Effects of deferoxamine on blood-brain barrier disruption after subarachnoid hemorrhage.
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ABSTRACT:
SUBMITTER: Li Y
PROVIDER: S-EPMC5332094 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Aneurysmal subarachnoid hemorrhage remains serious hemorrhagic stroke with high morbidities and mortalities. Aneurysm rupture causes arterial bleeding-induced mechanical brain tissue injuries and elevated intracranial pressure, followed by global cerebral ischemia. Post-subarachnoid hemorrhage ischemia, tissue injuries as well as extravasated blood components and the breakdown products activate microglia, astrocytes and Toll-like receptor 4, and disrupt blood-brain barrier associated with the induction of many inflammatory and other cascades. Once blood-brain barrier is disrupted, brain tissues are directly exposed to harmful blood contents and immune cells, which aggravate brain injuries furthermore. Blood-brain barrier disruption after subarachnoid hemorrhage may be developed by a variety of mechanisms including endothelial cell apoptosis and disruption of tight junction proteins. Many molecules and pathways have been reported to disrupt the blood-brain barrier after subarachnoid hemorrhage, but the exact mechanisms remain unclear. Multiple independent and/or interconnected signaling pathways may be involved in blood-brain barrier disruption after subarachnoid hemorrhage. This review provides recent understandings of the mechanisms and the potential therapeutic targets of blood-brain barrier disruption after subarachnoid hemorrhage.
| S-EPMC6425837 | biostudies-literature
Project description:Blood-brain barrier (BBB) injury critically exacerbates the poor prognosis of patients with subarachnoid hemorrhage (SAH). The massively increased matrix metalloproteinases 9 (MMP-9) plays a deleterious role in BBB. However, the main source and mechanism of MMP-9 production after SAH remain unclear. We reported that the increased MMP-9 was mainly derived from reactive astrocytes after SAH. Ndrg2 knockout in astrocytes inhibited MMP-9 expression after SAH and attenuated BBB damage. Astrocytic Ndrg2 knockout decreased the phosphorylation of Smad2/3 and the transcription of MMP-9. Notably, cytoplasmic NDRG2 bound to the protein phosphatase PPM1A and restricted the dephosphorylation of Smad2/3. Accordingly, TAT-QFNP12, a novel engineered peptide that could block the NDRG2-PPM1A binding and reduce Smad2/3 dephosphorylation, decreased astrocytic MMP-9 production and BBB disruption after SAH. In conclusion, this study identified NDRG2-PPM1A signaling in reactive astrocytes as a key switch for MMP-9 production and provided a novel therapeutic avenue for BBB protection after SAH.
| S-EPMC9524825 | biostudies-literature
Project description:OBJECTIVE:The potential roles and mechanisms of pericytes in maintaining blood-brain barrier (BBB) integrity, which would be helpful for the development of therapeutic strategies for subarachnoid hemorrhage (SAH), remain unclear. We sought to provide evidence on the potential role of pericytes in BBB disruption and possible involvement and mechanism of CypA signaling in both cultured pericytes and SAH models. METHODS:Three hundred fifty-three adult male C57B6J mice weighing 22 to 30 g, 29 CypA-/- mice, 30 CypA+/+ (flox/flox) mice, and 30 male neonatal C57B6J mice were used to investigate the time course of CypA expression in pericytes after SAH, the intrinsic function and mechanism of CypA in pericytes, and whether the known receptor CD147 mediates these effects. RESULTS:Our data demonstrated both intracellular CypA and CypA secretion increased after SAH and could activate CD147 receptor and downstream NF-κB pathway to induce MMP9 expression and proteolytic functions for degradation of endothelium tight junction proteins and basal membranes. CypA served as autocrine or paracrine ligand for its receptor, CD147. Although CypA could be endocytosed by pericytes, specific endocytosis inhibitor chlorpromazine did not have any effect on MMP9 activation. However, specific knockdown of CD147 could reverse the harmful effects of CypA expression in pericytes on the BBB integrity after SAH. CONCLUSIONS:This study demonstrated for the first time that CypA mediated the harmful effects of pericytes on BBB disruption after SAH, which potentially mediated by CD147/NF-κB/MMP9 signal, and junction protein degradation in the brain. By targeting CypA and pericytes, this study may provide new insights on the management of SAH patients.
| S-EPMC6954572 | biostudies-literature
Project description:We examined effects of isoflurane, volatile anesthetics, on blood-brain barrier disruption in the endovascular perforation model of subarachnoid hemorrhage (SAH) in mice.Animals were assigned to sham-operated, SAH+vehicle-air, SAH+1%, or 2% isoflurane groups. Neurobehavioral function, brain water content, Evans blue dye extravasation, and Western blotting for sphingosine kinases, occludin, claudin-5, junctional adhesion molecule, and vascular endothelial cadherin were evaluated at 24 hours post-SAH. Effects of sphingosine kinase (N,N-dimethylsphingosine) or sphingosine-1-phosphate receptor-1/3 (S1P1/3) inhibitors (VPC23019) on isoflurane's action were also examined.SAH aggravated neurological scores, brain edema, and blood-brain barrier permeability, which were prevented by 2% but not 1% isoflurane posttreatment. Two percent isoflurane increased sphingosine kinase-1 expression and prevented a post-SAH decrease in expressions of the blood-brain barrier-related proteins. Both N,N-dimethylsphingosine and VPC23019 abolished the beneficial effects of isoflurane.Two percent isoflurane can suppress post-SAH blood-brain barrier disruption, which may be mediated by sphingosine kinase 1 expression and sphingosine-1-phosphate receptor-1/3 activation.
