scholarly journals Meprin β: A novel regulator of blood–brain barrier integrity

2020 ◽  
Vol 41 (1) ◽  
pp. 31-44
Author(s):  
Markus Gindorf ◽  
Steffen E Storck ◽  
Anke Ohler ◽  
Franka Scharfenberg ◽  
Christoph Becker-Pauly ◽  
...  
Keyword(s):  
Water Content ◽  
Blood Brain Barrier ◽  
Mouse Brain ◽  
Brain Barrier ◽  
Brain Water Content ◽  
Cerebral Microvessels ◽  
Knock Out ◽  
Blood Brain ◽  
Primary Mouse ◽  
Brain Water

The metalloprotease meprin β (Mep1b) is capable of cleaving cell-adhesion molecules in different tissues (e.g. skin, kidney and intestine) and is dysregulated in several diseases associated with barrier breakdown (Alzheimer´s disease, kidney disruption, inflammatory bowel disease). In this study, we demonstrate that Mep1b is a novel regulator of tight junction (TJ) composition and blood–brain barrier (BBB) integrity in brain endothelium. In Mep1b-transfected mouse brain endothelial cells (bEnd.3), we observed a reduction of the TJ protein claudin-5, decreased transendothelial electrical resistance (TEER) and an elevated permeability to paracellular diffusion marker [14C]-inulin. Analysis of global Mep1b knock-out (Mep1b−/−) mice showed increased TJ protein expression (claudin-5, occludin, ZO-1) in cerebral microvessels and increased TEER in cultivated primary mouse brain endothelial compared to wild-type (wt) mice. Furthermore, we investigated the IgG levels in cerebrospinal fluid (CSF) and the brain water content as additional permeability markers and detected lower IgG levels and reduced brain water content in Mep1b−/− mice compared to wt mice. Showing opposing features in overexpression and knock-out, we conclude that Mep1b plays a role in regulating brain endothelial TJ-proteins and therefore affecting BBB tightness in vitro and in vivo.

Effects of postnatal dexamethasone on blood-brain barrier permeability and brain water content in newborn lambs

2001 ◽  
Vol 280 (2) ◽  
pp. R547-R553 ◽  
Author(s):  
Gregory D. Sysyn ◽  
Katherine H. Petersson ◽  
Clifford S. Patlak ◽  
Grazyna B. Sadowska ◽  
Barbara S. Stonestreet
Keyword(s):  
Water Content ◽  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Brain Water Content ◽  
Barrier Permeability ◽  
Blood Brain Barrier Permeability ◽  
Blood Brain ◽  
Brain Barrier Permeability ◽  
Postnatal Treatment ◽  
Brain Water

We showed that antenatal corticosteroids reduced blood-brain barrier permeability in fetuses at 60 and 80%, but not 90% of gestation, and decreased brain water content in fetuses. Our objective was to examine the effects of postnatal corticosteroids on regional blood-brain barrier permeability and brain water content in newborn lambs. Three dexamethasone treatment groups were studied in 3- to 5-day-old lambs. A 0.01 mg/kg dose was selected to estimate the amount of dexamethasone that might have reached fetuses via antenatal treatment of ewes in our previous studies. The other doses (0.25 and 0.5 mg/kg) were chosen to approximate those used clinically to treat infants with bronchopulmonary dysplasia. Lambs were randomly assigned to receive four intramuscular injections of dexamethasone or placebo given 12 h apart on days 3 and 4 of age. Blood-brain barrier function was measured with the blood-to-brain transfer constant ( K i) to α-aminoisobutyric acid, brain plasma volume was measured with polyethylene glycol for the calculation of K i, and brain water was measured by wet-to-dry tissue weights. Postnatal treatment with corticosteroids did not reduce barrier permeability in newborn lambs. Brain blood volume was higher in the 0.25 and 0.5 mg/kg dose dexamethasone groups than in the placebo group. Brain water content did not differ among the groups. We conclude that postnatal treatment with corticosteroids did not reduce regional blood-brain barrier permeability or brain water content but increased the brain plasma volume in newborn lambs. These findings are consistent with our previous work indicating that barrier permeability is responsive to corticosteroids at 60 and 80% of gestation and brain water regulation at 60% of gestation, but not in near-term fetuses or newborn lambs.

scholarly journals Mouse Adenovirus Type 1-Induced Breakdown of the Blood-Brain Barrier

