Abstract WP137: Time-Course Characterization of Blood-Brain Barrier Disruption in Secondary Thalamic Injury After Stroke

Stroke ◽  
2020 ◽  
Vol 51 (Suppl_1) ◽  
Author(s):  
Zhijuan Cao ◽  
Sean Harvey ◽  
Arjun Pendharkar ◽  
Terrance Chiang ◽  
Michelle Cheng ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Blood Brain Barrier ◽  
Stroke Recovery ◽  
Brain Barrier ◽  
Tube Length ◽  
Left Middle Cerebral Artery ◽  
Vessel Morphology ◽  
Blood Brain ◽  
Branching Points ◽  
Bbb Permeability

Introduction: A secondary degenerative injury occurs in the thalamus after primary cortical ischemic stroke. This secondary thalamic injury progresses long-term and is associated with somatosensory dysfunctions. Blood-brain barrier (BBB) disruption is one of the feature pathological changes in primary ischemic stroke, but whether BBB disruption happens in the secondary thalamic injury is unclear. In this study, we aim to investigate the BBB changes during the development of secondary thalamic injury after stroke. Methods: Cortical ischemic stroke was generated by permanent occlusion of the left middle cerebral artery on male C57BL6J mice (12-15 weeks). BBB permeability was assessed by Biocytin-TMR (869 Da, 1mg/mL) at post-stroke days (PD) 1, 3, 7, 14, 28, 56, and 84. Immunostainings of CD68 (inflammation) and CD31 (vascular morphology) were performed. Brain sections were imaged with Confocal LSM800 and quantified by NIH ImageJ and Wimasis Image Analysis. BBB permeability related genes were quantified by real-time PCR among naïve, PD7 and PD28. Results: In ipsilesional thalamus (iTH), the Biocytin-TMR was detected as early as PD3 in the secondary thalamic injury area and persisted until at least PD84. The fluorescence intensity of Biocytin-TMR significantly increased during PD28-84 and peaked at PD56, suggesting the BBB is chronically disrupted in iTH. Compared to naïve animals, stroke animals exhibited significant increase in tube length, total number of tubes and total number of branching points at PD56 and PD84. mRNA expression of ZO-2 significantly down-regulated at PD7 and returned to baseline levels by PD28. mRNA of Angiopoietin-1 ( Ang-1 ), VEGFa and Adam10 were significantly increased at PD28. Conclusion: Our data demonstrate that the BBB disruption begins early at PD3 and continues to progress until PD84 in the secondary degenerative thalamus. This BBB disruption is accompanied by changes in blood vessel morphology and permeability related genes. Current studies are examining the expression of key genes at PD56 using qPCR and immunohistochemistry. Our results will elucidate the cellular and molecular changes of BBB disruption involved in thalamic injury, which will provide potential targets for enhancing stroke recovery.

scholarly journals Pathophysiology of Blood–Brain Barrier Permeability Throughout the Different Stages of Ischemic Stroke and Its Implication on Hemorrhagic Transformation and Recovery

2020 ◽  
Vol 11 ◽  
Author(s):  
Sara Bernardo-Castro ◽  
João André Sousa ◽  
Ana Brás ◽  
Carla Cecília ◽  
Bruno Rodrigues ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Blood Brain Barrier ◽  
Arterial Occlusion ◽  
Hemorrhagic Transformation ◽  
Stroke Recovery ◽  
Brain Barrier ◽  
Vast Number ◽  
Blood Brain ◽  
Repair Mechanisms ◽  
Bbb Permeability

