scholarly journals Blood–Brain Barrier Permeability: Is 5-Hydroxytryptamine Receptor Type 4 a Game Changer?

Pharmaceutics ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 1856
Author(s):  
Guillaume Becker ◽  
Sylvia Da Silva ◽  
Amelia-Naomi Sabo ◽  
Maria Cristina Antal ◽  
Véronique Kemmel ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Serotonin Receptor ◽  
Brain Parenchyma ◽  
The Body ◽  
Brain Barrier ◽  
Blood Brain ◽  
Junction Protein ◽  
Bbb Permeability

Serotonin affects many functions in the body, both in the central nervous system (CNS) and the periphery. However, its effect on the blood–brain barrier (BBB) in separating these two worlds has been scarcely investigated. The aim of this work was to characterize the serotonin receptor 5-HT4 in the hCMEC/D3 cell line, in the rat and the human BBB. We also examined the effect of prucalopride, a 5-HT4 receptor agonist, on the permeability of the hCMEC/D3 in an in vitro model of BBB. We then confirmed our observations by in vivo experiments. In this work, we show that the 5-HT4 receptor is expressed by hCMEC/D3 cells and in the capillaries of rat and human brains. Prucalopride increases the BBB permeability by downregulating the expression of the tight junction protein, occludin. This effect is prevented by GR113808, a 5-HT4 receptor antagonist, and is mediated by the Src/ERK1/2 signaling pathway. The canonical G-protein-dependent pathway does not appear to be involved in this phenomenon. Finally, the administration of prucalopride increases the diffusion of Evans blue in the rat brain parenchyma, which is synonymous with BBB permeabilization. All these data indicate that the 5-HT4 receptor contributes to the regulation of BBB permeability.

scholarly journals Yuzu and Hesperidin Ameliorate Blood-Brain Barrier Disruption during Hypoxia via Antioxidant Activity

Antioxidants ◽  
2020 ◽  
Vol 9 (9) ◽  
pp. 843
Author(s):  
Bo Kyung Lee ◽  
Soo-Wang Hyun ◽  
Yi-Sook Jung
Keyword(s):  
Endothelial Cell ◽  
Blood Brain Barrier ◽  
Cell Model ◽  
Antioxidant Properties ◽  
Brain Barrier ◽  
Blood Brain ◽  
In Vivo Animal Model ◽  
Bbb Permeability

Yuzu and its main component, hesperidin (HSP), have several health benefits owing to their anti-inflammatory and antioxidant properties. We examined the effects of yuzu and HSP on blood–brain barrier (BBB) dysfunction during ischemia/hypoxia in an in vivo animal model and an in vitro BBB endothelial cell model, and also investigated the underlying mechanisms. In an in vitro BBB endothelial cell model, BBB permeability was determined by measurement of Evans blue extravasation in vivo and in vitro. The expression of tight junction proteins, such as claudin-5 and zonula occludens-1 (ZO-1), was detected by immunochemistry and western blotting, and the reactive oxygen species (ROS) level was measured by 2′7′-dichlorofluorescein diacetate intensity. Yuzu and HSP significantly ameliorated the increase in BBB permeability and the disruption of claudin-5 and ZO-1 in both in vivo and in vitro models. In bEnd.3 cells, yuzu and HSP were shown to inhibit the disruption of claudin-5 and ZO-1 during hypoxia, and the protective effects of yuzu and HSP on claudin-5 degradation seemed to be mediated by Forkhead box O 3a (FoxO3a) and matrix metalloproteinase (MMP)-3/9. In addition, well-known antioxidants, trolox and N-acetyl cysteine, significantly attenuated the BBB permeability increase, disruption of claudin-5 and ZO-1, and FoxO3a activation during hypoxia, suggesting that ROS are important mediators of BBB dysfunction during hypoxia. Collectively, these results indicate that yuzu and HSP protect the BBB against dysfunction via maintaining integrity of claudin-5 and ZO-1, and these effects of yuzu and HSP appear to be a facet of their antioxidant properties. Our findings may contribute to therapeutic strategies for BBB-associated neurodegenerative diseases.

