scholarly journals A Systematic Review and Meta-Analysis of Animal Studies Testing Intra-Arterial Chilled Infusates After Ischemic Stroke

2021 ◽  
Vol 11 ◽  
Author(s):  
Lane J. Liddle ◽  
Christine A. Dirks ◽  
Brittany A. Fedor ◽  
Mohammed Almekhlafi ◽  
Frederick Colbourne
Keyword(s):  
Systematic Review ◽  
Ischemic Stroke ◽  
Experimental Design ◽  
Sample Size ◽  
Blood Brain Barrier ◽  
Methodological Quality ◽  
Animal Studies ◽  
Infarct Volume ◽  
Brain Barrier ◽  
Sample Size Calculations

Background: As not all ischemic stroke patients benefit from currently available treatments, there is considerable need for neuroprotective co-therapies. Therapeutic hypothermia is one such co-therapy, but numerous issues have hampered its clinical use (e.g., pneumonia risk with whole-body cooling). Some problems may be avoided with brain-specific methods, such as intra-arterial selective cooling infusion (IA-SCI) into the arteries supplying the ischemic tissue.Objective: Our research question was about the efficacy of IA-SCI in animal middle cerebral artery occlusion models. We hypothesized that IA-SCI would be beneficial, but translationally-relevant study elements may be missing (e.g., aged animals).Methods: We completed a systematic review of the PubMed database following the PRISMA guidelines on May 21, 2020 for animal studies that administered IA-SCI in the peri-reperfusion period and assessed infarct volume, behavior (primary meta-analytic endpoints), edema, or blood-brain barrier injury (secondary endpoints). Our search terms included: “focal ischemia” and related terms, “IA-SCI” and related terms, and “animal” and related terms. Nineteen studies met inclusion criteria. We adapted a methodological quality scale from 0 to 12 for experimental design assessment (e.g., use of blinding/randomization, a priori sample size calculations).Results: Studies were relatively homogenous (e.g., all studies used young, healthy animals). Some experimental design elements, such as blinding, were common whereas others, such as sample size calculations, were infrequent (median methodological quality score: 5; range: 2–7). Our analyses revealed that IA-SCI provides benefit on all endpoints (mean normalized infarct volume reduction = 23.67%; 95% CI: 19.21–28.12; mean normalized behavioral improvement = 35.56%; 95% CI: 25.91–45.20; mean standardized edema reduction = 0.95; 95% CI: 0.56–1.34). Unfortunately, blood-brain barrier assessments were uncommon and could not be analyzed. However, there was substantial statistical heterogeneity and relatively few studies. Therefore, exploration of heterogeneity via meta-regression using saline infusion parameters, study quality, and ischemic duration was inconclusive.Conclusion: Despite convincing evidence of benefit in ischemic stroke models, additional studies are required to determine the scope of benefit, especially when considering additional elements (e.g., dosing characteristics). As there is interest in using this treatment alongside current ischemic stroke therapies, more relevant animal studies will be critical to inform patient studies.

Abstract TP80: Panaxatriol Saponins Attenuates Blood-brain Barrier Disruption and Promotes Angiogenesis After Ischemic Stroke in Rats

Stroke ◽  
2017 ◽  
Vol 48 (suppl_1) ◽  
Author(s):  
Hui Yang ◽  
Zhen Hui ◽  
Du Juan Sha ◽  
Yun Xu
Keyword(s):  
Ischemic Stroke ◽  
Blood Brain Barrier ◽  
Cerebral Perfusion ◽  
Infarct Volume ◽  
Immunofluorescence Staining ◽  
Brain Barrier ◽  
Shh Pathway ◽  
Blood Brain Barrier Disruption ◽  
Blood Brain ◽  
Brain Barrier Disruption