The blood–brain barrier (BBB) is a dynamic interface responsible for maintaining the central nervous system homeostasis. Its unique characteristics allow protecting the brain from unwanted compounds, but its impairment is involved in a vast number of pathological conditions. Disruption of the BBB and increase in its permeability are key in the development of several neurological diseases and have been extensively studied in stroke. Ischemic stroke is the most prevalent type of stroke and is characterized by a myriad of pathological events triggered by an arterial occlusion that can eventually lead to fatal outcomes such as hemorrhagic transformation (HT). BBB permeability seems to follow a multiphasic pattern throughout the different stroke stages that have been associated with distinct biological substrates. In the hyperacute stage, sudden hypoxia damages the BBB, leading to cytotoxic edema and increased permeability; in the acute stage, the neuroinflammatory response aggravates the BBB injury, leading to higher permeability and a consequent risk of HT that can be motivated by reperfusion therapy; in the subacute stage (1–3 weeks), repair mechanisms take place, especially neoangiogenesis. Immature vessels show leaky BBB, but this permeability has been associated with improved clinical recovery. In the chronic stage (>6 weeks), an increase of BBB restoration factors leads the barrier to start decreasing its permeability. Nonetheless, permeability will persist to some degree several weeks after injury. Understanding the mechanisms behind BBB dysregulation and HT pathophysiology could potentially help guide acute stroke care decisions and the development of new therapeutic targets; however, effective translation into clinical practice is still lacking. In this review, we will address the different pathological and physiological repair mechanisms involved in BBB permeability through the different stages of ischemic stroke and their role in the development of HT and stroke recovery.

scholarly journals Borneol for Regulating the Permeability of the Blood-Brain Barrier in Experimental Ischemic Stroke: Preclinical Evidence and Possible Mechanism

2019 ◽  
Vol 2019 ◽  
pp. 1-15 ◽  
Author(s):  
Zi-xian Chen ◽  
Qing-qing Xu ◽  
Chun-shuo Shan ◽  
Yi-hua Shi ◽  
Yong Wang ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Blood Brain Barrier ◽  
Ischemic Injury ◽  
Brain Barrier ◽  
Brain Diseases ◽  
Glycoprotein P ◽  
Blood Brain ◽  
Cerebral Ischemic Injury ◽  
Bbb Permeability ◽  
Cerebral Ischemic

Borneol, a natural product in the Asteraceae family, is widely used as an upper ushering drug for various brain diseases in many Chinese herbal formulae. The blood-brain barrier (BBB) plays an essential role in maintaining a stable homeostatic environment, while BBB destruction and the increasing BBB permeability are common pathological processes in many serious central nervous system (CNS) diseases, which is especially an essential pathological basis of cerebral ischemic injury. Here, we aimed to conduct a systematic review to assess preclinical evidence of borneol for experimental ischemic stroke as well as investigate in the possible neuroprotective mechanisms, which mainly focused on regulating the permeability of BBB. Seven databases were searched from their inception to July 2018. The studies of borneol for ischemic stroke in animal models were included. RevMan 5.3 was applied for data analysis. Fifteen studies investigated the effects of borneol in experimental ischemic stroke involving 308 animals were ultimately identified. The present study showed that the administration of borneol exerted a significant decrease of BBB permeability during cerebral ischemic injury according to brain Evans blue content and brain water content compared with controls (P<0.01). In addition, borneol could improve neurological function scores (NFS) and cerebral infarction area. Thus, borneol may be a promising neuroprotective agent for cerebral ischemic injury, largely through alleviating the BBB disruption, reducing oxidative reactions, inhibiting the occurrence of inflammation, inhibiting apoptosis, and improving the activity of lactate dehydrogenase (LDH) as well as P-glycoprotein (P-GP) and NO signaling pathway.

scholarly journals Nicotinamide Mononucleotide Adenylyltransferase 1 Regulates Cerebral Ischemia-Induced Blood–Brain Barrier Disruption Through NAD+/SIRT1 Signaling Pathway

2021 ◽  
Author(s):  
Yang Zhang ◽  
Xun Guo ◽  
Zhifeng Peng ◽  
Chang Liu ◽  
Lili Ren ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Signaling Pathway ◽  
Blood Brain Barrier ◽  
Molecular Mechanisms ◽  
Sirtuin 1 ◽  
Brain Barrier ◽  
Blood Brain ◽  
Nicotinamide Mononucleotide ◽  
Nicotinamide Mononucleotide Adenylyltransferase ◽  
Bbb Permeability

