Journal articles on the topic 'BBB leakage'
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Verheggen, Inge C. M., Joost J. A. de Jong, Martin P. J. van Boxtel, Alida A. Postma, Jacobus F. A. Jansen, Frans R. J. Verhey, and Walter H. Backes. "Imaging the role of blood–brain barrier disruption in normal cognitive ageing." GeroScience 42, no. 6 (October 6, 2020): 1751–64. http://dx.doi.org/10.1007/s11357-020-00282-1.
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AbstractTo investigate whether blood–brain barrier (BBB) disruption is a potential mechanism of usual age-related cognitive decline, we conducted dynamic contrast–enhanced (DCE) MRI to measure BBB leakage in a healthy sample, and investigated the association with longitudinal cognitive decline. In a sample of neurologically and cognitively healthy, older individuals, BBB leakage rate in the white and grey matter and hippocampus was measured using DCE MRI with pharmacokinetic modelling. Regression analysis was performed to investigate whether the leakage rate was associated with decline in cognitive performance (memory encoding, memory retrieval, executive functioning and processing speed) over 12 years. White and grey matter BBB leakages were significantly associated with decline in memory retrieval. No significant relations were found between hippocampal BBB leakage and cognitive performance. BBB disruption already being associated with usual cognitive ageing, supports that this neurovascular alteration is a possible explanation for the cognitive decline inherent to the ageing process. More insight into BBB leakage during the normal ageing process could improve estimation and interpretation of leakage rate in pathological conditions. The current results might also stimulate the search for strategies to maintain BBB integrity and help increase the proportion people experiencing successful ageing. Netherlands Trial Register number: NL6358, date of registration: 2017-03-24.
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Arba, Francesco, Richard Leigh, Domenico Inzitari, Steven J. Warach, Marie Luby, and Kennedy R. Lees. "Blood–brain barrier leakage increases with small vessel disease in acute ischemic stroke." Neurology 89, no. 21 (October 25, 2017): 2143–50. http://dx.doi.org/10.1212/wnl.0000000000004677.
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Objective:In patients with acute ischemic stroke, we aimed to investigate the relation between preexisting small vessel disease (SVD) and the amount of blood–brain barrier (BBB) leakage in ischemic and nonischemic area before IV thrombolysis.Methods:We retrospectively accessed anonymous patient-level data from the Stroke Imaging Repository and the Virtual International Stroke Trials Archive resources and included patients treated with IV thrombolysis with pretreatment MRI. We rated SVD features using validated qualitative magnetic resonance (MR) scales. Leakage of BBB was assessed with postprocessing of perfusion-weighted images. We evaluated associations between SVD features (individually and summed in a global SVD score) and BBB leakage using linear regression analysis, adjusting for major clinical confounders.Results:A total of 212 patients, mean age (±SD) 69.5 years (±16.1), 102 (48%) male, had available MR before IV thrombolysis. Evidence of BBB leakage was present in 175 (80%) and 205 (94%) patients in the ischemic and nonischemic area, respectively. Lacunar infarcts (β = 0.17, p = 0.042) were associated with BBB leakage in the ischemic area, and brain atrophy was associated with BBB leakage in both ischemic (β = 0.20, p = 0.026) and nonischemic (β = 0.27, p = 0.001) areas. Increasing SVD grade was independently associated with BBB leakage in both ischemic (β = 0.26, p = 0.007) and nonischemic (β = 0.27, p = 0.003) area.Conclusions:Global SVD burden is associated with increased BBB leakage in both acutely ischemic and nonischemic area. Our results support that SVD score has construct validity, and confirm a relation between SVD and BBB disruption also in patients with acute stroke.
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Hafezi-Moghadam, Ali, Kennard L. Thomas, and Denisa D. Wagner. "ApoE deficiency leads to a progressive age-dependent blood-brain barrier leakage." American Journal of Physiology-Cell Physiology 292, no. 4 (April 2007): C1256—C1262. http://dx.doi.org/10.1152/ajpcell.00563.2005.
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Previously, we reported a defect in the blood-brain barrier (BBB) of apolipoprotein E-deficient (apoE−/−) mice ( 24 ). Here, we investigate BBB permeability in wild-type (WT) and apoE−/− mice as a function of age. Both WT and apoE−/− mice showed significantly increased cortical BBB leakage with age. However, in apoE−/− mice, the leakage increased at a 3.7× higher rate compared with WT mice. Surprisingly, the cerebellum showed significantly more leakage than other brain regions across age, while there was no difference between the two hemispheres. To determine the contribution of tissue- vs. blood-borne apoE to vascular permeability, we generated chimeric mice by bone marrow transplantation and measured their BBB leakage. These experiments suggest that both blood- and tissue-derived apoE are equally important for BBB function. In sum, we find an age-dependent defect in the BBB that is exacerbated in apoE−/− mice. Since vascular defects are found in patients with age-related neurodegenerative diseases, such as Alzheimer's, age-related BBB leakage could underlie these defects and may thus be an important contributor to the cumulative neuronal damage of these diseases.
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Kamintsky, Lyna, Steven D. Beyea, John D. Fisk, Javeria A. Hashmi, Antonina Omisade, Cynthia Calkin, Tim Bardouille, et al. "Blood-brain barrier leakage in systemic lupus erythematosus is associated with gray matter loss and cognitive impairment." Annals of the Rheumatic Diseases 79, no. 12 (October 1, 2020): 1580–87. http://dx.doi.org/10.1136/annrheumdis-2020-218004.
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ObjectivesTo examine the association between blood-brain barrier (BBB) integrity, brain volume and cognitive dysfunction in adult patients with systemic lupus erythematosus (SLE).MethodsA total of 65 ambulatory patients with SLE and 9 healthy controls underwent dynamic contrast-enhanced MRI scanning, for quantitative assessment of BBB permeability. Volumetric data were extracted using the VolBrain pipeline. Global cognitive function was evaluated using a screening battery consisting of tasks falling into five broad cognitive domains, and was compared between patients with normal versus extensive BBB leakage.ResultsPatients with SLE had significantly higher levels of BBB leakage compared with controls (p=0.04). Extensive BBB leakage (affecting over >9% of brain volume) was identified only in patients with SLE (16/65; 24.6%), who also had smaller right and left cerebral grey matter volumes compared with controls (p=0.04). Extensive BBB leakage was associated with lower global cognitive scores (p=0.02), and with the presence of impairment on one or more cognitive tasks (p=0.01).ConclusionOur findings provide evidence for a link between extensive BBB leakage and changes in both brain structure and cognitive function in patients with SLE. Future studies should investigate the mechanisms underlying BBB-mediated cognitive impairment, validate the diagnostic utility of BBB imaging, and determine the potential of targeting the BBB as a therapeutic strategy in patients with SLE.
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Hanly, John G., Alexandra Legge, Lyna Kamintsky, Alon Friedman, Javeria A. Hashmi, Steven D. Beyea, John Fisk, et al. "Role of autoantibodies and blood–brain barrier leakage in cognitive impairment in systemic lupus erythematosus." Lupus Science & Medicine 9, no. 1 (June 2022): e000668. http://dx.doi.org/10.1136/lupus-2022-000668.
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ObjectiveCognitive impairment is common in patients with SLE but the cause is unknown. The current cross-sectional study examined the association between select SLE-related autoantibodies, other serological biomarkers and extensive blood–brain barrier (BBB) leakage in patients with SLE with and without cognitive impairment. In addition, we determined whether the relationship between SLE autoantibodies, other biomarkers and cognitive impairment differed depending on the presence or absence of concurrent extensive BBB leakage.MethodsConsecutive patients with SLE, recruited from a single academic medical centre, underwent formal neuropsychological testing for assessment of cognitive function. On the same day, BBB permeability was determined using dynamic contrast-enhanced MRI scanning. SLE autoantibodies and other serological biomarkers were measured. Regression modelling was used to determine the association between cognitive impairment, extensive BBB leakage and autoantibodies/biomarkers.ResultsThere were 102 patients with SLE; 90% were female and 88% were Caucasian, with a mean±SD age of 48.9±13.8 years. The mean±SD SLE disease duration was 14.8±11.0 years. Impairment in one or more cognitive tests was present in 47 of 101 (47%) patients and included deficits in information processing speed (9%), attention span (21%), new learning (8%), delayed recall (15%) and executive abilities (21%). Extensive BBB leakage was present in 20 of 79 (25%) patients and was associated with cognitive impairment (15 of 20 (75%) vs 24 of 59 (41%); p=0.01) and shorter disease duration (median (IQR): 7 (8–24 years) vs 15 (2–16 years); p=0.02). No serological parameters were associated with extensive BBB leakage and there was no statistically significant association between cognitive impairment and circulating autoantibodies even after adjusting for BBB leakage.ConclusionsExtensive BBB leakage alone was associated with cognitive impairment. These findings suggest that BBB leakage is an important contributor to cognitive impairment, regardless of circulating SLE-related autoantibodies.
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Bender, Benjamin, Kai Herz, Anagha Deshmane, Vivien Richter, Ghazaleh Tabatabai, Jens Schittenhelm, Marco Skardelly, et al. "GLINT: GlucoCEST in neoplastic tumors at 3 T—clinical results of GlucoCEST in gliomas." Magnetic Resonance Materials in Physics, Biology and Medicine 35, no. 1 (December 10, 2021): 77–85. http://dx.doi.org/10.1007/s10334-021-00982-5.
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Abstract Objective Clinical relevance of dynamic glucose enhanced (DGE) chemical exchange saturation transfer (CEST) imaging has mostly been demonstrated at ultra-high field (UHF) due to low effect size. Results of a cohort study at clinical field strength are shown herein. Materials and methods Motion and field inhomogeneity corrected T1ρ‐based DGE (DGE⍴) images were acquired before, during and after a d-glucose injection with 6.3 s temporal resolution to detect accumulation in the brain. Six glioma patients with clear blood–brain barrier (BBB) leakage, two glioma patients with suspected BBB leakage, and three glioma patients without BBB leakage were scanned at 3 T. Results In high-grade gliomas with BBB leakage, d-glucose uptake could be detected in the gadolinium (Gd) enhancing region as well as in the tumor necrosis with a maximum increase of ∆DGE⍴ around 0.25%, whereas unaffected white matter did not show any significant DGE⍴ increase. Glioma patients without Gd enhancement showed no detectable DGE⍴ effect within the tumor. Conclusion First application of DGE⍴ in a patient cohort shows an association between BBB leakage and DGE signal irrespective of the tumor grade. This indicates that glucoCEST corresponds more to the disruptions of BBB with Gd uptake than to the molecular tumor profile or tumor grading.