2009 ◽  
Vol 83 (18) ◽  
pp. 9398-9410 ◽  
Author(s):  
Lisa E. Gralinski ◽  
Shanna L. Ashley ◽  
Shandee D. Dixon ◽  
Katherine R. Spindler
Keyword(s):  
Endothelial Cells ◽  
Blood Brain Barrier ◽  
Mouse Brain ◽  
Adenovirus Type ◽  
Brain Barrier ◽  
Brain Endothelial Cells ◽  
Blood Brain ◽  
Mouse Brain Endothelial Cells ◽  
Primary Mouse ◽  
Infected Cells

ABSTRACT Infection with mouse adenovirus type 1 (MAV-1) results in fatal acute encephalomyelitis in susceptible mouse strains via infection of brain endothelial cells. Wild-type (wt) MAV-1 causes less brain inflammation than an early region 3 (E3) null virus in C57BL/6 mice. A mouse brain microvascular endothelial cell line infected with wt MAV-1 had higher expression of mRNAs for the proinflammatory chemokines CCL2 and CCL5 than mock- and E3 null virus-infected cells. Primary mouse brain endothelial cells infected with wt virus had elevated levels of CCL2 compared to mock- or E3 null virus-infected cells. Infection of C57BL/6 mice with wt MAV-1 or the E3 null virus caused a dose-dependent breakdown of the blood-brain barrier, primarily due to direct effects of virus infection rather than inflammation. The tight junction proteins claudin-5 and occludin showed reduced surface expression on primary mouse brain endothelial cells following infection with either wt MAV-1 or the E3 null virus. mRNAs and protein for claudin-5, occludin, and zona occludens 2 were also reduced in infected cells. MAV-1 infection caused a loss of transendothelial electrical resistance in primary mouse brain endothelial cells that was not dependent on E3 or on MAV-1-induced CCL2 expression. Taken together, these results demonstrate that MAV-1 infection caused breakdown of the blood-brain barrier accompanied by decreased surface expression of tight junction proteins. Furthermore, while the MAV-1-induced pathogenesis and inflammation were dependent on E3, MAV-1-induced breakdown of the blood-brain barrier and alteration of endothelial cell function were not dependent on E3 or CCL2.

scholarly journals GOLGA2/GM130 is a novel target of neuroprotection therapy in intracerebral hemorrhage

2021 ◽  
Author(s):  
shu wen deng ◽  
Qing Hu ◽  
Qiang He ◽  
Xi qian Chen ◽  
Qiang Lei ◽  
...  
Keyword(s):  
Brain Injury ◽  
Intracerebral Hemorrhage ◽  
Tight Junction ◽  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Brain Water Content ◽  
Autophagy Flux ◽  
Blood Brain ◽  
Brain Water

Abstract Background Impairment of the blood-brain barrier after intracerebral hemorrhage (ICH) can lead to secondary brain injury and aggravate neurological deficits. Owing in part to our lack of understanding of the mechanism of ICH injury to the blood-brain barrier, there are currently no effective methods to prevent or treat it. Here, we explored the effects of Golgi apparatus protein GM130 overexpression or silencing on the blood-brain barrier and neurological function after ICH, to better understand the mechanism involved and facilitate the development of new therapeutic methods. Results Levels of the tight junction-associated proteins ZO-1 and occludin decreased, while those of LC3-II, a marker for autophagosomes, increased in hemin-treated Bend.3 cells (p < 0.05). The levels of ZO-1 and occludin increased, while those of LC3-II decreased with GM130 overexpression (p < 0.05). ZO-1 and occludin expression decreased and LC3-II increased after siGM130 transfection, mimicking the effect of hemin (p < 0.05). Tight junctions were disconnected after hemin or siGM130 treatment and repaired with GM130 overexpression. siGM130 transfection in Bend.3 cells increased autophagy flux, whereas GM130 overexpression downregulated autophagy flux. Similar results were verified in an in vivo ICH model. Perihematomal ZO-1 and occludin expression increased, while LC3-II expression decreased in ICH rats (p < 0.05). ZO-1 and occluding expression further decreased and LC3-II expression increased in siGM130-treated ICH rats (p < 0.05), whereas a reverse effect was observed in AAV-GM130-treated ICH rats (p < 0.05). Perihematomal Evans blue and brain water content were much higher in siGM130-treated ICH rats than in the control ICH rats. AAV-GM130-treated ICH rats showed a lower perihematomal Evans blue and brain water content than the control ICH rats. Conclusions GM130 overexpression can protect the integrity of the blood-brain barrier from brain injury, inhibit excessive autophagy flux in an ICH in vivo model, and further improve the neurobehavioral prognosis. GM130 overexpression may mediate tight junction protein repair by directly reducing autophagy flux in an ICH in vitro model. GM130 may be a therapeutic target for acute brain injury after ICH.