| S-EPMC3429639 | biostudies-literature
Project description:We recently observed early white matter injury after experimental subarachnoid hemorrhage (SAH), but the underlying mechanisms are uncertain. This study investigated the potential role of matrix metalloproteinase (MMP)-9 in blood-brain barrier (BBB) disruption and consequent white matter injury.SAH was induced by endovascular perforation in adult male mice. The following 3 experiments were devised: (1) mice underwent magnetic resonance imaging at 24 h after SAH and were euthanized to determine BBB disruption and MMP-9 activation in white matter; (2) to investigate the role of MMP-9 in BBB disruption, lesion volumes on magnetic resonance imaging were compared between wild-type (WT) and MMP-9 knockout (MMP-9-/-) mice at 24 h after SAH; (3) WT and MMP-9-/- mice underwent magnetic resonance imaging at 1 and 8 days after SAH to detect time-dependent changes in brain injury. Brains were used to investigate myelin integrity in white matter.In WT mice with SAH, white matter showed BBB disruption (albumin leakage) and T2 hyperintensity on magnetic resonance imaging. MMP-9 activity was elevated at 24 h after SAH. MMP-9-/- mice had less white matter T2 hyperintensity after SAH than WT mice. At 8 days after SAH, WT mice had decreased myelin integrity and MMP-9-/- mice developed less white matter injury.SAH causes BBB disruption and consequent injury in white matter. MMP-9 plays an important role in those pathologies and could be a therapeutic target for SAH-induced white matter injury.
| S-EPMC4589516 | biostudies-literature
Project description:BackgroundSubarachnoid hemorrhage (SAH) is a life-threatening disease worldwide, and effective pharmaceutical treatment is still lacking. Celastrol is a plant-derived triterpene which showed neuroprotective potential in several types of brain insults. This study aimed to investigate the effects of celastrol on early brain injury (EBI) after SAH.MethodsA total of sixty-one male Sprague-Dawley rats were used in this study. Rat SAH endovascular perforation model was established to mimic the pathological changes of EBI after SAH. Multiple methods such as 3.0T MRI scanning, immunohistochemistry, western blotting and propidium iodide (PI) labeling were used to explore the therapeutic effects of celastrol on SAH.ResultsCelastrol treatment attenuated SAH-caused brain swelling, reduced T2 lesion volume and ventricular volume in MRI scanning, and improved overall neurological score. Albumin leakage and the degradation of tight junction proteins were also ameliorated after celastrol administration. Celastrol protected blood-brain bairrer integrity through inhibiting MMP-9 expression and anti-neuroinflammatory effects. Additionally, necroptosis-related proteins RIP3 and MLKL were down-regulated and PI-positive cells in the basal cortex were less in the celastrol-treated SAH group than that in untreated SAH group.ConclusionsCelastrol exhibits neuroprotective effects on EBI after SAH and deserves to be further investigated as an add-on pharmaceutical therapy.
| S-EPMC8266331 | biostudies-literature
Project description:ObjectiveThis study sought to confirm the relationship between the degree of blood-brain barrier (BBB) damage and the severity of intracranial hemorrhage (ICH) in a population of patients who received endovascular therapy.MethodsThe degree of BBB disruption on pretreatment MRI scans was analyzed, blinded to follow-up data, in the DEFUSE 2 cohort in which patients had endovascular therapy within 12 hours of stroke onset. BBB disruption was compared with ICH grade previously established by the DEFUSE 2 core lab. A prespecified threshold for predicting parenchymal hematoma (PH) was tested.ResultsOf the 108 patients in the DEFUSE 2 trial, 100 had adequate imaging and outcome data and were included in this study; 24 developed PH. Increasing amounts of BBB disruption on pretreatment MRIs was associated with increasing severity of ICH grade (p = 0.004). BBB disruption on the pretreatment scan was associated with PH (p = 0.020) with an odds ratio for developing PH of 1.69 for each 10% increase in BBB disruption (95% confidence interval 1.09-2.64), although a reliably predictive threshold was not identified.ConclusionsThe amount of BBB disruption on pretreatment MRI is associated with the severity of ICH after acute intervention. This relationship has now been identified in patients receiving IV, endovascular, and combined therapies. Further study is needed to determine its role in guiding treatment.