Prostate cancer-derived anti-GRP78 autoantibodies compromise the blood-brain barrier and accelerate atherosclerosis progression in vivo.

2019 ◽  
Vol 37 (7_suppl) ◽  
pp. 205-205
Author(s):  
Ali Al-Hashimi ◽  
Bobby Shayegan ◽  
Richard Austin ◽  
Kevin Doyoon Won
Keyword(s):  
Prostate Cancer ◽  
Blood Brain Barrier ◽  
Atherosclerotic Plaque ◽  
The Body ◽  
Brain Barrier ◽  
Blue Dye ◽  
Plaque Progression ◽  
Blood Brain

205 Background: Pathological conditions of prostate cancer (PCa) drive the translocation of the endoplasmic reticulum-resident chaperone, GRP78, to the cell surface (cs) where it acts as an antigenic protein with signaling properties. In PCa, csGRP78 drives the production of anti-GRP78 autoantibodies (AutoAbs) that engage csGRP78 and promote PCa survival/progression. New studies now demonstrate csGRP78 expression on endothelial cells (EC) that line the arterial vasculature and the blood-brain barrier (BBB) suggesting that these AutoAbs can affect other systems in the body. Based on this, we investigated how the engagement of anti-GRP78 AutoAbs to csGRP78 on EC can contribute to EC-dysfunction that can promote atherosclerosis and compromise the integrity of the BBB. Methods: Anti-GRP78 AutoAbs were purified from PCa patients (St. Joseph’s Healthcare Hamilton); human aortic EC and the ApoE -/- mouse model were used for in vitro and in vivo investigations, respectively. EC or mice were treated with anti-GRP78 AutoAbs or IgG control (60µg/mL); EC-dysfunction was investigated by measuring attachment protein expression, in vitro. In vivo evaluation was carried out by studying atherosclerotic plaque progression (immunohistochemistry; aorta); the BBB integrity was examined using the Evans Blue dye. Results: Mice injected with anti-GRP78 AutoAbs, and not human IgG, demonstrated larger atherosclerotic plaque volume and hallmarks of a leaky BBB. In terms of a mechanism, in vitro studies demonstrated that treating EC with anti-GRP78 AutoAbs resulted in activation of the NFκB pathway that led to increased expression of attachment proteins. All these effects were reversed by using a recombinant molecule that interfere with the binding of the AutoAb to csGRP78. Conclusions: We have identified anti-GRP78 AutoAb as a driver of EC-dysfunction that promote atherosclerotic plaque progression and damage to the BBB. Our results indicate that interfering with anti-GRP78 AutoAb:csGRP78 complex can reverse the pathological effects of the AutoAbs. This novel data suggests that patient-derived anti-GRP78 autoantibodies systemically drive pathologies, other than cancer, in vivo.

scholarly journals A host-gut microbial co-metabolite of aromatic amino acids, p-cresol glucuronide, promotes blood-brain barrier integrity in vivo

2022 ◽  
Author(s):  
Andrew V Stachulski ◽  
Tobias B-A Knausenberger ◽  
Sita N Shah ◽  
Lesley Hoyles ◽  
Simon McArthur
Keyword(s):  
Amino Acids ◽  
Blood Brain Barrier ◽  
Aromatic Amino Acids ◽  
Biologically Active ◽  
Brain Barrier ◽  
Whole Brain ◽  
Blood Brain ◽  
Bbb Permeability