Background: The induction of angiogenesis and maintain the integrity of the blood brain barrier (BBB) after stroke may enhance neurorestorative processes. Panaxatriol Saponins (PTS), extracted from traditional Chinese herb Panaxnotoginseng, could noticeably prevent BBB disruption and promote angiogenesis in rodent stroke model. Methods: Middle cerebral artery occlusion (MCAO) model were applied to mimic acute stroke in vivo. Ischemic infarct volume and neurological functions were evaluated through 2,3,5-triphenyltetrazolium chloride (TTC) staining and Longa Scores (LS) respectively. The micro-PET scan was adopted to assess cerebral perfusion; evans blue extravasation assay was used to test BBB permeability; real time PCR and Western blot were used to evaluate the level of vascular growth factors, pro-inflammation factors, the components of Sonic hedgehog (Shh) pathway and NF-κB pathway. Enzyme Linked Immunosorbent Assay (ELISA) was used to detect the levels of pro-inflammation factors in the brain. The capillaries density in ischemic penumbra and tight junction in BBB were measured by immunofluorescence staining. Results: PTS treatment improved neurological function and reduced infarct volume in MCAO-rats. The result of micro-PET scan indicated that PTS could significantly enhance cerebral perfusion after MCAO operation. Treatment of PTS significantly attenuated BBB destruction. PTS could significantly increase the VEGF, Ang-1, VEGFR-2, Tie-2, CD31 and α-SMA mRNA expression at 3 d and 7 d after MCAO compared to vehicle group. Moreover, the expression levels of inflammation factors were decreased after PTS treatment. The co-immunofluorescence staining of α-SMA and Brdu with CD31 respectively showed that PTS promotes angiogenesis and endothelial cell proliferation after MCAO. Meanwhile, co-immunofluorescence staining of Claudin-5, Occludin and ZO-1 with CD31 respectively showed that PTS could protect tight junction from ischemia/reperfusion injury. PTS could also activate Shh pathway and inhibited NF-κB pathway. Conclusions: PTS alleviated ischemic stroke injury through attenuates blood-brain barrier disruption and promotes angiogenesis. PTS could be a potential medication for combating ischemic brain injury.

scholarly journals MiRNA-132/212 regulates tight junction stabilization in blood–brain barrier after stroke

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Haomin Yan ◽  
Hideaki Kanki ◽  
Shigenobu Matsumura ◽  
Tomohiro Kawano ◽  
Kumiko Nishiyama ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Tight Junction ◽  
Blood Brain Barrier ◽  
Rna Binding ◽  
Infarct Volume ◽  
Brain Barrier ◽  
Neurological Deficits ◽  
Ischemic Damage ◽  
Upstream Regulator ◽  
Blood Brain

AbstractMicroRNA-132/212 has been supposed as a critical gene related to the blood–brain barrier (BBB) protection after stroke, but its regulation pathway including the upstream regulator and downstream targets is still unclear. Herein, we demonstrated the cAMP response element-binding protein (CREB)-regulated transcription coactivator-1 (CRTC1) to be the upstream regulator of miRNA-132/212 using CRTC1 knockout and wild-type mice. CRTC1 deletion led to the reduction of miRNA-132/212 expression in mice brain after ischemic stroke, significantly increased infarct volume, and aggravated BBB permeability with worsening neurological deficits. Furthermore, we identified that miRNA-132 repressed Claudin-1, tight junction-associated protein-1 (TJAP-1), and RNA-binding Fox-1 (RBFox-1) by directly binding to their respective 3′-untranslated regions, which alleviated the ischemic damage by enhancing neuronal survival and BBB integrity. Moreover, the co-culture of endothelial cells with CRTC1-deficient neurons aggravated the cell vulnerability to hypoxia, also supporting the idea that miRNA-132/212 cluster is regulated by CRTC1 and acts as a crucial role in the mitigation of ischemic damage. This work is a step forward for understanding the role of miRNA-132/212 in neurovascular interaction and may be helpful for potential gene therapy of ischemic stroke.

