of fasudil on blood-brain barrier integrity

2021 ◽  
Author(s):  
Kei Sato ◽  
Shinsuke Nakagawa ◽  
Yoichi Morofuji ◽  
Yuki Matsunaga ◽  
Takashi Fujimoto ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Ischemic Stroke ◽  
Tight Junction ◽  
Acute Ischemic Stroke ◽  
Blood Brain Barrier ◽  
Tight Junction Protein ◽  
Brain Barrier ◽  
Blood Brain ◽  
Junction Protein ◽  
Culture Models

Abstract Background Cerebral infarction accounts for 85% of all stroke cases. Even in an era of rapid and effective recanalization using an intravascular approach, the majority of patients have poor functional outcomes. Thus, there is an urgent need for the development of therapeutic agents to treat acute ischemic stroke. We evaluated the effect of fasudil, a Rho kinase inhibitor, on blood brain barrier (BBB) functions under normoxia or oxygen-glucose deprivation (OGD) conditions using a primary cell-based in vitro BBB model. Medhods: BBB models from rat primary cultures (brain capillary endothelial cells, astrocytes, and pericytes) were subjected to either normoxia or 6-hour OGD/24-hour reoxygenation. To assess the effects of fasudil on BBB functions, we evaluated real time impedance, transendothelial electrical resistance (TEER), sodium fluorescein permeability, and tight junction protein expression using immunohistochemistry and western blotting. Lastly, to understand the observed protective mechanism on BBB functions by fasudil we examined the role of cyclooxygenase-2 and thromboxane A2 receptor agonist U-46619 in BBB-forming cells. Results We found that treatment with 0.3–30 µM of fasudil increased cellular impedance. Fasudil enhanced barrier properties in a concentration-dependent manner, as measured by an increased (TEER) and decreased permeability. Fasudil also increased the expression of tight junction protein claudin-5. Reductions in TEER and increased permeability were observed after OGD/reoxygenation exposure in mono- and co-culture models. The improvement in BBB integrity by fasudil was confirmed in both of the models, but was significantly higher in the co-culture than in the monoculture model. Treatment with U-46619 did not show significant changes in TEER in the monoculture model, whereas it showed a significant reduction in TEER in the co-culture model. Fasudil significantly improved the U-46619-induced TEER reduction in the co-culture models. Pericytes and astrocytes have opposite effects on endothelial cells and may contribute to endothelial injury in hyperacute ischemic stroke. Overall, fasudil protects the integrity of BBB both by a direct protective effect on endothelial cells and by a pathway mediated via pericytes and astrocytes. Conclusions Our findings suggest that fasudil is a BBB-protective agent against acute ischemic stroke.

Early Blood Brain Barrier Changes in Acute Ischemic Stroke: A Sequential MRI Study

2015 ◽  
Vol 25 (6) ◽  
pp. 959-963 ◽  
Author(s):  
Marc Giraud ◽  
Tae-Hee Cho ◽  
Norbert Nighoghossian ◽  
Delphine Maucort-Boulch ◽  
Gianluca Deiana ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Acute Ischemic Stroke ◽  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Blood Brain ◽  
Mri Study

Blood-Brain Barrier Protection as a Therapeutic Strategy for Acute Ischemic Stroke

2017 ◽  
Vol 19 (4) ◽  
pp. 957-972 ◽  
Author(s):  
Ali Ehsan Sifat ◽  
Bhuvaneshwar Vaidya ◽  
Thomas J. Abbruscato
Keyword(s):  
Ischemic Stroke ◽  
Acute Ischemic Stroke ◽  
Blood Brain Barrier ◽  
Therapeutic Strategy ◽  
Brain Barrier ◽  
Blood Brain

Early Blood‐Brain Barrier Disruption after Mechanical Thrombectomy in Acute Ischemic Stroke

2018 ◽  
Vol 28 (3) ◽  
pp. 283-288 ◽  
Author(s):  
Zhong‐Song Shi ◽  
Gary R. Duckwiler ◽  
Reza Jahan ◽  
Satoshi Tateshima ◽  
Viktor Szeder ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Acute Ischemic Stroke ◽  
Blood Brain Barrier ◽  
Mechanical Thrombectomy ◽  
Brain Barrier ◽  
Barrier Disruption ◽  
Blood Brain Barrier Disruption ◽  
Blood Brain ◽  
Brain Barrier Disruption

Abstract TP340: The Level of Occludin in Blood as a Potential Biomarker for Blood-Brain Barrier Damage and Predicting Hemorrhage Transformation After Acute Ischemic Stroke

Stroke ◽  
2020 ◽  
Vol 51 (Suppl_1) ◽  
Author(s):  
Zhifeng Qi ◽  
Ke Jian Liu
Keyword(s):  
Ischemic Stroke ◽  
Acute Ischemic Stroke ◽  
Blood Brain Barrier ◽  
Brain Infarction ◽  
Critical Role ◽  
Onset Time ◽  
Brain Barrier ◽  
Cerebral Microvessels ◽  
Blood Brain ◽  
Potential Biomarker

Fear of hemorrhage transformation (HT) has been the primary reason for withholding the effective recanalization therapies (thrombolysis or thrombectomy) from most acute ischemic stroke (AIS) patients. Currently there is no reliable indicator available to predict HT before recanalization. The degradation of tight junction proteins plays a critical role in blood-brain barrier (BBB) disruption in ischemic stroke. We hypothesize that since occludin fragment in peripheral blood is derived from the degradation of occludin on cerebral microvessels, elevated blood occludin level directly reflects BBB disruption and may serve as a biomarker for BBB damage to predict the risk of HT after recanalization. In this study, we determined occludin fragment in the blood of rats, non-human primates and human patients after AIS using ELISA assay, and evaluated its level with BBB damage, HT, and other neurological outcomes. We found that ischemia induced rapid occludin degradation and BBB disruption, while occludin fragment was released into the blood circulation. Cerebral ischemia resulted in a dramatic increase of occludin fragments in rat blood samples after 4-hr ischemia, which was correlated well with occludin loss from ischemic cerebral microvessels. In the blood sample from ischemic rhesus monkeys, occludin level significantly increased after 2h ischemia from baseline, which correlated well with brain infarction shown in MRI images. We further collected the sera of AIS patients as early as they arrived at hospital. Our results indicated that the level of occludin increased in accord with ischemia onset time and neurological dysfunctions. The level of blood occludin in AIS patients with HT was much higher that those without HT. Together, our findings from rats, non-human primates and patients suggest that the level of occludin fragment in blood could serve as a biomarker for HT and neurological outcome following AIS, which could be used to safely guide recanalization for AIS in the clinic.

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