Purpose: The sequential activity of gut microbial and host processes can exert a powerful modulatory influence on dietary components, as exemplified by the metabolism of the amino acids tyrosine and phenylalanine to p-cresol by gut microbes, and then to p-cresol glucuronide (pCG) by host enzymes. Although such glucuronide conjugates are classically thought to be biologically inert, there is accumulating evidence that this may not always be the case. We investigated the activity of pCG, studying its interactions with the cerebral vasculature and the brain in vitro and in vivo. Methods: Male C57Bl/6J mice were used to assess blood-brain barrier (BBB) permeability and whole brain transcriptomic changes in response to pCG treatment. Effects were then further explored using the human cerebromicrovascular endothelial cell line hCMEC/D3, assessing paracellular permeability, transendothelial electrical resistance and barrier protein expression. Results: Mice exposed to pCG showed reduced BBB permeability and significant changes in whole brain transcriptome expression. Surprisingly, treatment of hCMEC/D3 cells with pCG had no notable effects until co-administered with bacterial lipopolysaccharide, at which point it was able to prevent the permeabilising effects of endotoxin. Further analysis suggested that pCG acts as an antagonist at the principal lipopolysaccharide receptor TLR4. Conclusion: The amino acid phase II metabolic product pCG is biologically active at the BBB, highlighting the complexity of gut microbe to host communication and the gut-brain axis.

scholarly journals Increase in Blood-Brain Barrier (BBB) Permeability Is Regulated by MMP3 via the ERK Signaling Pathway

2021 ◽  
Vol 2021 ◽  
pp. 1-14
Author(s):  
Qin Zhang ◽  
Mei Zheng ◽  
Cristian E. Betancourt ◽  
Lifeng Liu ◽  
Albert Sitikov ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Erk Signaling ◽  
Anesthesia Induction ◽  
Matrix Metalloproteinase 3 ◽  
Blood Brain ◽  
Bbb Permeability

Background. The blood-brain barrier (BBB) regulates the exchange of molecules between the brain and peripheral blood and is composed primarily of microvascular endothelial cells (BMVECs), which form the lining of cerebral blood vessels and are linked via tight junctions (TJs). The BBB is regulated by components of the extracellular matrix (ECM), and matrix metalloproteinase 3 (MMP3) remodels the ECM’s basal lamina, which forms part of the BBB. Oxidative stress is implicated in activation of MMPs and impaired BBB. Thus, we investigated whether MMP3 modulates BBB permeability. Methods. Experiments included in vivo assessments of isoflurane anesthesia and dye extravasation from brain in wild-type (WT) and MMP3-deficient (MMP3-KO) mice, as well as in vitro assessments of the integrity of monolayers of WT and MMP3-KO BMVECs and the expression of junction proteins. Results. Compared to WT mice, measurements of isoflurane usage and anesthesia induction time were higher in MMP3-KO mice and lower in WT that had been treated with MMP3 (WT+MMP3), while anesthesia emergence times were shorter in MMP3-KO mice and longer in WT+MMP3 mice than in WT. Extravasation of systemically administered dyes was also lower in MMP3-KO mouse brains and higher in WT+MMP3 mouse brains, than in the brains of WT mice. The results from both TEER and Transwell assays indicated that MMP3 deficiency (or inhibition) increased, while MMP3 upregulation reduced barrier integrity in either BMVEC or the coculture. MMP3 deficiency also increased the abundance of TJs and VE-cadherin proteins in BMVECs, and the protein abundance declined when MMP3 activity was upregulated in BMVECs, but not when the cells were treated with an inhibitor of extracellular signal related-kinase (ERK). Conclusion. MMP3 increases BBB permeability following the administration of isoflurane by upregulating the ERK signaling pathway, which subsequently reduces TJ and VE-cadherin proteins in BMVECs.

Modulators of Blood-Brain Barrier (BBB) Permeability: In Vitro and in Vivo Drug Transport to the Brain

2001 ◽  
pp. 83-97
Author(s):  
A. G. De Boer ◽  
P. J. Gaillard ◽  
I. C. J. Van Der Sandt ◽  
E. C. M. De Lange ◽  
D. D. Breimer
Keyword(s):  
Blood Brain Barrier ◽  
Drug Transport ◽  
Brain Barrier ◽  
Blood Brain ◽  
Bbb Permeability ◽  
The Brain

scholarly journals Dual microglia effects on blood brain barrier permeability induced by systemic inflammation

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Koichiro Haruwaka ◽  
Ako Ikegami ◽  
Yoshihisa Tachibana ◽  
Nobuhiko Ohno ◽  
Hiroyuki Konishi ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Systemic Inflammation ◽  
Systemic Disease ◽  
Brain Parenchyma ◽  
Physical Contact ◽  
Brain Barrier ◽  
Blood Brain ◽  
Junction Protein ◽  
Brain Barrier Permeability