Abstract The molecular mechanisms of blood–brain barrier (BBB) disruption in the early stage after ischemic stroke are poorly understood. In the present study, we investigated the potential role of nicotinamide mononucleotide adenylyltransferase 1 (NMNAT1) in ischemia-induced BBB damage using an animal middle cerebral artery occlusion (MCAO) model of ischemic stroke. Recombinant human NMNAT1 (rh-NMNAT1) was administered intranasally and Sirtuin 1 (SIRT1) siRNA was administered by intracerebroventricular injection. Our results indicated that rh-NMNAT1 reduced infarct volume, improved functional outcome and decreased BBB permeability in mice after ischemic stroke. Furthermore, rh-NMNAT1 prevented the loss of tight junction proteins (occludin and claudin-5) and reduced cell apoptosis in ischemic microvessels. NMNAT1-mediated BBB permeability was correlated with the elevation of nicotinamide adenine dinucleotide (NAD+)/NADH and SIRT1 level in ischemic microvessels. In addition, rh-NMNAT1 treatment significantly decreased the levels of acetylated nuclear factor-κB, acetylated p53 and matrix metalloproteinase-9 in ischemic microvessels. Moreover, the protective effects of rh-NMNAT1 were reversed by SIRT1 siRNA. In conclusion, these findings indicate that NMNAT1 protects BBB after ischemic stroke in mice which was in part via the NAD+/SIRT1 signaling pathway in brain microvascular endothelial cells. NMNAT1 may be a novel potential therapeutic target for reducing BBB disruption after ischemic stroke.

scholarly journals Temporal analysis of blood–brain barrier disruption and cerebrospinal fluid matrix metalloproteinases in rhesus monkeys subjected to transient ischemic stroke

2016 ◽  
Vol 37 (8) ◽  
pp. 2963-2974 ◽  
Author(s):  
Yingqian Zhang ◽  
Feng Fan ◽  
Guojun Zeng ◽  
Linlin Zhou ◽  
Yinbing Zhang ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Blood Brain Barrier ◽  
Dynamic Change ◽  
Fold Increase ◽  
Temporal Analysis ◽  
Brain Barrier ◽  
Infarction Size ◽  
Blood Brain Barrier Disruption ◽  
Blood Brain ◽  
Bbb Permeability

Blood–brain barrier (BBB) disruption plays an important role in pathophysiological progress of ischemic stroke. However, our knowledge of the dynamic change of BBB permeability and its mechanism remains limited. In the current study, we used a non-human primate (NHP) MCAO model and a serial CSF sampling method that allowed us to determine the dynamic change of BBB permeability by calculating the CSF/serum albumin ratio (AR). We showed that AR increased rapidly and significantly after ischemia, and the fold increase of AR is highly correlated with the infarction size during the subacute phase. Moreover, we determined the temporal change of MMP-1, MMP-2, MMP-3, MMP-9, MMP-10, MMP-13, TIMP-1, and TIMP-2 in CSF and serum. Each MMP and TIMP showed different change patterns when comparing their values in CSF and serum. Based on the longitudinal dataset, we showed that the fold increase of MMP-9 in serum and CSF are both correlated to infarction size. Among the measured MMPs and TIMPs, only MMP-2, MMP-13, and TIMP-2 in CSF correlated with AR to some extent. Our data suggest there is no single MMP or TIMP fully responsible for BBB breakdown, which is regulated by a much more complicated signal network and further investigations of the mechanisms are needed.