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Zhang, C. Eleana, Sau May Wong, Harm J. van de Haar, Julie Staals, Jacobus F. A. Jansen, Cécile R. L. P. N. Jeukens, Paul A. M. Hofman, Robert J. van Oostenbrugge, and Walter H. Backes. "Blood–brain barrier leakage is more widespread in patients with cerebral small vessel disease." Neurology 88, no. 5 (December 28, 2016): 426–32. http://dx.doi.org/10.1212/wnl.0000000000003556.
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Objective:As blood–brain barrier (BBB) dysfunction may occur in normal aging but may also play a pivotal role in the pathophysiology of cerebral small vessel disease (cSVD), we used dynamic contrast-enhanced (DCE)–MRI to quantify the rate and the spatial extent of BBB leakage in patients with cSVD and age- and sex-matched controls to discern cSVD-related BBB leakage from aging-related leakage.Methods:We performed structural brain MRI and DCE-MRI in 80 patients with clinically overt cSVD and 40 age- and sex-matched controls. Using the Patlak pharmacokinetic model, we calculated the leakage rate. The mean leakage rate and relative leakage volume were calculated using noise-corrected histogram analysis. Leakage rate and leakage volume were compared between patients with cSVD and controls for the normal-appearing white matter (NAWM), white matter hyperintensities (WMH), cortical gray matter (CGM), and deep gray matter.Results:Multivariable linear regression analyses adjusting for age, sex, and cardiovascular risk factors showed that the leakage volume of the NAWM, WMH, and CGM was significantly larger in patients with cSVD compared with controls. No significant difference was found for leakage rate in any of the tissue regions.Conclusion:We demonstrated a larger tissue volume with subtle BBB leakage in patients with cSVD than in controls. This was shown in the NAWM, WMH, and CGM, supporting the generalized nature of cSVD.
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Cho, Eunice E., Jelena Drazic, Milan Ganguly, Bojana Stefanovic, and Kullervo Hynynen. "Two-Photon Fluorescence Microscopy Study of Cerebrovascular Dynamics in Ultrasound-Induced Blood—Brain Barrier Opening." Journal of Cerebral Blood Flow & Metabolism 31, no. 9 (April 20, 2011): 1852–62. http://dx.doi.org/10.1038/jcbfm.2011.59.
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Blood-brain barrier (BBB) disruption can be achieved with ultrasound (US) and circulating microbubble (MB) contrast agent. Using dorsal US sonication and Definity, an MB contrast agent, responses of the cortical cerebral vasculature to BBB opening were observed with varying acoustic peak negative pressure (0.071 to 0.25 MPa) under two-photon microscope. Wistar rats with a craniotomy were sonicated with a single piezoelectric transducer following the intravenous injection of Texas Red for visualization of vasculature and leakage from BBB opening. Based on time-dependent intensity change in the extravascular area, the leakage was classified into three types: fast, sustained, and slow. Fast leakage was characterized by a rapid increase to peak intensity during sonication, but a decrease afterwards, occurring at all pressures and vessels sizes analyzed in our study. Sustained leakage was indicated by a similar, immediate increase to peak intensity but one that remained elevated for the duration of imaging, occurring at low-to-intermediate pressures. Slow leakage began 5 to 15 minutes after sonication, dominating at low pressures, and was more prevalent among smaller vessels than fast and sustained leakage. Our study showed the possibility of controlling leakage type and vessel size in US-induced BBB opening through varying acoustic pressure.
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Li, Xiaolong, Yan Cai, Zuo Zhang, and Jiyin Zhou. "Glial and Vascular Cell Regulation of the Blood-Brain Barrier in Diabetes." Diabetes & Metabolism Journal 46, no. 2 (March 31, 2022): 222–38. http://dx.doi.org/10.4093/dmj.2021.0146.
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As a structural barrier, the blood-brain barrier (BBB) is located at the interface between the brain parenchyma and blood, and modulates communication between the brain and blood microenvironment to maintain homeostasis. The BBB is composed of endothelial cells, basement membrane, pericytes, and astrocytic end feet. BBB impairment is a distinguishing and pathogenic factor in diabetic encephalopathy. Diabetes causes leakage of the BBB through downregulation of tight junction proteins, resulting in impaired functioning of endothelial cells, pericytes, astrocytes, microglia, nerve/glial antigen 2-glia, and oligodendrocytes. However, the temporal regulation, mechanisms of molecular and signaling pathways, and consequences of BBB impairment in diabetes are not well understood. Consequently, the efficacy of therapies diabetes targeting BBB leakage still lags behind the requirements. This review summarizes the recent research on the effects of diabetes on BBB composition and the potential roles of glial and vascular cells as therapeutic targets for BBB disruption in diabetic encephalopathy.
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Kerkhofs, Danielle, Sau May Wong, Eleana Zhang, Julie Staals, Jacobus F. A. Jansen, Robert J. van Oostenbrugge, and Walter H. Backes. "Baseline Blood-Brain Barrier Leakage and Longitudinal Microstructural Tissue Damage in the Periphery of White Matter Hyperintensities." Neurology 96, no. 17 (March 24, 2021): e2192-e2200. http://dx.doi.org/10.1212/wnl.0000000000011783.
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ObjectiveTo investigate the 2-year change in parenchymal diffusivity, a quantitative marker of microstructural tissue condition, and the relationship with baseline blood-brain barrier (BBB) permeability, in tissue at risk, i.e., the perilesional zone surrounding white matter hyperintensities (WMH) in patients with cerebral small vessel disease (cSVD).MethodsPatients with sporadic cSVD (lacunar stroke or mild vascular cognitive impairment) underwent 3T MRI at baseline, including dynamic contrast-enhanced MRI to quantify BBB permeability (i.e., leakage volume and rate) and intravoxel incoherent motion imaging (IVIM), a diffusion technique that provides parenchymal diffusivity D. After 2 years, IVIM was repeated. We assessed the relation between BBB leakage measures at baseline and change in parenchymal diffusivity (∆D) over 2 years in the perilesional zones (divided in 2-mm contours) surrounding WMH.ResultsWe analyzed 43 patients (age 68 ± 12 years, 58% male). In the perilesional zones, ∆D increased 0.10% (confidence interval [CI] 0.07–0.013%) (p < 0.01) per 2 mm closer to the WMH. Furthermore, ∆D over 2 years showed a positive correlation with both baseline BBB leakage volume (r = 0.29 [CI 0.06–0.52], p = 0.013) and leakage rate (r = 0.24 [CI 0.02–0.47], p = 0.034).ConclusionBBB leakage at baseline is related to the 2-year change in parenchymal diffusivity in the perilesional zone of WMH. These results support the hypothesis that BBB impairment might play an early role in subsequent microstructural white matter degeneration as part of the pathophysiology of cSVD.
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Sohet, Fabien, Christina Lin, Roeben N. Munji, Seo Yeon Lee, Nadine Ruderisch, Allison Soung, Thomas D. Arnold, et al. "LSR/angulin-1 is a tricellular tight junction protein involved in blood–brain barrier formation." Journal of Cell Biology 208, no. 6 (March 9, 2015): 703–11. http://dx.doi.org/10.1083/jcb.201410131.
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The blood–brain barrier (BBB) is a term used to describe the unique properties of central nervous system (CNS) blood vessels. One important BBB property is the formation of a paracellular barrier made by tight junctions (TJs) between CNS endothelial cells (ECs). Here, we show that Lipolysis-stimulated lipoprotein receptor (LSR), a component of paracellular junctions at points in which three cell membranes meet, is greatly enriched in CNS ECs compared with ECs in other nonneural tissues. We demonstrate that LSR is specifically expressed at tricellular junctions and that its expression correlates with the onset of BBB formation during embryogenesis. We further demonstrate that the BBB does not seal during embryogenesis in Lsr knockout mice with a leakage to small molecules. Finally, in mouse models in which BBB was disrupted, including an experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis and a middle cerebral artery occlusion (MCAO) model of stroke, LSR was down-regulated, linking loss of LSR and pathological BBB leakage.
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Janigro, Damir. "Does Leakage of the Blood–Brain Barrier Mediate Epileptogenesis?" Epilepsy Currents 7, no. 4 (July 2007): 105–7. http://dx.doi.org/10.1111/j.1535-7511.2007.00190.x.
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Blood-Brain Barrier Leakage May Lead to Progression of Temporal Lobe Epilepsy. van Vliet EA, da Costa Araujo S, Redeker S, van Schaik R, Aronica E, Gorter JA. Brain 2007;130(Pt 2):521–534. Leakage of the blood–brain barrier (BBB) is associated with various neurological disorders, including temporal lobe epilepsy (TLE). However, it is not known whether alterations of the BBB occur during epileptogenesis and whether this can affect progression of epilepsy. We used both human and rat epileptic brain tissue and determined BBB permeability using various tracers and albumin immunocytochemistry. In addition, we studied the possible consequences of BBB opening in the rat for the subsequent progression of TLE. Albumin extravasation in human was prominent after status epilepticus (SE) in astrocytes and neurons, and also in hippocampus of TLE patients. Similarly, albumin and tracers were found in microglia, astrocytes and neurons of the rat. The BBB was permeable in rat limbic brain regions shortly after SE, but also in the latent and chronic epileptic phase. BBB permeability was positively correlated to seizure frequency in chronic epileptic rats. Artificial opening of the BBB by mannitol in the chronic epileptic phase induced a persistent increase in the number of seizures in the majority of rats. These findings indicate that BBB leakage occurs during epileptogenesis and the chronic epileptic phase and suggest that this can contribute to the progression of epilepsy. TGF-Beta Receptor-Mediated Albumin Uptake into Astrocytes Is Involved in Neocortical Epileptogenesis. Ivens S, Kaufer D, Flores LP, Bechmann I, Zumsteg D, Tomkins O, Seiffert E, Heinemann U, Friedman A. Brain 2007; 130(Pt 2):535–547. It has long been recognized that insults to the cerebral cortex, such as trauma, ischaemia or infections, may result in the development of epilepsy, one of the most common neurological disorders. Human and animal studies have suggested that perturbations in neurovascular integrity and breakdown of the blood–brain barrier (BBB) lead to neuronal hypersynchronization and epileptiform activity, but the mechanisms underlying these processes are not known. In this study, we reveal a novel mechanism for epileptogenesis in the injured brain. We used focal neocortical, long-lasting BBB disruption or direct exposure to serum albumin in rats (51 and 13 animals, respectively, and 26 controls) as well as albumin exposure in brain slices in vitro. Most treated slices (72%, n = 189) displayed hypersynchronous propagating epileptiform field potentials when examined 5–49 days after treatment, but only 14% ( n = 71) of control slices showed similar responses. We demonstrate that direct brain exposure to serum albumin is associated with albumin uptake into astrocytes, which is mediated by transforming growth factor β receptors (TGF- βRs). This uptake is followed by down regulation of inward-rectifying potassium (Kir 4.1) channels in astrocytes, resulting in reduced buffering of extracellular potassium. This, in turn, leads to activity-dependent increased accumulation of extracellular potassium, resulting in facilitated N-methyl-D-aspartate-receptor-mediated neuronal hyperexcitability and eventually epileptiform activity. Blocking TGF- βR in vivo reduces the likelihood of epileptogenesis in albumin-exposed brains to 29.3% ( n = 41 slices, P < 0.05). We propose that the above-described cascade of events following common brain insults leads to brain dysfunction and eventually epilepsy and suggest TGF- βRs as a possible therapeutic target.