AbstractMicroglia survey brain parenchyma, responding to injury and infections. Microglia also respond to systemic disease, but the role of blood–brain barrier (BBB) integrity in this process remains unclear. Using simultaneous in vivo imaging, we demonstrated that systemic inflammation induces CCR5-dependent migration of brain resident microglia to the cerebral vasculature. Vessel-associated microglia initially maintain BBB integrity via expression of the tight-junction protein Claudin-5 and make physical contact with endothelial cells. During sustained inflammation, microglia phagocytose astrocytic end-feet and impair BBB function. Our results show microglia play a dual role in maintaining BBB integrity with implications for elucidating how systemic immune-activation impacts neural functions.

scholarly journals Penetration of the Blood-Brain Barrier by Bacillus anthracis Requires the pXO1-Encoded BslA Protein

2009 ◽  
Vol 191 (23) ◽  
pp. 7165-7173 ◽  
Author(s):  
Celia M. Ebrahimi ◽  
Justin W. Kern ◽  
Tamsin R. Sheen ◽  
Mohammad A. Ebrahimi-Fardooee ◽  
Nina M. van Sorge ◽  
...  
Keyword(s):  
Bacillus Anthracis ◽  
Blood Brain Barrier ◽  
Molecular Mechanisms ◽  
Human Infection ◽  
Brain Barrier ◽  
Brain Infection ◽  
Blood Brain ◽  
Junction Protein

ABSTRACT Anthrax is a zoonotic disease caused by the gram-positive spore-forming bacterium Bacillus anthracis. Human infection occurs after the ingestion, inhalation, or cutaneous inoculation of B. anthracis spores. The subsequent progression of the disease is largely mediated by two native virulence plasmids, pXO1 and pXO2, and is characterized by septicemia, toxemia, and meningitis. In order to produce meningitis, blood-borne bacteria must interact with and breach the blood-brain barrier (BBB) that is composed of a specialized layer of brain microvascular endothelial cells (BMEC). We have recently shown that B. anthracis Sterne is capable of penetrating the BBB in vitro and in vivo, establishing the classic signs of meningitis; however, the molecular mechanisms underlying the central nervous system (CNS) tropism are not known. Here, we show that attachment to and invasion of human BMEC by B. anthracis Sterne is mediated by the pXO1 plasmid and an encoded envelope factor, BslA. The results of studies using complementation analysis, recombinant BslA protein, and heterologous expression demonstrate that BslA is both necessary and sufficient to promote adherence to brain endothelium. Furthermore, mice injected with the BslA-deficient strain exhibited a significant decrease in the frequency of brain infection compared to mice injected with the parental strain. In addition, BslA contributed to BBB breakdown by disrupting tight junction protein ZO-1. Our results identify the pXO1-encoded BslA adhesin as a critical mediator of CNS entry and offer new insights into the pathogenesis of anthrax meningitis.

scholarly journals Functionalised LRP1 targeted carbon nanotubes across the blood-brain barrier in vitro and in vivo after intravenous injection

2019 ◽  
Vol 21 (Supplement_4) ◽  
pp. iv3-iv3
Author(s):  
Julie Wang ◽  
Houmam Kafa ◽  
Noelia Rubio ◽  
Sukhvinder Bansal ◽  
Frederic Festy ◽  
...  
Keyword(s):  
Carbon Nanotubes ◽  
Blood Brain Barrier ◽  
Intravenous Injection ◽  
Brain Parenchyma ◽  
Brain Barrier ◽  
Brain Targeting ◽  
Blood Brain ◽  
The Brain