scholarly journals Rehmannia and Rhubarb Decoction Exerts Neuroprotective Effects on the Blood-brain barrier during Acute Intracerebral Hemorrhage by Downregulating the HMGB1/TLR4/MMP9 signaling pathway

2020 ◽  
Author(s):  
Shan Jiang ◽  
Chun-Mei Li ◽  
Ding-Fang Cai ◽  
Jing-Si Zhang ◽  
Xiao-Fei Yu
Keyword(s):  
Intracerebral Hemorrhage ◽  
Protective Effect ◽  
Water Content ◽  
Signaling Pathway ◽  
Blood Brain Barrier ◽  
Evans Blue ◽  
Brain Barrier ◽  
Brain Water Content ◽  
Acute Intracerebral Hemorrhage ◽  
Brain Water

Abstract Background Blood-brain barrier (BBB) is a gate-keeping system with selective permeability that serves to protect the central nervous system. The underlying neuroprotective mechanism of the BBB during acute intracerebral hemorrhage (ICH) remains poorly understood. Rehmannia and rhubarb decoction (RRD) is a classic traditional Chinese medicine formula that has been extensively applied for hemorrhagic diseases in China. In the present study, the potential protective effects of RRD on the BBB during acute ICH and the underlying mechanism were investigated. Methods The ICH model was established by injection of autologous blood (100 µl) into spontaneously hypertensive rats, which were randomly divided into the following groups: i) Sham; ii) ICH; iii) RRD; iv) TAK-242; v) TAK-242 + RRD; vi) high mobility group box 1 protein (HMGB1) inhibitor ethyl pyruvate (EP); and vii) EP + RRD. Neurological deficits, pathological examination, brain water content, Evans blue(EB) extravasation, immunofluorescence staining and the expression levels of HMGB1, toll-like receptor 4 (TLR4), matrix metalloproteinase 9 (MMP-9), Claudin-5, Occludin and zona occludens − 1 (Zo-1) were subsequently examined in each group on day 3 following operation. In addition, MRI and transmission electron microscopy were also performed to observe the BBB structure. Results RRD treatment markedly improved neurological functions, reduced brain water content and Evans blue extravasation, ameliorated the disruption of BBB and downregulated HMGB1, TLR4 and MMP-9 expression whilst upregulating the expression of Claudin-5, Occludin and Zo-1. Conclusion These results demonstrate that RRD has a protective effect on the BBB in rats during ICH and this protective effect is related to the down-regulation of HMGB1/TLR4/MMP9 signaling pathway.

scholarly journals Histamine Induces Alzheimer’s Disease-Like Blood Brain Barrier Breach and Local Cellular Responses in Mouse Brain Organotypic Cultures

2015 ◽  
Vol 2015 ◽  
pp. 1-12 ◽  
Author(s):  
Jonathan C. Sedeyn ◽  
Hao Wu ◽  
Reilly D. Hobbs ◽  
Eli C. Levin ◽  
Robert G. Nagele ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Blood Brain Barrier ◽  
Mouse Brain ◽  
The United States ◽  
Model Systems ◽  
Brain Barrier ◽  
Astrocyte Activation ◽  
Blood Brain ◽  
Primary Mouse

Among the top ten causes of death in the United States, Alzheimer’s disease (AD) is the only one that cannot be cured, prevented, or even slowed down at present. Significant efforts have been exerted in generating model systems to delineate the mechanism as well as establishing platforms for drug screening. In this study, a promising candidate model utilizing primary mouse brain organotypic (MBO) cultures is reported. For the first time, we have demonstrated that the MBO cultures exhibit increased blood brain barrier (BBB) permeability as shown by IgG leakage into the brain parenchyma, astrocyte activation as evidenced by increased expression of glial fibrillary acidic protein (GFAP), and neuronal damage-response as suggested by increased vimentin-positive neurons occur upon histamine treatment. Identical responses—a breakdown of the BBB, astrocyte activation, and neuronal expression of vimentin—were then demonstrated in brains from AD patients compared to age-matched controls, consistent with other reports. Thus, the histamine-treated MBO culture system may provide a valuable tool in combating AD.