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Granholm, Ann-Charlotte E., Maria Curtis, David M. Diamond, Berrilyn J. Branch, Karen L. Heman, and Gregory M. Rose. "Development of an Intact Blood-Brain Barrier in Brain Tissue Transplants is Dependent on the Site of Transplantation." Cell Transplantation 5, no. 2 (March 1996): 305–14. http://dx.doi.org/10.1177/096368979600500219.
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Transplantation of fetal septal forebrain tissue was performed to the anterior chamber of the eye, or intracranially to the rostral hippocampal formation in rats, to evaluate the impact of transplantation site on the development of an intact blood–brain barrier (BBB). The tissue was studied at 1, 2, 3, and 4 wk following transplantation by means of intravenous injection of Trypan blue, which is a vital stain not normally penetrating the BBB, as well as with an antibody specifically directed against the rat BBB, SMI71. In the intraocular septal transplants, there was a significant leakage of Trypan blue 1 wk postgrafting, associated with a few laminin-immunoreactive blood vessels that did not contain any SMI71-immunoreactivity. However, at 2 wk postgrafting, the intraocular grats exhibited an extensive plexus of thin-walled blood vessels expressing SMI71 immunoreactivity and no Trypan blue leakage. Thus, it appeared that a BBB had developed to some degree by 2 wk postgrafting in oculo. In the intracranial grafts, on the other hand, Trypan blue leakage could be seen as long as 3 wk postgrafting, and a dense plexus of blood vessels with SMI71 immunoreactivity was first seen at 4 wk postgrafting. Thus, the development of Trypan blue impermeability was delayed with 1 to 2 wk in the intracranial versus the intraocular grafts. Control experiments using psychological stress in adult rats as a means to transiently disrupt the BBB revealed that an increase in Trypan blue leakage correlated well with the disappearance of SMI71 immunoreactivity. Taken together, these studies demonstrate that the site of transplantation can influence the development of an intact BBB in neural tissue grafts.
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Jiang, Quan, James R. Ewing, Guang Liang Ding, Li Zhang, Zheng Gang Zhang, Lian Li, Polly Whitton, et al. "Quantitative Evaluation of BBB Permeability after Embolic Stroke in Rat Using MRI." Journal of Cerebral Blood Flow & Metabolism 25, no. 5 (February 16, 2005): 583–92. http://dx.doi.org/10.1038/sj.jcbfm.9600053.
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We sought to identify magnetic resonance imaging (MRI) parameters that can identify as well as predict disruption of the blood–brain barrier (BBB) after embolic stroke in the rat. Rats subjected to embolic stroke with ( n=13) and without ( n=13) rt-PA treatment were followed with MRI using quantitative permeability-related parameters, consisting of: transfer constant ( K i) of Gd- DTPA, the distribution volume ( Vp) of the mobile protons, and the inverse of the apparent forward transfer rate for magnetization transfer ( kinv), as well as the apparent diffusion coefficient of water ( ADCw), T2, and cerebral cerebral blood flow (CBF). Tissue progressing to fibrin leakage resulting from BBB disruption and adjacent tissue were then analyzed to identify MRI markers that characterize BBB disruption. Animals were killed after final MRI measurements at 24 h after induction of embolic stroke and cerebral tissues were perfused and stained to detect fibrin leakage. K i, Vp, and kinv were the most sensitive early (2 to 3 h) indices of the cerebral tissue that progresses to fibrin leakage. Cerebral blood flow was not significantly different between ischemic tissue with a compromised and an intact BBB. Our data indicate that compromise of the BBB can be sensitively predicted using a select set of MR parameters.
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Katsu, Masataka, Kuniyasu Niizuma, Hideyuki Yoshioka, Nobuya Okami, Hiroyuki Sakata, and Pak H. Chan. "Hemoglobin-Induced Oxidative Stress Contributes to Matrix Metalloproteinase Activation and Blood–Brain Barrier Dysfunction in vivo." Journal of Cerebral Blood Flow & Metabolism 30, no. 12 (March 31, 2010): 1939–50. http://dx.doi.org/10.1038/jcbfm.2010.45.
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Hemoglobin (Hb) released from extravasated erythrocytes is implicated in brain edema after intracerebral hemorrhage (ICH). Hemoglobin is a major component of blood and a potent mediator of oxidative stress after ICH. Oxidative stress and matrix metalloproteinases (MMPs) are associated with blood–brain barrier (BBB) dysfunction. This study was designed to elucidate whether Hb-induced oxidative stress contributes to MMP-9 activation and BBB dysfunction in vivo. An intracerebral injection of Hb into rat striata induced increased hydroethidine (HEt) signals in parallel with MMP-9 levels. In situ gelatinolytic activity colocalized with oxidized HEt signals in vessel walls, accompanied by immunoglobulin G leakage and a decrease in immunoactivity of endothelial barrier antigen, a marker of endothelial integrity. Administration of a nonselective MMP inhibitor prevented MMP-9 levels and albumin leakage in injured striata. Moreover, reduction in oxidative stress by copper/zinc-superoxide dismutase (SOD1) overexpression reduced oxidative stress, MMP-9 levels, albumin leakage, and subsequent apoptosis compared with wild-type littermates. We speculate that Hb-induced oxidative stress may contribute to early BBB dysfunction and subsequent apoptosis, partly through MMP activation, and that SOD1 overexpression may reduce Hb-induced oxidative stress, BBB dysfunction, and apoptotic cell death.
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van der Werf, Y. D., M. J. L. de Jongste, and G. J. ter Horst. "Myocardial infarction causes regional reproducible BBB leakage via cytokines." Journal of Neuroimmunology 54, no. 1-2 (October 1994): 205. http://dx.doi.org/10.1016/0165-5728(94)90582-7.
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Soon, D., DJ Tozer, DR Altmann, PS Tofts, and DH Miller. "Quantification of subtle blood-brain barrier disruption in non-enhancing lesions in multiple sclerosis: a study of disease and lesion subtypes." Multiple Sclerosis Journal 13, no. 7 (April 27, 2007): 884–94. http://dx.doi.org/10.1177/1352458507076970.
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Few attempts have been made to detect subtle blood-brain barrier (BBB) leakage in visibly non-enhancing MRI lesions in multiple sclerosis (MS). For 19 patients, longitudinal relaxation time (T1) maps were generated from MRI scans obtained before, and at 20, 40 and 60 minutes after injection of gadolinium (Gd)-DTPA (0.3 mmol/kg). Regions of interest (ROI) were placed around non-enhancing lesions, and in paired contralateral normal appearing brain tissue (NABT). Post-Gd rate of R1 (=1/T1) rise (ΔR1/Δt), was used to quantify leakage. ΔR1/Δt was greater in lesions than paired NABT ( P ≤ 0.001 at all post-Gd timepoints). ΔR1/Δt was greater in T1 hypointense than isointense lesions ( P = 0.001 and 0.01 for first and second timepoints respectively), and negatively related to lesion cross sectional area ( P ≤ 0.001 at all post-Gd timepoints). Relapsing remitting (RRMS) lesions had a greater initial ΔR1/Δt than secondary progressive (SPMS) lesions ( P = 0.04), but this was not seen in subsequent timepoints. ΔR1/Δt in visibly enhancing lesions was significantly greater than in visibly non-enhancing lesions, with no overlap in the normal ranges of the two populations. Subtle BBB leakage is a consistent feature in non-enhancing lesions, and is distinct from the overt BBB leakage observed in visibly enhancing lesions. It is detectable using quantitative contrast-enhanced MRI. It is apparent in all clinical and lesion subtypes studied, and greater in T1 hypointense and smaller lesions. Larger initial ΔR1/Δt in RRMS than SPMS lesions may reflect differences in blood volume rather than BBB leakage. Multiple Sclerosis 2007; 13: 884—894. http://msj.sagepub.com
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Semyachkina-Glushkovskaya, Oxana, Aysel Mamedova, Valeria Vinnik, Maria Klimova, Elena Saranceva, Vasily Ageev, Tingting Yu, Dan Zhu, Thomas Penzel, and Jürgen Kurths. "Brain Mechanisms of COVID-19-Sleep Disorders." International Journal of Molecular Sciences 22, no. 13 (June 28, 2021): 6917. http://dx.doi.org/10.3390/ijms22136917.
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2020 and 2021 have been unprecedented years due to the rapid spread of the modified severe acute respiratory syndrome coronavirus around the world. The coronavirus disease 2019 (COVID-19) causes atypical infiltrated pneumonia with many neurological symptoms, and major sleep changes. The exposure of people to stress, such as social confinement and changes in daily routines, is accompanied by various sleep disturbances, known as ‘coronasomnia’ phenomenon. Sleep disorders induce neuroinflammation, which promotes the blood–brain barrier (BBB) disruption and entry of antigens and inflammatory factors into the brain. Here, we review findings and trends in sleep research in 2020–2021, demonstrating how COVID-19 and sleep disorders can induce BBB leakage via neuroinflammation, which might contribute to the ‘coronasomnia’ phenomenon. The new studies suggest that the control of sleep hygiene and quality should be incorporated into the rehabilitation of COVID-19 patients. We also discuss perspective strategies for the prevention of COVID-19-related BBB disorders. We demonstrate that sleep might be a novel biomarker of BBB leakage, and the analysis of sleep EEG patterns can be a breakthrough non-invasive technology for diagnosis of the COVID-19-caused BBB disruption.
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Wong, Sau May, Jacobus F. A. Jansen, C. Eleana Zhang, Erik I. Hoff, Julie Staals, Robert J. van Oostenbrugge, and Walter H. Backes. "Blood-brain barrier impairment and hypoperfusion are linked in cerebral small vessel disease." Neurology 92, no. 15 (March 13, 2019): e1669-e1677. http://dx.doi.org/10.1212/wnl.0000000000007263.