| S-EPMC4955280 | biostudies-literature
Project description:This article reviews current knowledge of the mechanisms underlying the initial hemorrhage and secondary blood-brain barrier (BBB) dysfunction in primary spontaneous intracerebral hemorrhage (ICH) in adults. Multiple etiologies are associated with ICH, for example, hypertension, Alzheimer's disease, vascular malformations and coagulopathies (genetic or drug-induced). After the initial bleed, there can be continued bleeding over the first 24 hours, so-called hematoma expansion, which is associated with adverse outcomes. A number of clinical trials are focused on trying to limit such expansion. Significant progress has been made on the causes of BBB dysfunction after ICH at the molecular and cell signaling level. Blood components (e.g. thrombin, hemoglobin, iron) and the inflammatory response to those components play a large role in ICH-induced BBB dysfunction. There are current clinical trials of minimally invasive hematoma removal and iron chelation which may limit such dysfunction. Understanding the mechanisms underlying the initial hemorrhage and secondary BBB dysfunction in ICH is vital for developing methods to prevent and treat this devastating form of stroke.
| S-EPMC4130123 | biostudies-literature
Project description:BackgroundDisease progression and delayed neurological complications are common after aneurysmal subarachnoid hemorrhage (aSAH). We explored the potential of quantitative blood-brain barrier (BBB) imaging to predict disease progression and neurological outcome.MethodsData were collected as part of the Co-Operative Studies of Brain Injury Depolarizations (COSBID). We analyzed retrospectively, blinded and semi-automatically magnetic resonance images from 124 aSAH patients scanned at 4 time points (24-48 h, 6-8 days, 12-15 days and 6-12 months) after the initial hemorrhage. Volume of brain with apparent pathology and/or BBB dysfunction (BBBD), subarachnoid space and lateral ventricles were measured. Neurological status on admission was assessed using the World Federation of Neurosurgical Societies and Rosen-Macdonald scores. Outcome at ≥6 months was assessed using the extended Glasgow outcome scale and disease course (progressive or non-progressive based on imaging-detected loss of normal brain tissue in consecutive scans). Logistic regression was used to define biomarkers that best predict outcomes. Receiver operating characteristic analysis was performed to assess accuracy of outcome prediction models.FindingsIn the present cohort, 63% of patients had progressive and 37% non-progressive disease course. Progressive course was associated with worse outcome at ≥6 months (sensitivity of 98% and specificity of 97%). Brain volume with BBBD was significantly larger in patients with progressive course already 24-48 h after admission (2.23 (1.23-3.17) folds, median with 95%CI), and persisted at all time points. The highest probability of a BBB-disrupted voxel to become pathological was found at a distance of ≤1 cm from the brain with apparent pathology (0·284 (0·122-0·594), p < 0·001, median with 95%CI). A multivariate logistic regression model revealed power for BBBD in combination with RMS at 24-48 h in predicting outcome (ROC area under the curve = 0·829, p < 0·001).InterpretationWe suggest that early identification of BBBD may serve as a key predictive biomarker for neurological outcome in aSAH. FUND: Dr. Dreier was supported by grants from the Deutsche Forschungsgemeinschaft (DFG) (DFG DR 323/5-1 and DFG DR 323/10-1), the Bundesministerium für Bildung und Forschung (BMBF) Center for Stroke Research Berlin 01 EO 0801 and FP7 no 602150 CENTER-TBI. Dr. Friedman was supported by grants from Israel Science Foundation and Canada Institute for Health Research (CIHR). Dr. Friedman was supported by grants from European Union's Seventh Framework Program (FP7/2007-2013; grant #602102).
| S-EPMC6558266 | biostudies-literature
Project description:Despite the substantial efforts to elucidate the role of early brain injury in subarachnoid hemorrhage (SAH), an effective pharmaceutical therapy for patients with SAH continues to be unavailable. This study aims to reveal the role of necroptosis after SAH, and explore whether the disruption of the blood-brain barrier (BBB) and RIP3-mediated necroptosis following SAH in a rat SAH model are altered by necrostatin-1 via its selective inhibition of receptor-interacting protein kinase 1 (RIP1). Sixty-five rats were used in the experiments. The SAH model was established using endovascular perforation. Necrostatin-1 was intracerebroventricularly injected 1 h before SAH induction. The neuroprotective effects of necrostatin-1 were evaluated with multiple methods such as magnetic resonance imaging (MRI) scanning, immunohistochemistry, propidium iodide (PI) labeling, and western blotting. Pretreatment with necrostatin-1 attenuated brain swelling and reduced the lesion volume on T2 sequence and ventricular volume on MRI 72 h after SAH induction. Albumin leakage and the degradation of tight junction proteins were also ameliorated by necrostatin-1 administration. In addition, necrostatin-1 decreased the number of PI-positive cells in the basal cortex, reduced the levels of the RIP3 and MLKL proteins, and inhibited the production of the pro-inflammatory cytokines IL-1?, IL-6, and TNF-?. Based on the findings from the present study, the selective RIP1 inhibitor necrostatin-1 functioned as a neuroprotective agent after SAH by attenuating brain swelling and BBB disruption. Moreover, the necrostatin-1 pretreatment prevented SAH-induced necroptosis by suppressing the activity of the RIP3/MLKL signaling pathway. These results will provide insights into new drugs and pharmacological targets to manage SAH, which are worth further study.
| S-EPMC6802141 | biostudies-literature