scholarly journals Oral Ursodeoxycholic acid crosses the blood brain barrier in patients with retinal detachment and protects against retinal degeneration in an ex vivo model

2022 ◽  
Vol 100 (S267) ◽  
Author(s):  
Alejandra Daruich‐Matet ◽  
Thara Jaworski ◽  
Hugues Henry ◽  
Marta Zola ◽  
Jenny Youale ◽  
...  
Keyword(s):  
Retinal Detachment ◽  
Ursodeoxycholic Acid ◽  
Retinal Degeneration ◽  
Blood Brain Barrier ◽  
Ex Vivo ◽  
Brain Barrier ◽  
Ex Vivo Model ◽  
Blood Brain

Regulation by cannabinoid receptors of anandamide transport across the blood-brain barrier and through other endothelial cells

2006 ◽  
Vol 95 (01) ◽  
pp. 117-127 ◽  
Author(s):  
Anna Fiori ◽  
Monica Bari ◽  
Filippo Granata ◽  
Valeria Gasperi ◽  
M. De Stefano ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Blood Brain Barrier ◽  
Cannabinoid Receptors ◽  
Ex Vivo ◽  
Acid Amide ◽  
Brain Barrier ◽  
No Production ◽  
Ex Vivo Model ◽  
Subsequent Increase ◽  
Blood Brain

SummaryThe endocannabinoid anandamide (AEA) has many neurovascular activities. However, it is not yet clear how AEA can be metabolized at the neurovascular interface, and how it can move through the vascular and the cerebral compartments. The results reported in this article show that isolated bovine brain microvessels, an ex vivo model of the blood-brain barrier, have detectable levels of endogenous AEA and possess the biochemical machinery to bind and metabolize it, i. e. type-1 and type-2 cannabinoid receptors (CB1R and CB2R), a selective AEA membrane transporter (AMT), an AEA-degrading fatty acid amide hydrolase, and the AEA-synthesizing enzymes N-acyltransferase and N-acyl-phosphatidylethanolamines-specific phospholipase D. We also show that activation of CB1R enhances AMT activity through increased nitric oxide synthase (NOS) activity and subsequent increase of NO production. AMT activity is instead reduced by activation of CB2R, which inhibits NOS and NO release. In addition, binding experiments and immunoelectronmicroscopy demonstrate that different endothelial cells vary in the expression of CB1R and CB2R on the luminal and/or abluminal sides. The different localization of CBRs can lead to a diverse effect on AMT activity on the luminal and abluminal membranes, suggesting that the distribution of these receptors may drive AEA directional transport through the blood-brain barrier and other endothelial cells.

scholarly journals 17-β-Estradiol: A Powerful Modulator of Blood–Brain Barrier BCRP Activity

2010 ◽  
Vol 30 (10) ◽  
pp. 1742-1755 ◽  
Author(s):  
Anika MS Hartz ◽  
Anne Mahringer ◽  
David S Miller ◽  
Björn Bauer
Keyword(s):  
Blood Brain Barrier ◽  
Ex Vivo ◽  
Brain Barrier ◽  
Cancer Resistance ◽  
Transport Activity ◽  
Brain Capillaries ◽  
Therapeutic Drugs ◽  
Blood Brain ◽  
Capillary Membranes ◽  
Blood Brain Barrier Model

The ATP-driven efflux transporter, breast cancer resistance protein (BCRP), handles many therapeutic drugs, including chemotherapeutics, limiting their ability to cross the blood–brain barrier. This study provides new insight into rapid, nongenomic regulation of BCRP transport activity at the blood–brain barrier. Using isolated brain capillaries from rats and mice as an ex vivo blood–brain barrier model, we show that BCRP protein is highly expressed in brain capillary membranes and functionally active in intact capillaries. We show that nanomolar concentrations of 17-β-estradiol (E2) rapidly reduced BCRP transport activity in the brain capillaries. This E2-mediated effect occurred within minutes and did not involve transcription, translation, or proteasomal degradation, indicating a nongenomic mechanism. Removing E2 after 1 h fully reversed the loss of BCRP activity. Experiments using agonists and antagonists for estrogen receptor (ER)α and ERβ and brain capillaries from ERα and ERβ knockout mice demonstrated that E2 could signal through either receptor to reduce BCRP transport function. We speculate that this nongenomic E2-signaling pathway could potentially be used for targeting BCRP at the blood–brain barrier, in brain tumors, and in brain tumor stem cells to improve chemotherapy of the central nervous system.

scholarly journals 2,4,6-Tribromophenol Exposure Decreases P-Glycoprotein Transport at the Blood-Brain Barrier

2019 ◽  
Vol 171 (2) ◽  
pp. 463-472 ◽  
Author(s):  
Andrew W Trexler ◽  
Gabriel A Knudsen ◽  
Sascha C T Nicklisch ◽  
Linda S Birnbaum ◽  
Ronald E Cannon
Keyword(s):  
Blood Brain Barrier ◽  
Ex Vivo ◽  
Female Rats ◽  
Brain Barrier ◽  
Transport Activity ◽  
Fish Food ◽  
P Glycoprotein ◽  
Blood Brain ◽  
Male And Female Rats

