Morphologic mechanisms of increased vascular permeability of triolein emulsion to the blood-brain barrier

2017 ◽  
Vol 66 (5) ◽  
pp. 366-370 ◽  
Author(s):  
Yuri Sol ◽  
Seon Hee Choi ◽  
Hak Jin Kim ◽  
Yong-Woo Kim ◽  
Byung Mann Cho ◽  
...  
Keyword(s):  
Vascular Permeability ◽  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Blood Brain

scholarly journals Engineered human blood–brain barrier microfluidic model for vascular permeability analyses

2022 ◽  
Author(s):  
Cynthia Hajal ◽  
Giovanni S. Offeddu ◽  
Yoojin Shin ◽  
Shun Zhang ◽  
Olga Morozova ◽  
...  
Keyword(s):  
Vascular Permeability ◽  
Blood Brain Barrier ◽  
Human Blood ◽  
Brain Barrier ◽  
Blood Brain

scholarly journals Anti-Nogo-A antibodies prevent vascular leakage and act as pro-angiogenic factors following stroke

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Ruslan Rust ◽  
Rebecca Z. Weber ◽  
Lisa Grönnert ◽  
Geertje Mulders ◽  
Michael A. Maurer ◽  
...  
Keyword(s):  
Vascular Permeability ◽  
Blood Brain Barrier ◽  
Neurite Growth ◽  
Brain Barrier ◽  
Vascular Repair ◽  
Blood Brain Barrier Disruption ◽  
Vascular Regeneration ◽  
Blood Brain ◽  
Brain Barrier Disruption ◽  
Endothelial Growth Factor

AbstractAngiogenesis is a key restorative process following stroke but has also been linked to increased vascular permeability and blood brain barrier (BBB) disruption. Previous pre-clinical approaches primarily focused on the administration of vascular endothelial growth factor (VEGF) to promote vascular repair after stroke. Although shown to improve angiogenesis and functional recovery from stroke, VEGF increased the risk of blood brain barrier disruption and bleedings to such an extent that its clinical use is contraindicated. As an alternative strategy, antibodies against the neurite growth inhibitory factor Nogo-A have recently been shown to enhance vascular regeneration in the ischemic central nervous system (CNS); however, their effect on vascular permeability is unknown. Here, we demonstrate that antibody-mediated Nogo-A neutralization following stroke has strong pro-angiogenic effects but does not increase vascular permeability as opposed to VEGF. Moreover, VEGF-induced vascular permeability was partially prevented when VEGF was co-administered with anti-Nogo-A antibodies. This study may provide a novel therapeutic strategy for vascular repair and maturation in the ischemic brain.

scholarly journals R-CHOP preceded by blood-brain barrier permeabilization with engineered tumor necrosis factor-α in primary CNS lymphoma

Blood ◽  
2019 ◽  
Vol 134 (3) ◽  
pp. 252-262 ◽  
Author(s):  
Andrés J. M. Ferreri ◽  
Teresa Calimeri ◽  
Gian Marco Conte ◽  
Dario Cattaneo ◽  
Federico Fallanca ◽  
...  
Keyword(s):  
Tumor Necrosis Factor ◽  
Vascular Permeability ◽  
Blood Brain Barrier ◽  
Tumor Necrosis ◽  
Tumor Necrosis Factor Α ◽  
Brain Barrier ◽  
Emission Computed Tomography ◽  
Blood Brain ◽  
Factor Α ◽  
Necrosis Factor

Abstract Patients with primary central nervous system lymphoma (PCNSL) are treated with high-dose methotrexate-based chemotherapy, which requires hospitalization and extensive expertise to manage related toxicity. The use of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) could overcome these difficulties, but blood-brain barrier (BBB) penetration of related drugs is poor. Tumor necrosis factor-α coupled with NGR (NGR-hTNF), a peptide targeting CD13+ vessels, induces endothelial permeabilization and improves tumor access of cytostatics. We tested the hypothesis that NGR-hTNF can break the BBB, thereby improving penetration and activity of R-CHOP in patients with relapsed/refractory PCNSL (NCT03536039). Patients received six R-CHOP21 courses, alone at the first course and preceded by NGR-hTNF (0.8 μg/m2) afterward. This trial included 2 phases: an “explorative phase” addressing the effect of NGR-hTNF on drug pharmacokinetic parameters and on vessel permeability, assessed by dynamic contrast-enhanced magnetic resonance imaging and 99mTc-diethylene-triamine-pentacetic acid–single-photon emission computed tomography, and the expression of CD13 on tumor tissue; and an “expansion phase” with overall response rate as the primary end point, in which the 2-stage Simon Minimax design was used. At the first stage, if ≥4 responses were observed among 12 patients, the study accrual would have continued (sample size, 28). Herein, we report results of the explorative phase and the first-stage analysis (n = 12). CD13 was expressed in tumor vessels of all cases. NGR-hTNF selectively increased vascular permeability in tumoral/peritumoral areas, without interfering with drug plasma/cerebrospinal fluid concentrations. The NGR-hTNF/R-CHOP combination was well tolerated: there were only 2 serious adverse events, and grade 4 toxicity was almost exclusively hematological, which were resolved without dose reductions or interruptions. NGR-hTNF/R-CHOP was active, with 9 confirmed responses (75%; 95% confidence interval, 51-99), 8 of which were complete. In conclusion, NGR-hTNF/R-CHOP was safe in these heavily pretreated patients. NGR-hTNF enhanced vascular permeability specifically in tumoral/peritumoral areas, which resulted in fast and sustained responses.