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 Systematic review and stratified meta-analysis of the efficacy of carnosine in animal models of ischemic stroke

2016 ◽  
Vol 36 (10) ◽  
pp. 1686-1694 ◽  
Author(s):  
Charles K Davis ◽  
Peter J Laud ◽  
Zsanett Bahor ◽  
GK Rajanikant ◽  
Arshad Majid
Keyword(s):  
Systematic Review ◽  
Ischemic Stroke ◽  
Methodological Quality ◽  
Infarct Volume ◽  
Weighted Mean Difference ◽  
Meta Analysis ◽  
Young Male ◽  
In Vivo Models

Carnosine is a naturally occurring pleotropic dipeptide which influences multiple deleterious mechanisms that are activated during stroke. Numerous published studies have reported that carnosine has robust efficacy in ischemic stroke models. To further evaluate these data, we have conducted a systematic review and meta-analysis of published studies. We included publications describing in vivo models of ischemic stroke where the neuroprotective efficacy of carnosine was being evaluated through the reporting of infarct volume and/or neurological score as outcomes. Overall efficacy was evaluated using weighted mean difference random effects meta-analysis. We also evaluated for study quality and publication bias. We identified eight publications that met our inclusion criteria describing a total of 29 comparisons and 454 animals. Overall methodological quality of studies was moderate (median = 4/9). Carnosine reduced infarct volume by 29.4% (95% confidence interval (CI), 24.0% to 34.9%; 29 comparisons). A clear dose-response effect was observed, and efficacy was reduced when carnosine was administered more than 6 h after ischemia. Our findings suggest that carnosine administered before or after the onset of ischemia exhibits robust efficacy in experimental ischemic stroke. However, the methodological quality of some of the studies was low and testing occurred only in healthy young male animals.

scholarly journals DL-3n-Butylphthalide Improves Blood–Brain Barrier Integrity in Rat After Middle Cerebral Artery Occlusion

2021 ◽  
Vol 14 ◽  
Author(s):  
Muyassar Mamtilahun ◽  
Zhenyu Wei ◽  
Chuan Qin ◽  
Yongting Wang ◽  
Yaohui Tang ◽  
...  
Keyword(s):  
Enzyme Activity ◽  
Ischemic Stroke ◽  
Blood Brain Barrier ◽  
Infarct Volume ◽  
Artery Occlusion ◽  
Brain Barrier ◽  
Barrier Integrity ◽  
Aqp4 Expression ◽  
Blood Brain ◽  
Blood Brain Barrier Integrity

Objective: DL-3n-butylphthalide (NBP) has beneficial effects in different stages of ischemic stroke. Our previous studies have demonstrated that NBP promoted angiogenesis in the perifocal region of the ischemic brain. However, the molecular mechanism of NBP for blood–brain barrier protection in acute ischemic stroke was unclear. Here, we explored the neuroprotective effects of NBP on blood–brain barrier integrity in the acute phase of ischemic stroke in a rat model.Methods: Adult male Sprague–Dawley rats (n = 82) underwent 2 h of transient middle cerebral artery occlusion and received 90 mg/kg of NBP for 3 days. Brain edema, infarct volume, surface blood flow, and neurological severity score were evaluated. Blood–brain barrier integrity was evaluated by Evans blue leakage and changes in tight junction proteins. We further examined AQP4 and eNOS expression, MMP-9 enzyme activity, and possible signaling pathways for the role of NBP after ischemic stroke.Results: NBP treatment significantly increased eNOS expression and surface blood flow in the brain, reduced brain edema and infarct volume, and improved neurological severity score compared to the control group (p < 0.05). Furthermore, NBP attenuated Evans blue and IgG leakage and increased tight junction protein expression compared to the control after 1 and 3 days of ischemic stroke (p < 0.05). Finally, NBP decreased AQP4 expression, MMP-9 enzyme activity, and increased MAPK expression during acute ischemic stroke.Conclusion: NBP protected blood–brain barrier integrity and attenuated brain injury in the acute phase of ischemic stroke by decreasing AQP4 expression and MMP-9 enzyme activity. The MAPK signaling pathway may be associated in this process.