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ObjectiveTo investigate the link between blood-brain-barrier (BBB) permeability and cerebral blood flow (CBF) and the relation with white matter hyperintensities (WMH) in cerebral small vessel disease (cSVD).MethodsTwenty-seven patients with cSVD received dynamic susceptibility contrast and dynamic contrast-enhanced MRI to determine CBF and BBB permeability (expressed as leakage rate and volume), respectively. Structural MRI were segmented into normal-appearing white matter (NAWM) and WMH, for which a perilesional zone was defined. In these regions, we investigated the BBB permeability, CBF, and their relation using Pearson correlation r.ResultsWe found a decrease in CBF of 2.2 mL/min/100 g (p < 0.01) and an increase in leakage volume of 0.7% (p < 0.01) per mm closer to the WMH in the perilesional zones. Lower CBF values correlated with higher leakage measures in the NAWM and WMH (−0.53 < r < −0.40, p < 0.05). This relation was also observed in the perilesional zones, which became stronger in the proximity of WMH (p = 0.03).ConclusionBBB impairment and hypoperfusion appear in the WMH and NAWM, which increase in the proximity of the WMH, and are linked. Both BBB and CBF are regulated in the neurovascular unit (NVU) and the observed link might be due to the physiologic regulation mechanism of the NVU. This link may suggest an early overall deterioration of this unit.
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Gattringer, Thomas, Maria Valdes Hernandez, Anna Heye, Paul A. Armitage, Stephen Makin, Francesca Chappell, Daniela Pinter, et al. "Predictors of Lesion Cavitation After Recent Small Subcortical Stroke." Translational Stroke Research 11, no. 3 (November 8, 2019): 402–11. http://dx.doi.org/10.1007/s12975-019-00741-8.
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Abstract Morphologic evolution of recent small subcortical infarcts (RSSI) ranges from lesion disappearance to lacune formation and the reasons for this variability are still poorly understood. We hypothesized that diffusion tensor imaging (DTI) and blood-brain-barrier (BBB) abnormalities early on can predict tissue damage 1 year after an RSSI. We studied prospectively recruited patients with a symptomatic MRI-defined RSSI who underwent baseline and two pre-specified MRI examinations at 1–3-month and 1-year post-stroke. We defined the extent of long-term tissue destruction, termed cavitation index, as the ratio of the 1-year T1-weighted cavity volume to the baseline RSSI volume on FLAIR. We calculated fractional anisotropy and mean diffusivity (MD) of the RSSI and normal-appearing white matter, and BBB leakage in different tissues on dynamic contrast-enhanced MRI. Amongst 60 patients, at 1-year post-stroke, 44 patients showed some degree of RSSI cavitation on FLAIR, increasing to 50 on T2- and 56 on T1-weighted high-resolution scans, with a median cavitation index of 7% (range, 1–36%). Demographic, clinical, and cerebral small vessel disease features were not associated with the cavitation index. While lower baseline MD of the RSSI (rs = − 0.371; p = 0.004) and more contrast leakage into CSF (rs = 0.347; p = 0.007) were associated with the cavitation index in univariable analysis, only BBB leakage in CSF remained independently associated with cavitation (beta = 0.315, p = 0.046). Increased BBB leakage into CSF may indicate worse endothelial dysfunction and increased risk of tissue destruction post RSSI. Although cavitation was common, it only affected a small proportion of the original RSSI.
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Huggins, Matthew, Fang Jin, and Aaron Johnson. "CD8 T cell mediated disruption of tight junctions is associated with vascular permeability in vital brain regions during experimental cerebral malaria (MPF7P.708)." Journal of Immunology 194, no. 1_Supplement (May 1, 2015): 203.9. http://dx.doi.org/10.4049/jimmunol.194.supp.203.9.
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Abstract One of the most severe complications of Plasmodium falciparum infection in humans is cerebral malaria. Cerebral malaria causes coma, neurological deficits, and potentially death. The disease is characterized by blood-brain barrier (BBB) disruption leading to vascular permeability. In this study, we investigated cerebral endothelial cell tight junction protein alterations and BBB breakdown in the Plasmodium berghei ANKA (PbA) model of experimental cerebral malaria. PbA infected C57BL/6 mice displayed significant areas of vascular leakage within the central nervous system at six days post infection. Regions of permeability co-localized with disruption of the BBB tight junction proteins claudin-5 and occludin on microvasculature as shown using confocal microscopy. Additionally, 3D MRI analysis revealed that PbA infected mice exhibited vascular leakage specific to the hypothalamus, thalamus, and brain stem. In contrast, PbA infected perforin deficient mice retained tight junction integrity and displayed significantly reduced vascular leakage. We propose that CD8 T cells initiate vascular permeability through disruption of cerebral endothelial cell tight junctions. In turn, the resulting imbalance of homeostasis in vital brain regions likely contributes to the pathology and morbidity associated with PbA infection.
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Himmerich, Hubertus, Armin Szegedi, Christoph Klawe, Ion Anghelescu, and Matthias J. Müller. "Distigmine bromide induced acute psychotic disorder in a patient with multiple sclerosis." European Psychiatry 18, no. 6 (October 2003): 318–19. http://dx.doi.org/10.1016/j.eurpsy.2002.11.001.
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AbstractA female patient with multiple sclerosis (MS) suffered from an acute psychotic disorder after taking distigmine bromide for detrusor dysfunction. She showed a dramatic relief of her symptoms after the medication, distigmine bromide, was stopped. Distigmine is not supposed to penetrate the blood-brain barrier (BBB). However, in MS patients a leakage of the BBB could be hypothesized.
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Semyachkina-Glushkovskaya, Oxana, Dmitry Postnov, Thomas Penzel, and Jürgen Kurths. "Sleep as a Novel Biomarker and a Promising Therapeutic Target for Cerebral Small Vessel Disease: A Review Focusing on Alzheimer’s Disease and the Blood-Brain Barrier." International Journal of Molecular Sciences 21, no. 17 (August 31, 2020): 6293. http://dx.doi.org/10.3390/ijms21176293.
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Cerebral small vessel disease (CSVD) is a leading cause of cognitive decline in elderly people and development of Alzheimer’s disease (AD). Blood–brain barrier (BBB) leakage is a key pathophysiological mechanism of amyloidal CSVD. Sleep plays a crucial role in keeping health of the central nervous system and in resistance to CSVD. The deficit of sleep contributes to accumulation of metabolites and toxins such as beta-amyloid in the brain and can lead to BBB disruption. Currently, sleep is considered as an important informative platform for diagnosis and therapy of AD. However, there are no effective methods for extracting of diagnostic information from sleep characteristics. In this review, we show strong evidence that slow wave activity (SWA) (0–0.5 Hz) during deep sleep reflects glymphatic pathology, the BBB leakage and memory deficit in AD. We also discuss that diagnostic and therapeutic targeting of SWA in AD might lead to be a novel era in effective therapy of AD. Moreover, we demonstrate that SWA can be pioneering non-invasive and bed–side technology for express diagnosis of the BBB permeability. Finally, we review the novel data about the methods of detection and enhancement of SWA that can be biomarker and a promising therapy of amyloidal CSVD and CSVD associated with the BBB disorders.
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Kuntz, Mélanie, Caroline Mysiorek, Olivier Pétrault, Maud Pétrault, Rustem Uzbekov, Régis Bordet, Laurence Fenart, Roméo Cecchelli, and Vincent Bérézowski. "Stroke-Induced Brain Parenchymal Injury Drives Blood–Brain Barrier Early Leakage Kinetics: A Combined in Vivo/in Vitro Study." Journal of Cerebral Blood Flow & Metabolism 34, no. 1 (October 2, 2013): 95–107. http://dx.doi.org/10.1038/jcbfm.2013.169.
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The disappointing clinical outcomes of neuroprotectants challenge the relevance of preclinical stroke models and data in defining early cerebrovascular events as potential therapeutic targets. The kinetics of blood–brain barrier (BBB) leakage after reperfusion and the link with parenchymal lesion remain debated. By using in vivo and in vitro approaches, we conducted a kinetic analysis of BBB dysfunction during early reperfusion. After 60 minutes of middle cerebral artery occlusion followed by reperfusion times up to 24 hours in mice, a non-invasive magnetic resonance imaging method, through an original sequence of diffusion-weighted imaging, determined brain water mobility in microvascular compartments ( D∗) apart from parenchymal compartments (apparent diffusion coefficient). An increase in D∗ found at 4 hours post reperfusion concurred with the onset of both Evans blue/Dextran extravasations and in vitro BBB opening under oxygen-glucose deprivation and reoxygenation ( R). The BBB leakage coincided with an emerging cell death in brain tissue as well as in activated glial cells in vitro. The co-culture of BBB endothelial and glial cells evidenced a recovery of endothelium tightness when glial cells were absent or non-injured during R. Preserving the ischemic brain parenchymal cells within 4 hours of reperfusion may improve therapeutic strategies for cerebrovascular protection against stroke.
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Jolink, Wilmar MT, Arjen Lindenholz, Ellis S. van Etten, Koen M. van Nieuwenhuizen, Floris HBM Schreuder, Hugo J. Kuijf, Matthias JP van Osch, et al. "Contrast leakage distant from the hematoma in patients with spontaneous ICH: A 7 T MRI study." Journal of Cerebral Blood Flow & Metabolism 40, no. 5 (May 29, 2019): 1002–11. http://dx.doi.org/10.1177/0271678x19852876.
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Disruption of the blood–brain barrier (BBB) might play a role in the pathophysiology of cerebral small vessel disease-related ICH. The aim of this study was to assess presence and extent of contrast agent leakage distant from the hematoma as a marker of BBB disruption in patients with spontaneous ICH. We prospectively performed 7 tesla MRI in adult patients with spontaneous ICH and assessed contrast leakage distant from the hematoma on 3D FLAIR images. Thirty-one patients were included (mean age 60 years, 29% women). Median time between ICH and MRI was 20 days (IQR 9–67 days). Seventeen patients (54%; seven lobar, nine deep, one infratentorial ICH) had contrast leakage, located cortical in 16 and cortical and deep in one patient. Patients with contrast leakage more often had lobar cerebral microbleeds (CMBs; 77%) than those without (36%; RR 2.5, 95% CI 1.1–5.7) and a higher number of lobar CMBs (patients with contrast leakage: median 2, IQR 1–8 versus those without: median 0, IQR 0–2; p = 0.02). This study shows that contrast leakage distant from the hematoma is common in days to weeks after spontaneous ICH. It is located predominantly cortical and related to lobar CMBs and therefore possibly to cerebral amyloid angiopathy.
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Chu, Po-Chun, Wen-Yen Chai, Han-Yi Hsieh, Jiun-Jie Wang, Shiaw-Pyng Wey, Chiung-Yin Huang, Kuo-Chen Wei, and Hao-Li Liu. "Pharmacodynamic Analysis of Magnetic Resonance Imaging-Monitored Focused Ultrasound-Induced Blood-Brain Barrier Opening for Drug Delivery to Brain Tumors." BioMed Research International 2013 (2013): 1–13. http://dx.doi.org/10.1155/2013/627496.