scholarly journals Protein Kinase C Activation Modulates Reversible Increase in Cortical Blood–Brain Barrier Permeability and Tight Junction Protein Expression during Hypoxia and Posthypoxic Reoxygenation

2010 ◽  
Vol 30 (11) ◽  
pp. 1847-1859 ◽  
Author(s):  
Colin L Willis ◽  
Diana S Meske ◽  
Thomas P Davis
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Protein Expression ◽  
Tight Junction ◽  
Vascular Permeability ◽  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Kinase C ◽  
Blood Brain ◽  
Junction Protein

Hypoxia (Hx) is a component of many disease states including stroke. Ischemic stroke occurs when there is a restriction of cerebral blood flow and oxygen to part of the brain. During the ischemic, and subsequent reperfusion phase of stroke, blood–brain barrier (BBB) integrity is lost with tight junction (TJ) protein disruption. However, the mechanisms of Hx and reoxygenation (HR)-induced loss of BBB integrity are not fully understood. We examined the role of protein kinase C (PKC) isozymes in modifying TJ protein expression in a rat model of global Hx. The Hx (6% O2) induced increased hippocampal and cortical vascular permeability to 4 and 10 kDa dextran fluorescein isothiocyanate (FITC) and endogenous rat-IgG. Cortical microvessels revealed morphologic changes in nPKC-θ distribution, increased nPKC-θ and aPKC-ζ protein expression, and activation by phosphorylation of nPKC-θ (Thr538) and aPKC-ζ (Thr410) residues after Hx treatment. Claudin-5, occludin, and ZO-1 showed disrupted organization at endothelial cell margins, whereas Western blot analysis showed increased TJ protein expression after Hx. The PKC inhibition with chelerythrine chloride (5 mg/kg intraperitoneally) attenuated Hx-induced hippocampal vascular permeability and claudin-5, PKC (θ and ζ) expression, and phosphorylation. This study supports the hypothesis that nPKC-θ and aPKC-ζ signaling mediates TJ protein disruption resulting in increased BBB permeability.

scholarly journals Inhibition of Src Activity Decreases Tyrosine Phosphorylation of Occludin in Brain Capillaries and Attenuates Increase in Permeability of the Blood-Brain Barrier after Transient Focal Cerebral Ischemia

2009 ◽  
Vol 29 (6) ◽  
pp. 1099-1108 ◽  
Author(s):  
Yuji Takenaga ◽  
Norio Takagi ◽  
Kazutoshi Murotomi ◽  
Kouichi Tanonaka ◽  
Satoshi Takeo
Keyword(s):  
Cerebral Ischemia ◽  
Vascular Permeability ◽  
Tyrosine Phosphorylation ◽  
Blood Brain Barrier ◽  
Focal Cerebral Ischemia ◽  
Infarct Volume ◽  
Brain Barrier ◽  
Brain Capillaries ◽  
Blood Brain ◽  
Transient Focal Cerebral Ischemia

Disruption of the blood-brain barrier (BBB) caused by cerebral ischemia can initiate the development and progression of brain injuries, which may lead to irreversible dysfunction of the central nervous system. It is likely that tyrosine phosphorylation of a membrane-associated tight junctional protein, occludin, is important for the interaction of occludin with intracellular proteins, ZO-1 to ZO-3, and it regulates vascular permeability. Little is known about the pathophysiological alterations of tight junctional proteins after transient focal cerebral ischemia. In this study, we examined the tyrosine phosphorylation of occludin in isolated brain capillaries after transient focal cerebral ischemia. We further examined the effects of the Src-family tyrosine kinase inhibitor, PP2, on the tyrosine phosphorylation of occludin and on vascular permeability and infarct volume. Transient focal ischemia increased the tyrosine phosphorylation of occludin in the isolated brain capillaries. The administration of PP2 attenuated this phosphorylation, which was coincident with an inhibition of BBB leakage and a decrease in infarct volume. These results suggest that the increase in the tyrosine phosphorylation of occludin in the brain capillaries may be linked to the disruption of tight junctions, whose disruption can cause dysfunction of the BBB and the consequent increase in infarct volume.

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