Abstract TP102: Apolipoprotein E Mimetic Pentapeptide (CN 105) Improves Outcome in a Murine Model of Ischemic Stroke

Stroke ◽  
2017 ◽  
Vol 48 (suppl_1) ◽  
Author(s):  
Tian Ming Tu ◽  
Haichen Wang ◽  
Daniel Laskowitz
Keyword(s):  
Ischemic Stroke ◽  
Apolipoprotein E ◽  
Blood Brain Barrier ◽  
Murine Model ◽  
Repeated Measures ◽  
Functional Outcomes ◽  
Infarct Volume ◽  
Brain Barrier ◽  
Occlusion Time ◽  
Blood Brain

Introduction: Apolipoprotein E (apoE) is an endogenous brain protein synthesized in response to brain injury and modifies neuroinflammatory responses by downregulating glial activation and release of inflammatory mediators. Due to its size, however, the intact apoE holoprotein does not cross the blood brain barrier, and thus has limited therapeutic potential. We have demonstrated that a small 5 amino acid apoE-mimetic peptide (CN-105) derived from the receptor-binding region of apoE retains the neuroprotective effects of the intact holoprotein, is well tolerated, and effectively crosses the blood brain barrier. This study investigates whether CN105 improves functional and histological outcomes in a murine model of transient focal ischemia and reperfusion. Methods: We used the transient middle cerebral artery occlusion murine model of ischemic stroke for all our experiments. Thirty-minutes ischemic occlusion time was used for infarct volume and survival analysis at 72 hours while 15 minutes ischemic occlusion time was used for functional outcome analysis performed 7 days post stroke. A dose of CN-105 (0.1mg/kg) in 100 μl volume was administered as a single dose 30 minutes post-perfusion via tail vein injection. Motor-sensory functional outcomes were evaluated using daily rotarod assessment for 7 days and 4-limb wire hanging test on days 2 and 7 days post injury. Infarct volume was evaluated using 2,3,5-Triphenyltetrazolium chloride staining method. Independent t-test was used for infarct volume analysis, repeated measures ANOVA was used for functional outcomes evaluation and log-rank test was used for survival evaluation. Experiments were performed in a randomized and blinded fashion. Results: Administration of CN-105 improved motor and sensory functional outcomes at 7 days in rotarod (p = 0.035) and 4-limb wire hanging test (p=0.013) when compared to vehicle. There was also a survival benefit (n = 8 (66.7%) vs n = 3 (25%), p=0.037) and a significant reduction of infarct volumes (79 ± 43 mm 3 ) compared to vehicle (127 ± 31 mm 3 ) (p = 0.039) at 72 hours. Conclusion: Intravenous administration of CN-105 is associated with functional, survival, and histological benefits in a murine ischemic stroke model when given at 30 minutes post-reperfusion.

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 Sustained Opening of the Blood-Brain Barrier with Progressive Accumulation of White Matter Hyperintensities Following Ischemic Stroke

2019 ◽  
Vol 9 (1) ◽  
pp. 16 ◽  
Author(s):  
Imama Naqvi ◽  
Emi Hitomi ◽  
Richard Leigh
Keyword(s):  
Ischemic Stroke ◽  
White Matter ◽  
Acute Stroke ◽  
Blood Brain Barrier ◽  
White Matter Hyperintensities ◽  
Brain Barrier ◽  
Common Finding ◽  
Blood Brain ◽  
History Of ◽  
Iv Tpa