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Microbubble-enhanced focused ultrasound (FUS) can enhance the delivery of therapeutic agents into the brain for brain tumor treatment. The purpose of this study was to investigate the influence of brain tumor conditions on the distribution and dynamics of small molecule leakage into targeted regions of the brain after FUS-BBB opening. A total of 34 animals were used, and the process was monitored by 7T-MRI. Evans blue (EB) dye as well as Gd-DTPA served as small molecule substitutes for evaluation of drug behavior. EB was quantified spectrophotometrically. Spin-spin (R1) relaxometry and area under curve (AUC) were measured by MRI to quantify Gd-DTPA. We found that FUS-BBB opening provided a more significant increase in permeability with small tumors. In contrast, accumulation was much higher in large tumors, independent of FUS. The AUC values of Gd-DTPA were well correlated with EB delivery, suggesting that Gd-DTPA was a good indicator of total small-molecule accumulation in the target region. The peripheral regions of large tumors exhibited similar dynamics of small-molecule leakage after FUS-BBB opening as small tumors, suggesting that FUS-BBB opening may have the most significant permeability-enhancing effect on tumor peripheral. This study provides useful information toward designing an optimized FUS-BBB opening strategy to deliver small-molecule therapeutic agents into brain tumors.
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Uchida, Yuto, Hirohito Kan, Keita Sakurai, Nobuyuki Arai, Shohei Inui, Susumu Kobayashi, Daisuke Kato, Yoshino Ueki, and Noriyuki Matsukawa. "Iron leakage owing to blood–brain barrier disruption in small vessel disease CADASIL." Neurology 95, no. 9 (June 25, 2020): e1188-e1198. http://dx.doi.org/10.1212/wnl.0000000000010148.
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ObjectiveTo assess the relationship among iron accumulation, blood–brain barrier (BBB) damage, and cognitive function in patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL).MethodsWe enrolled 21 patients with NOTCH3 mutations and 21 age-matched healthy controls in this cross-sectional study. All participants underwent global physical and cognitive assessments and brain MRI using voxel-based quantitative susceptibility mapping (QSM; iron deposition measure) and dynamic contrast-enhanced MRI (BBB permeability measure). We compared behavioral and imaging data between the groups and analyzed the correlations in each group.ResultsAmong 21 NOTCH3 mutation carriers, 10 were symptomatic and 11 asymptomatic. Montreal Cognitive Assessment scores were significantly different among the groups (symptomatic < asymptomatic < control participants). Voxel-based QSM analysis revealed that the symptomatic group had higher QSM values than did the asymptomatic group in the putamen, caudate nucleus, temporal pole, and centrum semiovale. These QSM values were positively correlated with regional BBB permeabilities (putamen: r = 0.57, p = 0.006; caudate nucleus: r = 0.51, p = 0.019; temporal pole: r = 0.48, p = 0.030; centrum semiovale: r = 0.45, p = 0.044) and negatively correlated with Montreal Cognitive Assessment scores (caudate nucleus: r = −0.53, p = 0.012; temporal pole: r = −0.56, p = 0.008).ConclusionsThis study showed that cerebral iron burden was associated with regional BBB permeability and cognitive dysfunction in patients with CADASIL, highlighting the potential of these imaging techniques as auxiliary biomarkers to monitor the course of small vessel disease.
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St-Amour, Isabelle, Isabelle Paré, Wael Alata, Katherine Coulombe, Cassandra Ringuette-Goulet, Janelle Drouin-Ouellet, Milène Vandal, Denis Soulet, Renée Bazin, and Frédéric Calon. "Brain Bioavailability of Human Intravenous Immunoglobulin and its Transport through the Murine Blood–Brain Barrier." Journal of Cerebral Blood Flow & Metabolism 33, no. 12 (September 18, 2013): 1983–92. http://dx.doi.org/10.1038/jcbfm.2013.160.
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Intravenous immunoglobulin (IVIg) is currently evaluated in clinical trials for the treatment of various disorders of the central nervous system. To assess its capacity to reach central therapeutic targets, the brain bioavailability of IVIg must be determined. We thus quantified the passage of IVIg through the blood–brain barrier (BBB) of C57Bl/6 mice using complementary quantitative and qualitative methodologies. As determined by enzyme-linked immunosorbent assay, a small proportion of systemically injected IVIg was detected in the brain of mice (0.009±0.001% of injected dose in the cortex) whereas immunostaining revealed localization mainly within microvessels and less frequently in neurons. Pharmacokinetic analyses evidenced a low elimination rate constant (0.0053 per hour) in the cortex, consistent with accumulation within cerebral tissue. In situ cerebral perfusion experiments revealed that a fraction of IVIg crossed the BBB without causing leakage. A dose-dependent decrease of brain uptake was consistent with a saturable blood-to-brain transport mechanism. Finally, brain uptake of IVIg after a subchronic treatment was similar in the 3xTg-AD mouse model of Alzheimer disease compared with nontransgenic controls. In summary, our results provide evidence of BBB passage and bioavailability of IVIg into the brain in the absence of BBB leakage and in sufficient concentration to interact with the therapeutic targets.
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Park, T. S., Ernesto R. Gonzales, and Jeffrey M. Gidday. "Platelet-Activating Factor Mediates Ischemia-Induced Leukocyte-Endothelial Adherence in Newborn Pig Brain." Journal of Cerebral Blood Flow & Metabolism 19, no. 4 (April 1999): 417–24. http://dx.doi.org/10.1097/00004647-199904000-00007.
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The authors examined the involvement of platelet-activating factor (PAF) in mediating leukocyte adherence to brain postcapillary pial venules and altering blood-brain barrier (BBB) permeability during basal conditions and during reoxygenation after asphyxia in newborn piglets. Intravital epifluorescence videomicroscopy, closed cranial windows, and labeling of leukocytes with rhodamine 6G allowed us to obtain serial measurements of adherent leukocytes within postcapillary venules. Blood-brain barrier breakdown was determined by optical measures of cortical extravascular fluorescence intensity after intravenous sodium fluorescein. Superfusion of PAF over the cortex induced a dose-dependent increase in leukocyte adherence to cerebral venules and leakage of fluorescein; with 1 μmol/L PAF, the magnitude of adherence and BBB breakdown was similar to that seen during reoxygenation after 9 minutes of asphyxia. Both adherence and loss of BBB integrity resulting from either exogenous PAF or asphyxia-reoxygenation could be significantly attenuated by intravenous administration of WEB 2086, a PAF receptor antagonist. Window superfusion of superoxide dismutase with PAF attenuated PAF-induced increases in adherence and associated fluorescein leakage. These findings indicate that PAF exhibits proinflammatory effects in piglet brain and that PAF contributes to leukocyte adherence and BBB breakdown after cerebral ischemia. These PAF effects are mediated by increases in superoxide radical generation.
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Jiang, Yinghua, Li Lin, Ning Liu, Qingzhi Wang, Jing Yuan, Yadan Li, Kelly K. Chung, Shuzhen Guo, Zhanyang Yu, and Xiaoying Wang. "FGF21 Protects against Aggravated Blood-Brain Barrier Disruption after Ischemic Focal Stroke in Diabetic db/db Male Mice via Cerebrovascular PPARγ Activation." International Journal of Molecular Sciences 21, no. 3 (January 28, 2020): 824. http://dx.doi.org/10.3390/ijms21030824.
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Recombinant fibroblast growth factor 21 (rFGF21) has been shown to be potently beneficial for improving long-term neurological outcomes in type 2 diabetes mellitus (T2DM) stroke mice. Here, we tested the hypothesis that rFGF21 protects against poststroke blood–brain barrier (BBB) damage in T2DM mice via peroxisome proliferator-activated receptor gamma (PPARγ) activation in cerebral microvascular endothelium. We used the distal middle cerebral occlusion (dMCAO) model in T2DM mice as well as cultured human brain microvascular endothelial cells (HBMECs) subjected to hyperglycemic and inflammatory injury in the current study. We detected a significant reduction in PPARγ DNA-binding activity in the brain tissue and mRNA levels of BBB junctional proteins and PPARγ-targeting gene CD36 and FABP4 in cerebral microvasculature at 24 h after stroke. Ischemic stroke induced a massive BBB leakage two days after stroke in T2DM mice compared to in their lean controls. Importantly, all abnormal changes were significantly prevented by rFGF21 administration initiated at 6 h after stroke. Our in vitro experimental results also demonstrated that rFGF21 protects against hyperglycemia plus interleukin (IL)-1β-induced transendothelial permeability through upregulation of junction protein expression in an FGFR1 activation and PPARγ activity elevation-dependent manner. Our data suggested that rFGF21 has strong protective effects on acute BBB leakage after diabetic stroke, which is partially mediated by increasing PPARγ DNA-binding activity and mRNA expression of BBB junctional complex proteins. Together with our previous investigations, rFGF21 might be a promising candidate for treating diabetic stroke.
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Le, Chen-sheng, Xiao-di Hao, Jia-wen Li, Jia-wei Zhong, Hao-ran Lin, Yi-ting Zhou, Zachary D. Travis, Lu-sha Tong, and Feng Gao. "CD200Fc Improves Neurological Function by Protecting the Blood–brain Barrier after Intracerebral Hemorrhage." Cell Transplantation 28, no. 9-10 (June 17, 2019): 1321–28. http://dx.doi.org/10.1177/0963689719857655.
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CD200 is widely distributed in the central nervous system and plays an essential role in the immune response in neurological diseases. However, little is currently known about the effects of CD200 signaling on the blood–brain barrier (BBB) function after intracerebral hemorrhage (ICH). In this study, the role of CD200 during ICH in an autologous blood induced mouse ICH model was investigated. Following ICH, critical protein expression, BBB permeability, and neurological function were measured with or without CD200Fc administration. Our results showed that both the expression of CD200 and CD200R1 decreased after ICH and administration of CD200Fc attenuated BBB leakage and improved neurological functions. In conclusion, our work demonstrated that CD200Fc might be a potential treatment option for ICH by protecting the BBB and improving functional outcomes.
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Chauhan, Anil K., Atul F. Kamath, Janka Kisucka, Vandana S. Dole, Joseph Loscalzo, Diane E. Handy, and Denisa D. Wagner. "Elevated Levels of Homocysteine Compromise Blood-Brain Barrier Integrity in Mice." Blood 106, no. 11 (November 16, 2005): 3856. http://dx.doi.org/10.1182/blood.v106.11.3856.3856.