Glucose transport by isolated plasma membranes of the bovine blood-brain barrier

1997 ◽  
Vol 272 (5) ◽  
pp. C1552-C1557 ◽  
Author(s):  
W. J. Lee ◽  
D. R. Peterson ◽  
E. J. Sukowski ◽  
R. A. Hawkins
Keyword(s):  
Glucose Transport ◽  
Blood Brain Barrier ◽  
Plasma Membranes ◽  
Glucose Transporter ◽  
Extracellular Fluid ◽  
Brain Barrier ◽  
Maximal Velocity ◽  
Plasma Membrane Vesicles ◽  
Cerebral Microvessels ◽  
Blood Brain

Luminal and abluminal endothelial plasma membrane vesicles were isolated from bovine cerebral microvessels, the site of the blood-brain barrier. Glucose transport across each membrane was measured using a rapid-filtration technique. Glucose transport into luminal vesicles occurred by a stereospecific energy-independent transporter [Michaelis-Menten constant (K(m)) = 10.3 +/- 2.8 (SE) mM and maximal velocity (Vmax) = 8.6 +/- 2.0 nmol.mg protein(-1).min-1]. Kinetic analysis of abluminal vesicles also showed a transport system with characteristics similar to the luminal transporter (K(m) = 12.5 +/- 2.3 mM and Vmax = 10.0 +/- 1.0 nmol.mg protein-1.min-1). These functional, facilitative glucose transporters were symmetrically distributed between the luminal and abluminal membrane domains, providing a mechanism for glucose movement between blood and brain. The studies also revealed a Na-dependent transporter on the abluminal membrane with a higher affinity and lower capacity than the facilitative transporters (K(m) = 130 +/- 20 microM and Vmax = 1.59 +/- 0.44 nmol.mg protein-1.min-1. The abluminal Na-dependent glucose transporter is in a position to transport glucose from the brain extracellular fluid into the endothelial cells of the blood-brain barrier. The functional significance of its presence there remains to be determined.

Activation of PKC modulates blood-brain barrier endothelial cell permeability changes induced by hypoxia and posthypoxic reoxygenation

2005 ◽  
Vol 289 (5) ◽  
pp. H2012-H2019 ◽  
Author(s):  
Melissa A. Fleegal ◽  
Sharon Hom ◽  
Lindsay K. Borg ◽  
Thomas P. Davis
Keyword(s):  
Blood Brain Barrier ◽  
Paracellular Permeability ◽  
Cell Permeability ◽  
Brain Barrier ◽  
Cerebral Microvessels ◽  
Permeability Changes ◽  
Blood Brain ◽  
Brain Microvessel

The blood-brain barrier (BBB) is a metabolic and physiological barrier important for maintaining brain homeostasis. The aim of this study was to determine the role of PKC activation in BBB paracellular permeability changes induced by hypoxia and posthypoxic reoxygenation using in vitro and in vivo BBB models. In rat brain microvessel endothelial cells (RMECs) exposed to hypoxia (1% O2-99% N2; 24 h), a significant increase in total PKC activity was observed, and this was reduced by posthypoxic reoxygenation (95% room air-5% CO2) for 2 h. The expression of PKC-βII, PKC-γ, PKC-η, PKC-μ, and PKC-λ also increased following hypoxia (1% O2-99% N2; 24 h), and these protein levels remained elevated following posthypoxic reoxygenation (95% room air-5% CO2; 2 h). Increases in the expression of PKC-ε and PKC-ζ were also observed following posthypoxic reoxygenation (95% room air-5% CO2; 2 h). Moreover, inhibition of PKC with chelerythrine chloride (10 μM) attenuated the hypoxia-induced increases in [14C]sucrose permeability. Similar to what was observed in RMECs, total PKC activity was also stimulated in cerebral microvessels isolated from rats exposed to hypoxia (6% O2-94% N2; 1 h) and posthypoxic reoxygenation (room air; 10 min). In contrast, hypoxia (6% O2-94% N2; 1 h) and posthypoxic reoxygenation (room air; 10 min) significantly increased the expression levels of only PKC-γ and PKC-θ in the in vivo hypoxia model. These data demonstrate that hypoxia-induced BBB paracellular permeability changes occur via a PKC-dependent mechanism, possibly by differentially regulating the protein expression of the 11 PKC isozymes.

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