Abstract 2,4,6-Tribromophenol (TBP, CAS No. 118-79-6) is a brominated chemical used in the production of flame-retardant epoxy resins and as a wood preservative. In marine environments, TBP is incorporated into shellfish and consumed by predatory fish. Food processing and water treatment facilities produce TBP as a byproduct. 2,4,6-Tribromophenol has been detected in human blood and breast milk. Biologically, TBP interferes with estrogen and thyroid hormone signaling, which regulate important transporters of the blood-brain barrier (BBB). The BBB is a selectively permeable barrier characterized by brain microvessels which are composed of endothelial cells mortared by tight-junction proteins. ATP-binding cassette (ABC) efflux transporters on the luminal membrane facilitate the removal of unwanted endobiotics and xenobiotics from the brain. In this study, we examined the in vivo and ex vivo effects of TBP on two important transporters of the BBB: P-glycoprotein (P-gp, ABCB1) and Multidrug Resistance-associated Protein 2 (MRP2, ABCC2), using male and female rats and mice. 2,4,6-Tribromophenol exposure ex vivo resulted in a time- (1–3 h) and dose- (1–100 nM) dependent decrease in P-gp transport activity. MRP2 transport activity was unchanged under identical conditions. Immunofluorescence and western blotting measured decreases in P-gp expression after TBP treatment. ATPase assays indicate that TBP is not a substrate and does not directly interact with P-gp. In vivo dosing with TBP (0.4 µmol/kg) produced decreases in P-gp transport. Co-treatment with selective protein kinase C (PKC) inhibitors prevented the TBP-mediated decreases in P-gp transport activity.

scholarly journals EXTH-67. IDENTIFICATION AND DEVELOPMENT OF NEURAL ECM-BINDING LAMPREY ANTIBODIES (VARIABLE LYMPHOCYTE RECEPTORS) THAT TARGET GLIOBLASTOMA

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi96-vi96
Author(s):  
Benjamin Umlauf ◽  
Paul Clark ◽  
Jason Lajoie ◽  
Julia Georgieva ◽  
Samantha Bremner ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Ex Vivo ◽  
High Specificity ◽  
Recognition System ◽  
Brain Barrier ◽  
Disease Markers ◽  
Blood Brain ◽  
Lymphocyte Receptors

Abstract INTRODUCTION The median survival of glioblastoma (GBM) patients remains less than two years even with state-of-the-art treatment. Current targeted GBM therapies demonstrate initial therapeutic benefit; however, patients relapse due to therapeutic selection of treatment resistant GBM cellular populations. Therefore, we propose targeting pathologic disruption of the blood brain barrier (BBB) via exposure of neural ECM, rather than disease markers, to overcome therapy-resistant GBM. METHODS We identify Variable Lymphocyte Receptors (VLRs, the antigen recognition system used by lamprey) that demonstrate high specificity for neural ECM. Candidate VLRs underwent further refinement using in vitro binding assays and ex vivo tissue staining. Utilizing pathologic disruption of BBB as an approach for targeting GBM was confirmed in vivo using intracranial murine glioblastoma models. RESULTS The lead neural ECM-binding VLR candidate, named P1C10, demonstrates diffuse binding to parenchymal neural ECM, without detectable binding to other tissues. P1C10 demonstrates nanomolar affinity for in vitro derived neural ECM, and preferentially accumulates at intracranial GL261 and U87 lesions in murine GBM models. Finally, administration of P1C10-targeted doxorubicin-loaded liposomes significantly extends the survival of mice bearing intracranial U87 GBM. CONCLUSIONS We identified VLRs that bind neural ECM, and demonstrate their utility for delivering compounds and nanoparticles to sites of GBM induced blood brain barrier disruption. This novel strategy allows for targeting therapeutics via the underlying physiology of GBM rather than relying on cellular disease markers that are often lost in patients that relapse after targeting therapies.

scholarly journals The Size of Blood–Brain Barrier Opening Induced by Focused Ultrasound is Dictated by the Acoustic Pressure

2014 ◽  
Vol 34 (7) ◽  
pp. 1197-1204 ◽  
Author(s):  
Hong Chen ◽  
Elisa E Konofagou
Keyword(s):  
Blood Brain Barrier ◽  
Focused Ultrasound ◽  
Acoustic Pressure ◽  
Ex Vivo ◽  
Brain Barrier ◽  
Hydrodynamic Diameter ◽  
Molecular Weights ◽  
Blood Brain ◽  
Cavitation Detection ◽  
Bbb Opening

Focused ultrasound (FUS) in combination with microbubbles (MBs) has been successfully used in the delivery of various-size therapeutic agents across the blood–brain barrier (BBB). This study revealed that FUS-induced BBB opening size, defined by the size of the largest molecule that can permeate through the BBB, can be controlled by the acoustic pressure as dictated by cavitational mechanisms. Focused ultrasound was applied onto the mouse hippocampus in the presence of systemically administered MBs for trans-BBB delivery of fluorescently labeled dextrans with molecular weights 3 to 2,000 kDa (hydrodynamic diameter: 2.3 to 54.4 nm). The dextran delivery outcomes were evaluated using ex vivo fluorescence imaging. Cavitation detection was employed to monitor the MB cavitation activity associated with the delivery of these agents. It was found that the BBB opening size was smaller than 3 kDa (2.3 nm) at 0.31 MPa, up to 70 kDa (10.2 nm) at 0.51 MPa, and up to 2,000 kDa (54.4 nm) at 0.84 MPa. Relatively smaller opening size (up to 70 kDa) was achieved with stable cavitation only; however, inertial cavitation was associated with relatively larger BBB opening size (above 500 kDa). These findings indicate that the BBB opening size can be controlled by the acoustic pressure and predicted using cavitation detection.

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