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Abstract Elevated levels of plasma homocysteine (Hcy) correlate with increased risks of cardiovascular and Alzheimer’s diseases. We studied the effect of elevated Hcy on the blood-brain barrier (BBB) to explore the possibility of a vascular link between the two diseases. On a methionine-enriched diet, cystathionine beta-synthase (CBS) heterozygous mice develop hyperhomocysteinemia (HHcy). To evaluate the extent of HHcy induced by an 8-week methionine-enriched diet (Diet), we determined plasma Hcy concentration. Concentrations were 23.5 ± 5 μM for wild type (WT) and 98.4 ± 22 μM for CBS+/− on Diet and 4.1 ± 0.20 μM for WT on normal chow. Inflammation can lead to BBB breakdown, therefore we first determined whether we could detect systemic endothelial activation/increased leukocyte adherence in the CBS+/− mice as an indicator of inflammation. We observed mesenteric venules (200–300 μm) in WT and CBS +/− mice fed Diet and compared them with WT on chow. Leukocyte rolling velocity was slower in CBS+/− than in WT mice indicating an increase in the density of adhesion molecules on the endothelium. In CBS+/− mice, 60% of leukocytes rolled at a velocity of < 10 μm/s as compared with only 8% in WT mice on Diet (P<0.002) and 3% WT on chow. The slower leukocyte velocity was due at least in part to higher expression of P-selectin on the endothelium. Infusion of fluorescent beads coated with antibody to P-selectin showed a several fold increase in their binding to venules of CBS +/− mice with HHcy as compared with WT on Diet (P<0.05). We also observed increased leukocyte adherence in CBS +/− mice (P<0.05). We then compared BBB function in mice after the 8-week Diet. We injected Evans blue (EB) dye intraperitoneally. EB binds to albumin and does not readily cross the BBB. The CBS+/− mice exhibited 25% greater EB in cortex compared with WT. EB leakage in WT mice was 3.19 ± 0.09, while CBS+/− leakage was 3.99 ± 0.29 (P < 0.03). WT mice on Diet showed slightly higher plasma Hcy levels than on normal chow; but this increase was not sufficient to break the BBB, as the BBB leakage in the WT mice on Diet was similar to that of WT mice on normal chow. Our study suggests an important toxic effect of elevated Hcy on brain microvessels and implicates Hcy in the disruption of the BBB.
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Johnson, Aaron, Holly Johnson, Matthew Huggins, Aurelie N'Songo, Lisa Hanson, Stephanie LaFrance, Fang Jin, Istvan Pirko, Noah Butler, and John Harty. "Perforin expression is required for fatal blood-brain barrier disruption in the Plasmodium berghei ANKA model of cerebral malaria (P3061)." Journal of Immunology 190, no. 1_Supplement (May 1, 2013): 187.6. http://dx.doi.org/10.4049/jimmunol.190.supp.187.6.
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Abstract The most severe clinical complication of Plasmodium falciparum infection is cerebral malaria (CM). Plasmodium berghei ANKA (PbA) infection of C57BL/6 mice is an established model of CM. Previous work has implied a role for CD8 T cells and perforin expression in fatal stages of PbA infection. We therefore infected C57BL/6 and C57BL/6 Perforin-/- mice with PbA and assessed the CNS for cerebral endothelial cell blood-brain barrier (BBB) disruption using FITC albumin leakage into tissue, confocal microscopy and 3D volumetric T2 and T1 gadolinium enhanced MRI. PbA infected C57BL/6 mice: 1.) had extensive disruption of BBB tight junction proteins Occludin and Claudin 5, 2.) developed severe CNS vascular permeability of FITC albumin and gadolinium leakage, and 3.) became moribund. We also observed increased VEGF cytokine expression coinciding with CNS vascular permeability in these animals. Despite having similar CD8 T cell infiltration into the brain, PbA infected C57BL/6 Perforin-/- mice had intact BBB tight junction, were devoid of CNS vascular permeability, presented with normal brain MRI, and had normal behavioral scores on the rotarod assay. This study is therefore the first to demonstrate the critical importance of perforin expression in promoting BBB tight junction alteration during PbA infection. Therefore, development of therapies to block factors related perforin mediated delivery could have significant benefit to the treatment of CM.
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Liang, Tao, Huihui Ju, Yile Zhou, Yajie Yang, Yi Shi, and Hao Fang. "Inhibition of glycogen synthase kinase 3β improves cognitive function in aged mice by upregulating claudin presences in cerebral endothelial cells." Acta Biochimica et Biophysica Sinica 52, no. 4 (March 6, 2020): 363–70. http://dx.doi.org/10.1093/abbs/gmaa002.
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Abstract Glycogen synthase kinase-3β (GSK-3β), a serine/threonine protein kinase, is widely distributed in mammalian brains. Since GSK-3β plays a vital role in the development of neurodegenerative disorders, the present study was designed to investigate the role of GSK-3β in the blood–brain barrier (BBB) permeability in aged mice. Morris water maze test was used to examine mouse cognitive function. BBB permeability was examined by the leakage of fluorescence signals of low-molecular weight dextran. GSK-3β inhibitor, 4-benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione (TDZD-8), was administrated in aged mice and in cultured mouse brain microvascular endothelial cells (bEnd.3). Compared with young mice, aged mice had increased leftover signals of dextran in the hippocampus and a lower score in the maze test, suggesting that aged mice have abnormal leakage of BBB and cognitive dysfunction. The protein expression of Toll-like receptor 4 (TLR4) was increased, whereas the protein expressions of junction proteins (claudin1 and claudin5) were reduced in endothelial cells of BBB in aged mice. Phosphorylated level of serine 9, an inhibitory residue in GSK-3β protein, was decreased. TDZD-8 treatment downregulated TLR4 protein expression, upregulated claudin1 and claudin5 protein expressions, and significantly improved cognitive function in aged mice. In bEnd.3 cells, TDZD-8 treatment reduced TLR4 expression and increased claudin5 expression in cells stimulated with lipopolysaccharides. In conclusion, the inhibition of GSK-3β activity downregulates aging-induced TLR4 expression and restores the BBB integrity, resulting in the improvement of cognitive function in aged mice.
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Zhang, Zheng Gang, Li Zhang, Wayne Tsang, Hamid Soltanian-Zadeh, Daniel Morris, Ruilan Zhang, Anton Goussev, Cecylia Powers, Thomas Yeich, and Michael Chopp. "Correlation of VEGF and Angiopoietin Expression with Disruption of Blood–Brain Barrier and Angiogenesis after Focal Cerebral Ischemia." Journal of Cerebral Blood Flow & Metabolism 22, no. 4 (April 2002): 379–92. http://dx.doi.org/10.1097/00004647-200204000-00002.
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In an effort to elucidate the molecular mechanisms underlying cerebral vascular alteration after stroke, the authors measured the spatial and temporal profiles of blood–brain barrier (BBB) leakage, angiogenesis, vascular endothelial growth factor (VEGF), associated receptors, and angiopoietins and receptors after embolic stroke in the rat. Two to four hours after onset of ischemia, VEGF mRNA increased, whereas angiopoietin 1 (Ang 1) mRNA decreased. Three-dimensional immunofluorescent analysis revealed spatial coincidence between increases of VEGF immunoreactivity and BBB leakage in the ischemic core. Two to 28 days after the onset of stroke, increased expression of VEGF/VEGF receptors and Ang/Tie2 was detected at the boundary of the ischemic lesion. Concurrently, enlarged and thin-walled vessels were detected at the boundary of the ischemic lesion, and these vessels developed into smaller vessels via sprouting and intussusception. Three-dimensional quantitative analysis of cerebral vessels at the boundary zone 14 days after ischemia revealed a significant ( P < 0.05) increase in numbers of vessels (n = 365) compared with numbers (n = 66) in the homologous tissue of the contralateral hemisphere. Furthermore, capillaries in the penumbra had a significantly smaller diameter (4.8 ± 2.0 μm) than capillaries (5.4 ± 1.5 μm) in the homologous regions of the contralateral hemisphere. Together, these data suggest that acute alteration of VEGF and Ang 1 in the ischemic core may mediate BBB leakage, whereas upregulation of VEGF/VEGF receptors and Ang/Tie2 at the boundary zone may regulate neovascularization in ischemic brain.
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Natah, Sirajedin S., Sathya Srinivasan, Quentin Pittman, Zonghang Zhao, and Jeff F. Dunn. "Effects of acute hypoxia and hyperthermia on the permeability of the blood-brain barrier in adult rats." Journal of Applied Physiology 107, no. 4 (October 2009): 1348–56. http://dx.doi.org/10.1152/japplphysiol.91484.2008.
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Acute mountain sickness (AMS) develops within a few hours after arrival at high altitude and includes headache, anorexia, nausea, vomiting, and malaise. This afflicts 15–25% of the general tourist population at moderate altitudes. High-altitude cerebral edema (HACE) is considered to be the end stage of severe AMS and has been suggested to be a vasogenic edema, raising the possibility that acute hypoxia may increase blood-brain barrier (BBB) permeability. At present, there are no good small-animal models to study this syndrome. We hypothesize 1) that acute hypoxia can damage the BBB and 2) that rat can be used as a model to study hypoxia-induced changes in BBB permeability, especially if hypoxia-induced hypothermia could be minimized with high ambient temperature (HAT). Male Wistar rats were exposed to 1, 2, and 7 days of hypobaric hypoxia (equivalent to 0.5 atm), and changes in the temperature and BBB permeability were studied. The extravasation of endogenous immunoglobulin G, a large molecule, did not increase during room temperature hypoxia but did increase when hypoxia was combined with HAT. Hypoxia caused a significant increase in the leakage of sodium fluorescein (mol wt 376 Da). The expression of endothelial barrier antigen (EBA), a protein associated with the BBB, was reduced to 50% between 24 and 48 h after exposure to hypoxia, and the loss was exacerbated by HAT. The values almost returned to control levels by 7 days, showing adaptation to hypoxia. Hypoxic rats exhibited sodium fluorescein leakage mainly in focal areas in the brain parenchyma. In conclusion, it is possible to have transient BBB damage through exposure to acute hypoxia, and this damage is exacerbated by increasing body temperature to more of a normothermic value.
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Hasan-Olive, Md Mahdi, Hans-Arne Hansson, Rune Enger, Erlend A. Nagelhus, and Per Kristian Eide. "Blood-Brain Barrier Dysfunction in Idiopathic Intracranial Hypertension." Journal of Neuropathology & Experimental Neurology 78, no. 9 (July 4, 2019): 808–18. http://dx.doi.org/10.1093/jnen/nlz063.