Objective: To report a patient in whom an acute ischemic stroke precipitated chronic blood-brain barrier (BBB) disruption and expansion of vascular white matter hyperintensities (WMH) into regions of normal appearing white matter (NAWM) during the following year. Background: WMH are a common finding in patients with vascular risk factors such as a history of stroke. The pathophysiology of WMH is not fully understood; however, there is growing evidence to suggest that the development of WMH may be preceded by the BBB disruption in the NAWM. Methods: We studied a patient enrolled in the National Institutes of Health Natural History of Stroke Study who was scanned with magnetic resonance imaging (MRI) after presenting to the emergency room with an acute stroke. After a treatment with IV tPA, she underwent further MRI scanning at 2 h, 24 h, 5 days, 30 days, 90 days, 6 months, and 1-year post stroke. BBB permeability images were generated from the perfusion weighted imaging (PWI) source images. MRIs from each time point were co-registered to track changes in BBB disruption and WMH over time. Results: An 84-year-old woman presented after acute onset right hemiparesis, right-sided numbness and aphasia with an initial NIHSS of 13. MRI showed diffusion restriction in the left frontal lobe and decreased blood flow on perfusion imaging. Fluid attenuated inversion recovery (FLAIR) imaging showed bilateral confluent WMH involving the deep white matter and periventricular regions. She was treated with IV tPA without complication and her NIHSS improved initially to 3 and ultimately to 0. Permeability maps identified multiple regions of chronic BBB disruption remote from the acute stroke, predominantly spanning the junction of WMH and NAWM. The severity of BBB disruption was greatest at 24 h after the stroke but persisted on subsequent MRI scans. Progression of WMH into NAWM over the year of observation was detected bilaterally but was most dramatic in the regions adjacent to the initial stroke. Conclusions: WMH-associated BBB disruption may be exacerbated by an acute stroke, even in the contralateral hemisphere, and can persist for months after the initial event. Transformation of NAWM to WMH may be evident in areas of BBB disruption within a year after the stroke. Further studies are needed to investigate the relationship between chronic BBB disruption and progressive WMH in patients with a history of cerebrovascular disease and the potential for acute stroke to trigger or exacerbate the process leading to the development of WMH.

scholarly journals TRAIL and Cardiovascular Disease—A Risk Factor or Risk Marker: A Systematic Review

2021 ◽  
Vol 10 (6) ◽  
pp. 1252
Author(s):  
Katarzyna Kakareko ◽  
Alicja Rydzewska-Rosołowska ◽  
Edyta Zbroch ◽  
Tomasz Hryszko
Keyword(s):  
Systematic Review ◽  
Risk Factor ◽  
Ischemic Stroke ◽  
Cardiovascular Diseases ◽  
Animal Studies ◽  
Gestational Hypertension ◽  
Cochrane Library ◽  
Major Adverse Cardiovascular Events ◽  
Risk Marker ◽  
Artery Disease

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a pro-apoptotic protein showing broad biological functions. Data from animal studies indicate that TRAIL may possibly contribute to the pathophysiology of cardiomyopathy, atherosclerosis, ischemic stroke and abdominal aortic aneurysm. It has been also suggested that TRAIL might be useful in cardiovascular risk stratification. This systematic review aimed to evaluate whether TRAIL is a risk factor or risk marker in cardiovascular diseases (CVDs) focusing on major adverse cardiovascular events. Two databases (PubMed and Cochrane Library) were searched until December 2020 without a year limit in accordance to the PRISMA guidelines. A total of 63 eligible original studies were identified and included in our systematic review. Studies suggest an important role of TRAIL in disorders such as heart failure, myocardial infarction, atrial fibrillation, ischemic stroke, peripheral artery disease, and pulmonary and gestational hypertension. Most evidence associates reduced TRAIL levels and increased TRAIL-R2 concentration with all-cause mortality in patients with CVDs. It is, however, unclear whether low TRAIL levels should be considered as a risk factor rather than a risk marker of CVDs. Further studies are needed to better define the association of TRAIL with cardiovascular diseases.

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