Abstract Despite extensive research in drug development, brain cancer is still lacking an efficacious cure due to the inability to deliver current therapeutics to the brain across the blood-brain barrier (BBB). Chemically functionalized carbon nanotubes (f-CNT) constitute a novel class of nanomaterials with attractive physical, chemical and electronic properties. The key advantage of f-CNTs is the extremely high surface area to size ratio allowing a high degree of chemical functionalization making them invaluable tools for designing drug delivery systems to the brain. One of the most interesting characteristics of f-CNTs is their ability to translocate across plasma membranes and enter the cells either passively by direct translocation across membranes or actively via endocytosis. Herein, we confirmed the ability of f-CNTs to cross the BBB and reach the brain in in vitro using a co-culture model of PBEC and primary rat astrocytes and in vivo after intravenous injection. Thanks to their unique optical properties, the uptake of f-CNT in brain was confirmed using state-of-the-art spectroscopic imaging techniques such as multi-photon luminescence imaging, fluorescence lifetime microscopy and Raman spectroscopy. Conjugation with angiopep-2 (ANG), a small peptide targeting the LRP1 receptor overexpressed in the BBB and glioma cells, further enhanced brain parenchyma accumulation in healthy brains. Higher uptake in glioma than brain parenchyma was also observed in glioma-bearing mice after intravenous administration. The inherent brain accumulation ability of f-CNTs coupled with improved brain-targeting by ANG favours the future clinical applications of f-CNTs-ANG to deliver active therapeutics for brain glioma therapy.

scholarly journals LC–MS/MS-based in vitro and in vivo investigation of blood–brain barrier integrity by simultaneous quantitation of mannitol and sucrose

2020 ◽  
Vol 17 (1) ◽  
Author(s):  
Behnam Noorani ◽  
Ekram Ahmed Chowdhury ◽  
Faleh Alqahtani ◽  
Yeseul Ahn ◽  
Dhavalkumar Patel ◽  
...  
Keyword(s):  
Molecular Weight ◽  
Stable Isotope ◽  
Blood Brain Barrier ◽  
Critical Role ◽  
Brain Barrier ◽  
Uptake Mechanism ◽  
Blood Brain ◽  
Bbb Permeability

Abstract Background Understanding the pathophysiology of the blood brain–barrier (BBB) plays a critical role in diagnosis and treatment of disease conditions. Applying a sensitive and specific LC–MS/MS technique for the measurement of BBB integrity with high precision, we have recently introduced non-radioactive [13C12]sucrose as a superior marker substance. Comparison of permeability markers with different molecular weight, but otherwise similar physicochemical properties, can provide insights into the uptake mechanism at the BBB. Mannitol is a small hydrophilic, uncharged molecule that is half the size of sucrose. Previously only radioactive [3H]mannitol or [14C]mannitol has been used to measure BBB integrity. Methods We developed a UPLC–MS/MS method for simultaneous analysis of stable isotope-labeled sucrose and mannitol. The in vivo BBB permeability of [13C6]mannitol and [13C12]sucrose was measured in mice, using [13C6]sucrose as a vascular marker to correct for brain intravascular content. Moreover, a Transwell model with induced pluripotent stem cell-derived brain endothelial cells was used to measure the permeability coefficient of sucrose and mannitol in vitro both under control and compromised (in the presence of IL-1β) conditions. Results We found low permeability values for both mannitol and sucrose in vitro (permeability coefficients of 4.99 ± 0.152 × 10−7 and 3.12 ± 0.176 × 10−7 cm/s, respectively) and in vivo (PS products of 0.267 ± 0.021 and 0.126 ± 0.025 µl g−1 min−1, respectively). Further, the in vitro permeability of both markers substantially increased in the presence of IL-1β. Corrected brain concentrations (Cbr), obtained by washout vs. vascular marker correction, were not significantly different for either mannitol (0.071 ± 0.007 and 0.065 ± 0.009 percent injected dose per g) or sucrose (0.035 ± 0.003 and 0.037 ± 0.005 percent injected dose per g). These data also indicate that Cbr and PS product values of mannitol were about twice the corresponding values of sucrose. Conclusions We established a highly sensitive, specific and reproducible approach to simultaneously measure the BBB permeability of two classical low molecular weight, hydrophilic markers in a stable isotope labeled format. This method is now available as a tool to quantify BBB permeability in vitro and in vivo in different disease models, as well as for monitoring treatment outcomes.

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