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Abstract Idiopathic intracranial hypertension (IIH) is traditionally considered benign and characterized by symptoms related to increased intracranial pressure, including headache and impaired vision. We have previously demonstrated that brains of IIH patients exhibit patchy astrogliosis, increased perivascular expression of the water channel aquaporin-4 (AQP4) as well as degenerating pericyte processes and capillary basement membranes. Given the established association between pericyte degeneration and blood-brain barrier (BBB) dysfunction, we investigated blood protein leakage by light microscopic immunohistochemistry. We also assessed perivascular AQP4 expression by immunogold transmission electron microscopy. The study included 14 IIH patients and 14 reference (REF) subjects undergoing neurosurgery for epilepsy, aneurysm, or tumor. Evidence of BBB dysfunction, measured as area extravasated fibrinogen/fibrin, was significantly more pronounced in IIH than REF individuals. The extent of extravasated fibrinogen was positively correlated with increasing degree of astrogliosis and vascular AQP4 immunoreactivity, determined by light microscopy. Immunogold transmission electron microscopy revealed no overall changes in AQP4 expression at astrocytic vascular endfeet in IIH (n = 8) compared to REF (n = 11) individuals. Our results provide evidence of BBB leakage in IIH, signifying that IIH is a more serious neurodegenerative disease than previously considered.
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Zhou, Min, Samuel X. Shi, Ning Liu, Yinghua Jiang, Mardeen S. Karim, Samuel J. Vodovoz, Xiaoying Wang, Boli Zhang, and Aaron S. Dumont. "Caveolae-Mediated Endothelial Transcytosis across the Blood-Brain Barrier in Acute Ischemic Stroke." Journal of Clinical Medicine 10, no. 17 (August 25, 2021): 3795. http://dx.doi.org/10.3390/jcm10173795.
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Blood-brain barrier (BBB) disruption following ischemic stroke (IS) contributes to hemorrhagic transformation, brain edema, increased neural dysfunction, secondary injury, and mortality. Brain endothelial cells form a para and transcellular barrier to most blood-borne solutes via tight junctions (TJs) and rare transcytotic vesicles. The prevailing view attributes the destruction of TJs to the resulting BBB damage following IS. Recent studies define a stepwise impairment of the transcellular barrier followed by the paracellular barrier which accounts for the BBB leakage in IS. The increased endothelial transcytosis that has been proven to be caveolae-mediated, precedes and is independent of TJs disintegration. Thus, our understanding of post stroke BBB deficits needs to be revised. These recent findings could provide a conceptual basis for the development of alternative treatment strategies. Presently, our concept of how BBB endothelial transcytosis develops is incomplete, and treatment options remain limited. This review summarizes the cellular structure and biological classification of endothelial transcytosis at the BBB and reviews related molecular mechanisms. Meanwhile, relevant transcytosis-targeted therapeutic strategies for IS and research entry points are prospected.
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Nakamura, Kuniyuki, Tomoko Ikeuchi, Kazuki Nara, Craig S. Rhodes, Peipei Zhang, Yuta Chiba, Saiko Kazuno, et al. "Perlecan regulates pericyte dynamics in the maintenance and repair of the blood–brain barrier." Journal of Cell Biology 218, no. 10 (September 20, 2019): 3506–25. http://dx.doi.org/10.1083/jcb.201807178.
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Ischemic stroke causes blood–brain barrier (BBB) breakdown due to significant damage to the integrity of BBB components. Recent studies have highlighted the importance of pericytes in the repair process of BBB functions triggered by PDGFRβ up-regulation. Here, we show that perlecan, a major heparan sulfate proteoglycan of basement membranes, aids in BBB maintenance and repair through pericyte interactions. Using a transient middle cerebral artery occlusion model, we found larger infarct volumes and more BBB leakage in conditional perlecan (Hspg2)-deficient (Hspg2−/−-TG) mice than in control mice. Control mice showed increased numbers of pericytes in the ischemic lesion, whereas Hspg2−/−-TG mice did not. At the mechanistic level, pericytes attached to recombinant perlecan C-terminal domain V (perlecan DV, endorepellin). Perlecan DV enhanced the PDGF-BB–induced phosphorylation of PDGFRβ, SHP-2, and FAK partially through integrin α5β1 and promoted pericyte migration. Perlecan therefore appears to regulate pericyte recruitment through the cooperative functioning of PDGFRβ and integrin α5β1 to support BBB maintenance and repair following ischemic stroke.
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Beard, Richard S., Brian A. Hoettels, Jamie E. Meegan, Travis S. Wertz, Byeong J. Cha, Xiaoyuan Yang, Julia T. Oxford, Mack H. Wu, and Sarah Y. Yuan. "AKT2 maintains brain endothelial claudin-5 expression and selective activation of IR/AKT2/FOXO1-signaling reverses barrier dysfunction." Journal of Cerebral Blood Flow & Metabolism 40, no. 2 (December 21, 2018): 374–91. http://dx.doi.org/10.1177/0271678x18817512.
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Inflammation-induced blood–brain barrier (BBB) dysfunction and microvascular leakage are associated with a host of neurological disorders. The tight junction protein claudin-5 (CLDN5) is a crucial protein necessary for BBB integrity and maintenance. CLDN5 is negatively regulated by the transcriptional repressor FOXO1, whose activity increases during impaired insulin/AKT signaling. Owing to an incomplete understanding of the mechanisms that regulate CLDN5 expression in BBB maintenance and dysfunction, therapeutic interventions remain underdeveloped. Here, we show a novel isoform-specific function for AKT2 in maintenance of BBB integrity. We identified that AKT2 during homeostasis specifically regulates CLDN5-dependent barrier integrity in brain microvascular endothelial cells (BMVECs) and that intervention with a selective insulin-receptor (IR) agonist, demethylasterriquinone B1 (DMAQ-B1), rescued IL-1β-induced AKT2 inactivation, FOXO1 nuclear accumulation, and loss of CLDN5-dependent barrier integrity. Moreover, DMAQ-B1 attenuated preclinical CLDN5-dependent BBB dysfunction in mice subjected to experimental autoimmune encephalomyelitis. Taken together, the data suggest a regulatory role for IR/AKT2/FOXO1-signaling in CLDN5 expression and BBB integrity during neuroinflammation.
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Louboutin, Jean-Pierre, and David S. Strayer. "Blood-Brain Barrier Abnormalities Caused by HIV-1 gp120: Mechanistic and Therapeutic Implications." Scientific World Journal 2012 (2012): 1–15. http://dx.doi.org/10.1100/2012/482575.
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The blood-brain barrier (BBB) is compromised in many systemic and CNS diseases, including HIV-1 infection of the brain. We studied BBB disruption caused by HIV-1 envelope glycoprotein 120 (gp120) as a model. Exposure to gp120, whether acute [by direct intra-caudate-putamen (CP) injection] or chronic [using SV(gp120), an experimental model of ongoing production of gp120] disrupted the BBB, and led to leakage of vascular contents. Gp120 was directly toxic to brain endothelial cells. Abnormalities of the BBB reflect the activity of matrix metalloproteinases (MMPs). These target laminin and attack the tight junctions between endothelial cells and BBB basal laminae. MMP-2 and MMP-9 were upregulated following gp120-injection. Gp120 reduced laminin and tight junction proteins. Reactive oxygen species (ROS) activate MMPs. Injecting gp120 induced lipid peroxidation. Gene transfer of antioxidant enzymes protected against gp120-induced BBB abnormalities. NMDA upregulates the proform of MMP-9. Using the NMDA receptor (NMDAR-1) inhibitor, memantine, we observed partial protection from gp120-induced BBB injury. Thus, (1) HIV-envelope gp120 disrupts the BBB; (2) this occurs via lesions in brain microvessels, MMP activation and degradation of vascular basement membrane and vascular tight junctions; (3) NMDAR-1 activation plays a role in this BBB injury; and (4) antioxidant gene delivery as well as NMDAR-1 antagonists may protect the BBB.
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Jiang, Xijuan, Maojuan Guo, Jinling Su, Bin Lu, Dongming Ma, Ruifeng Zhang, Lin Yang, Qiang Wang, Yiwen Ma, and Yingchang Fan. "Simvastatin Blocks Blood-Brain Barrier Disruptions Induced by Elevated Cholesterol Both In Vivo and In Vitro." International Journal of Alzheimer's Disease 2012 (2012): 1–7. http://dx.doi.org/10.1155/2012/109324.
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Background. Hypercholesterolemia and disruptions of the blood brain barrier (BBB) have been implicated as underlying mechanisms in the pathogenesis of Alzheimer's disease (AD). Simvastatin therapy may be of benefit in treating AD; however, its mechanism has not been yet fully understood.Objective. To explore whether simvastatin could block disruption of BBB induced by cholesterol both in vivo and in vitro.Methods. New Zealand rabbits were fed cholesterol-enriched diet with or without simvastatin. Total cholesterol of serum and brain was measured. BBB dysfunction was evaluated. To further test the results in vivo, rat brain microvascular endothelial cells (RBMECs) were stimulated with cholesterol in the presence/absence of simvastatin in vitro. BBB disruption was evaluated.Results. Simvastatin blocked cholesterol-rich diet induced leakage of Evan's blue dye. Cholesterol content in the serum was affected by simvastatin, but not brain cholesterol. Simvastatin blocked high-cholesterol medium-induced decrease in TEER and increase in transendothelial FITC-labeled BSA Passage in RBMECs.Conclusions. The present study firstly shows that simvastatin improves disturbed BBB function both in vivo and in vitro. Our data provide that simvastatin may be useful for attenuating disturbed BBB mediated by hypercholesterolemia.
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Cottarelli, Azzurra, Monica Corada, Galina V. Beznoussenko, Alexander A. Mironov, Maria A. Globisch, Saptarshi Biswas, Hua Huang, et al. "Fgfbp1 promotes blood-brain barrier development by regulating collagen IV deposition and maintaining Wnt/β-catenin signaling." Development 147, no. 16 (August 3, 2020): dev185140. http://dx.doi.org/10.1242/dev.185140.
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ABSTRACTCentral nervous system (CNS) blood vessels contain a functional blood-brain barrier (BBB) that is necessary for neuronal survival and activity. Although Wnt/β-catenin signaling is essential for BBB development, its downstream targets within the neurovasculature remain poorly understood. To identify targets of Wnt/β-catenin signaling underlying BBB maturation, we performed a microarray analysis that identified Fgfbp1 as a novel Wnt/β-catenin-regulated gene in mouse brain endothelial cells (mBECs). Fgfbp1 is expressed in the CNS endothelium and secreted into the vascular basement membrane during BBB formation. Endothelial genetic ablation of Fgfbp1 results in transient hypervascularization but delays BBB maturation in specific CNS regions, as evidenced by both upregulation of Plvap and increased tracer leakage across the neurovasculature due to reduced Wnt/β-catenin activity. In addition, collagen IV deposition in the vascular basement membrane is reduced in mutant mice, leading to defective endothelial cell-pericyte interactions. Fgfbp1 is required cell-autonomously in mBECs to concentrate Wnt ligands near cell junctions and promote maturation of their barrier properties in vitro. Thus, Fgfbp1 is a crucial extracellular matrix protein during BBB maturation that regulates cell-cell interactions and Wnt/β-catenin activity.