DCE-MRI blood–brain barrier assessment in acute ischemic stroke

Neurology ◽  
2016 ◽  
Vol 88 (5) ◽  
pp. 433-440 ◽  
Author(s):  
Kersten Villringer ◽  
Borja E. Sanz Cuesta ◽  
Ann-Christin Ostwaldt ◽  
Ulrike Grittner ◽  
Peter Brunecker ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Blood Brain Barrier ◽  
Symptom Onset ◽  
Brain Barrier ◽  
Stroke Patients ◽  
Dce Mri ◽  
Link Type ◽  
Blood Brain ◽  
Bbb Permeability

Objective:To quantitatively evaluate blood–brain barrier changes in ischemic stroke patients using dynamic contrast-enhanced (DCE) MRI.Methods:We examined 54 stroke patients (clinicaltrials.govNCT00715533, NCT02077582) in a 3T MRI scanner within 48 hours after symptom onset. Twenty-eight patients had a follow-up examination on day 5–7. DCE T1 mapping and Patlak analysis were employed to assess BBB permeability changes.Results:Median stroke Ktrans values (0.7 × 10−3 min−1 [interquartile range (IQR) 0.4–1.8] × 10−3 min−1) were more than 3-fold higher compared to median mirror Ktrans values (0.2 × 10−3 min−1, IQR 0.1–0.7 × 10−3 min−1, p < 0.001) and further increased at follow-up (n = 28, 2.3 × 10−3 min−1, IQR 0.8–4.6 × 10−3 min−1, p < 0.001). By contrast, mirror Ktrans values decreased over time with a clear interaction of timepoint and stroke/mirror side (p < 0.001). Median stroke Ktrans values were 2.5 times lower than in hemorrhagic transformed regions (0.7 vs 1.8 × 10−3 min−1; p = 0.055). There was no association between stroke Ktrans values and the delay from symptom onset to baseline examination, age, and presence of hyperintense acute reperfusion marker.Conclusion:BBB in acute stroke patients can be successfully assessed quantitatively. The decrease of BBB permeability in unaffected regions at follow-up may be an indicator of global BBB leakage even in vessel territories remote from the index infarct.

scholarly journals Continuous Blood-Brain Barrier Breakdown In Acute Ischemic Stroke Patients

2021 ◽  
Author(s):  
Kersten Villringer ◽  
Uchralt Temuulen ◽  
Ralf Mekle ◽  
Jochen B. Fiebach ◽  
Christin H. Nolte ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Blood Brain Barrier ◽  
Symptom Onset ◽  
Time Course ◽  
Functional Disability ◽  
Brain Barrier ◽  
Rank Test ◽  
Stroke Patients ◽  
Blood Brain ◽  
Bbb Permeability

Abstract Neurological diseases such as ischemic stroke and dementia are associated with compromised blood-brain barrier (BBB) permeability. Knowledge about the time course of BBB leakage may have impact on therapeutic interventions and diagnostic measures such as testing for blood biomarkers. However, reports on the timeline and pattern of this leakage are contradictory. Therefore, we aimed to assess the time course of BBB permeability in ischemic stroke patients during the first 24 hours after symptom onset using dynamic contrast enhanced (DCE) MRI at 3 Tesla. We categorized time from stroke symptom onset to imaging into the following groups 1) 0-6 hours (n=10), 2) 6-16 hours (n=14) and 3) 16-24 hours (n=29). BBB permeability differed significantly between stroke lesions and the contralesional tissue for groups 2 and 3 (p=0.006, p<0.001, Wilcoxon-signed rank test). Using univariate or multivariate linear regression analyses we found no association between BBB leakage and age, sex, hyperintense reperfusion marker (another marker of BBB permeability) hemorrhagic transformation, white matter lesion load, symptom severity, functional disability and cerebrovascular risk factors. The results of our study therefore suggest continuous BBB leakage in the first 24 hours after stroke.

scholarly journals Rivaroxaban Does Not Increase Hemorrhage after Thrombolysis in Experimental Ischemic Stroke

2013 ◽  
Vol 34 (3) ◽  
pp. 495-501 ◽  
Author(s):  
Robert Ploen ◽  
Li Sun ◽  
Wei Zhou ◽  
Stefan Heitmeier ◽  
Markus Zorn ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Blood Brain Barrier ◽  
Intravenous Thrombolysis ◽  
Recombinant Tissue Plasminogen Activator ◽  
International Normalized Ratio ◽  
Brain Barrier ◽  
Secondary Hemorrhage ◽  
Blood Brain ◽  
Increased Risk ◽  
Bbb Permeability