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Namioka, Takahiro, Ai Namioka, Masanori Sasaki, Yuko Kataoka-Sasaki, Shinichi Oka, Masahito Nakazaki, Rie Onodera, et al. "Intravenous infusion of mesenchymal stem cells promotes functional recovery in a rat model of chronic cerebral infarction." Journal of Neurosurgery 131, no. 4 (October 2019): 1289–96. http://dx.doi.org/10.3171/2018.5.jns18140.
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OBJECTIVEIntravenous infusion of mesenchymal stem cells (MSCs) derived from adult bone marrow improves behavioral function in rat models of cerebral infarction. Although clinical studies are ongoing, most studies have focused on the acute or subacute phase of stroke. In the present study, MSCs derived from bone marrow of rats were intravenously infused 8 weeks after the induction of a middle cerebral artery occlusion (MCAO) to investigate whether delayed systemic injection of MSCs improves functional outcome in the chronic phase of stroke in rats.METHODSEight weeks after induction of the MCAO, the rats were randomized and intravenously infused with either MSCs or vehicle. Ischemic volume and behavioral performance were examined. Blood-brain barrier (BBB) integrity was assessed by quantifying the leakage of Evans blue into the brain parenchyma after intravenous infusion. Immunohistochemical analysis was also performed to evaluate the stability of the BBB.RESULTSMotor recovery was better in the MSC-treated group than in the vehicle-treated group, with rapid improvement (evident at 1 week post-infusion). In MSC-treated rats, reduced BBB leakage and increased microvasculature/repair and neovascularization were observed.CONCLUSIONSThese results indicate that the systemic infusion of MSCs results in functional improvement, which is associated with structural changes in the chronic phase of cerebral infarction, including in the stabilization of the BBB.
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Bolton, C. "Neurovascular damage in experimental allergic encephalomyelitis: a target for pharmacological control." Mediators of Inflammation 6, no. 5-6 (1997): 295–302. http://dx.doi.org/10.1080/09629359791415.
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The blood-brain barrier (BBB) is composed of a continuous endothelial layer with pericytes and astrocytes in close proximity to offer homeostatic control to the neurovasculature. The human demyelinating disease multiple sclerosis and the animal counterpart experimental allergic encephalomyelitis (EAE) are characterized by enhanced permeability of the BBB facilitating oedema formation and recruitment of systemically derived inflammatory-type cells into target tissues to mediate eventual myelin loss and neuronal dysfunction. EAE is considered a useful model for examining the pathology which culminates in loss of BBB integrity and the disease is now proving valuable in assessing compounds for efficacy in limiting damage at neurovascular sites. The precise mechanisms culminating in EAE-induced BBB breakdown are unclear although several potentially disruptive mediators have been implicated and have been previously identified as potent effectors of cerebrovascular damage in non-disease related conditions of the central nervous system. The review considers evidence that common mechanisms may mediate cerebrovascular permeability changes irrespective of the initial insult and discusses therapeutic approaches for the control of BBB leakage in the demyelinating diseases.
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Bondan, Eduardo Fernandes, and Maria de Fátima Monteiro Martins. "Blood-brain barrier breakdown and repair following gliotoxic drug injection in the brainstem of streptozotocin-diabetic rats." Arquivos de Neuro-Psiquiatria 70, no. 3 (March 2012): 221–25. http://dx.doi.org/10.1590/s0004-282x2012000300013.
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Ethidium bromide (EB) causes local astrocytic disappearance, with glia limitans disruption and blood-brain barrier (BBB) breakdown. The aim of this study was to evaluate the BBB integrity after the injection of 0.1% EB or 0.9% saline solution into the cisterna pontis of Wistar rats submitted or not to the streptozotocin diabetogenic model. Brainstem sections were collected from 24 hours to 31 days post-injection for ultrastructural analysis and glial fibrillary acidic protein immunohistochemical staining. Some animals received colloidal carbon ink by intravenous route at the same periods. In rats injected with EB, results revealed astrocyte disappearance and leakage of carbon particles beginning at 48 hours and persisting for 7 days in non-diabetic rats and for 15 days in the diabetic ones, although, in both groups, several areas remained devoid of astrocytic processes up to 31 days. In rats injected with saline, there was no sign of astrocytic loss or carbon particles leakage.
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Wang, Hanghui, Yixin Song, Dingjun Hao, and Lianfang Du. "Molecular mechanisms for NG-nitro-L-arginine methyl ester action against cerebral ischemia–reperfusion injury-induced blood–brain barrier dysfunction." Asian Biomedicine 8, no. 2 (April 1, 2014): 173–84. http://dx.doi.org/10.5372/1905-7415.0802.277.
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Abstract Background: Ischemic stroke, an acute neurological injury lacking an effective therapy, is a leading cause of death worldwide. The unmet need in stroke research is to identify viable therapeutic targets and to understand their interplay during cerebral ischemia-reperfusion (I/R) injury. Objective: To explore the protective effects and molecular mechanism of NG-nitro-L-arginine methyl ester (L-NAME) in cerebral ischemia-reperfusion injury-induced blood-brain barrier (BBB) dysfunction. Methods: Two hundred fifty-six rats were randomly assigned to a sham operation group, I/R group, and I/R with L-NAME treatment group. Brain water content was determined by calculating dry/wet weight. The permeability of the BBB was observed using an electron microscope and by determining the Evans Blue leakage from brain tissue on the ischemic side. The expression of brain MMP-9 and GFAP was determined using an immunohistochemical method. The expression of ZO-1 protein was determined by western blotting. Results: We found that L-NAME remarkably attenuated the permeability of the BBB after I/R as assessed by Evans Blue leakage and brain water content (p < 0.05). This was further confirmed by examination of the ultrastructural morphology of the BBB using a transmission electron microscope. Furthermore, we found that expression of the zonae occludens-1 (ZO-1) was decreased in endothelial cells, and expression of MMP-9 and GFAP was increased in the basement membrane and astrocyte end-feet in vehicle control groups, respectively, but these changes could be prevented by L-NAME pretreatment. Conclusion: These results suggested that the neuroprotective effects of L-NAME against BBB damage induced by I/R might be related to the upregulation of tight junction proteins and inhibition of MMP-9 and GFAP expression. L-NAME can be used as a potential MMP-9-based multiple targeting therapeutic strategy in cerebral I/R injury.
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Serlin, Yonatan, Jaime Levy, and Hadar Shalev. "Vascular Pathology and Blood-Brain Barrier Disruption in Cognitive and Psychiatric Complications of Type 2 Diabetes Mellitus." Cardiovascular Psychiatry and Neurology 2011 (February 17, 2011): 1–10. http://dx.doi.org/10.1155/2011/609202.
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Vascular pathology is recognized as a principle insult in type 2 diabetes mellitus (T2DM). Co-morbidities such as structural brain abnormalities, cognitive, learning and memory deficits are also prevailing in T2DM patients. We previously suggested that microvascular pathologies involving blood-brain barrier (BBB) breakdown results in leakage of serum-derived components into the brain parenchyma, leading to neuronal dysfunction manifested as psychiatric illnesses. The current postulate focuses on the molecular mechanisms controlling BBB permeability in T2DM, as key contributors to the pathogenesis of mental disorders in patients. Revealing the mechanisms underlying BBB dysfunction and inflammatory response in T2DM and their role in metabolic disturbances, abnormal neurovascular coupling and neuronal plasticity, would contribute to the understanding of the mechanisms underlying psychopathologies in diabetic patients. Establishing this link would offer new targets for future therapeutic interventions.
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Edvinsson, L., and P. Tfelt-Hansen. "The Blood-Brain Barrier in Migraine Treatment." Cephalalgia 28, no. 12 (December 2008): 1245–58. http://dx.doi.org/10.1111/j.1468-2982.2008.01675.x.
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Salient aspects of the anatomy and function of the blood-barrier barrier (BBB) are reviewed in relation to migraine pathophysiology and treatment. The main function of the BBB is to limit the access of circulating substances to the neuropile. Smaller lipophilic substances have some access to the central nervous system by diffusion, whereas other substances can cross the BBB by carrier-mediated influx transport, receptor-mediated transcytosis and absorptive-mediated transcytosis. Studies of drugs relevant to migraine pathophysiology and treatment have been examined with the pressurized arteriography method. The drugs, given both luminally and abluminally, provide important notions regarding antimigraine site of action, probably abluminal to the BBB. The problems with the BBB in animal models designed to study the pathophysiology, acute treatment models and preventive treatments are discussed with special emphasize on the triptans and calcitonin gene-related peptide (CGRP). The human experimental headache model, especially the use of glycerol trinitrate (the nitric oxide model), and experiences with CGRP administrations utilize the systemic administration of the agonists with effects on other vascular beds also. We discuss how this can be related to genuine migraine attacks. Our view is that there exists no clear proof of breakdown or leakage of the BBB during migraine attacks, and that antimigraine drugs need to pass the BBB for efficacy.
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Gao, Li, Zhenghong Song, Jianhua Mi, Pinpin Hou, Chong Xie, Jianquan Shi, Yansheng Li, and Anatol Manaenko. "The Effects and Underlying Mechanisms of Cell Therapy on Blood-Brain Barrier Integrity After Ischemic Stroke." Current Neuropharmacology 18, no. 12 (December 1, 2020): 1213–26. http://dx.doi.org/10.2174/1570159x18666200914162013.
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Ischemic stroke is one of the main causes of mortality and disability worldwide. However, efficient therapeutic strategies are still lacking. Stem/progenitor cell-based therapy, with its vigorous advantages, has emerged as a promising tool for the treatment of ischemic stroke. The mechanisms involve new neural cells and neuronal circuitry formation, antioxidation, inflammation alleviation, angiogenesis, and neurogenesis promotion. In the past decades, in-depth studies have suggested that cell therapy could promote vascular stabilization and decrease blood-brain barrier (BBB) leakage after ischemic stroke. However, the effects and underlying mechanisms on BBB integrity induced by the engrafted cells in ischemic stroke have not been reviewed yet. Herein, we will update the progress in research on the effects of cell therapy on BBB integrity after ischemic stroke and review the underlying mechanisms. First, we will present an overview of BBB dysfunction under the ischemic condition and cells engraftment for ischemic treatment. Then, we will summarize and discuss the current knowledge about the effects and underlying mechanisms of cell therapy on BBB integrity after ischemic stroke. In particular, we will review the most recent studies in regard to the relationship between cell therapy and BBB in tissue plasminogen activator (t-PA)-mediated therapy and diabetic stroke.