The management of acute ischemic stroke during anticoagulation with a novel oral anticoagulant (NOAC) is challenging because intravenous thrombolysis is contraindicated because of a putative increased risk of intracerebral hemorrhagic complications. We examined the risk of secondary postischemic hemorrhage after thrombolysis in rodents pretreated with rivaroxaban or warfarin. Mice were pretreated with either rivaroxaban (30 mg/kg), warfarin (target international normalized ratio 2 to 3) or vehicle. After 2 or 3 hours, middle cerebral artery occlusion (MCAO), mice received 9 mg/kg recombinant tissue plasminogen activator. Twenty-four hours after MCAO, secondary hemorrhage was quantified using a macroscopic hemorrhage score and hemoglobin spectrophotometry. Blood–brain barrier (BBB) permeability was measured by Evans Blue spectrofluorometry. To increase the validity of our findings, experiments were also performed using a thromboembolic model in anticoagulated rats. Infarct size did not differ among groups. Pretreatment with warfarin led to significantly more secondary hemorrhage compared with rivaroxaban and nonanticoagulated controls after 2- and 3-hour ischemia in mice as well as in rats. Blood–brain barrier permeability was significantly higher in the warfarin group compared with rivaroxaban and control. Thus, rivaroxaban in contrast to warfarin does not increase secondary hemorrhage after thrombolysis in experimental cerebral ischemia. Less effects of rivaroxaban on postischemic BBB permeability may account for this difference.

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 Could Lipoxins Represent a New Standard in Ischemic Stroke Treatment?

2021 ◽  
Vol 22 (8) ◽  
pp. 4207
Author(s):  
Nikola Tułowiecka ◽  
Dariusz Kotlęga ◽  
Andrzej Bohatyrewicz ◽  
Małgorzata Szczuko
Keyword(s):  
Ischemic Stroke ◽  
Cardiovascular Diseases ◽  
Blood Brain Barrier ◽  
Inflammatory Cytokines ◽  
The Body ◽  
Brain Barrier ◽  
Lipoxin A4 ◽  
Stroke Treatment ◽  
Blood Brain ◽  
Anti Inflammatory

Introduction: Cardiovascular diseases including stroke are one of the most common causes of death. Their main cause is atherosclerosis and chronic inflammation in the body. An ischemic stroke may occur as a result of the rupture of unstable atherosclerotic plaque. Cardiovascular diseases are associated with uncontrolled inflammation. The inflammatory reaction produces chemical mediators that stimulate the resolution of inflammation. One of these mediators is lipoxins—pro-resolving mediators that are derived from the omega-6 fatty acid family, promoting inflammation relief and supporting tissue regeneration. Aim: The aim of the study was to review the available literature on the therapeutic potential of lipoxins in the context of ischemic stroke. Material and Methods: Articles published up to 31 January 2021 were included in the review. The literature was searched on the basis of PubMed and Embase in terms of the entries: ‘stroke and lipoxin’ and ‘stroke and atherosclerosis’, resulting in over 110 articles in total. Studies that were not in full-text English, letters to the editor, and conference abstracts were excluded. Results: In animal studies, the injection/administration of lipoxin A4 improved the integrity of the blood–brain barrier (BBB), decreased the volume of damage caused by ischemic stroke, and decreased brain edema. In addition, lipoxin A4 inhibited the infiltration of neutrophils and the production of cytokines and pro-inflammatory chemokines, such as interleukin (Il-1β, Il-6, Il-8) and tumor necrosis factor-α (TNF-α). The beneficial effects were also observed after introducing the administration of lipoxin A4 analog—BML-111. BML-111 significantly reduces the size of a stroke and protects the cerebral cortex, possibly by reducing the permeability of the blood–brain barrier. Moreover, more potent than lipoxin A4, it has an anti-inflammatory effect by inhibiting the production of pro-inflammatory cytokines and increasing the amount of anti-inflammatory cytokines. Conclusions: Lipoxins and their analogues may find application in reducing damage caused by stroke and improving the prognosis of patients after ischemic stroke.

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