scholarly journals In vivo and ex vivo regulation of breast cancer resistant protein (Bcrp) by peroxisome proliferator-activated receptor alpha (Pparα) at the blood-brain barrier

2015 ◽  
Vol 135 (6) ◽  
pp. 1113-1122 ◽  
Author(s):  
Md. Tozammel Hoque ◽  
Arpit Shah ◽  
Vijay More ◽  
David S. Miller ◽  
Reina Bendayan
Keyword(s):  
Breast Cancer ◽  
Blood Brain Barrier ◽  
Ex Vivo ◽  
Brain Barrier ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Receptor Alpha ◽  
Breast Cancer Resistant Protein ◽  
Blood Brain

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 Tariquidar, a Selective P-glycoprotein Inhibitor, Does Not Potentiate Loperamide’s Opioid Brain Effects in Humans despite Full Inhibition of Lymphocyte P-glycoprotein

2008 ◽  
Vol 109 (6) ◽  
pp. 1092-1099 ◽  
Author(s):  
Daniel Kurnik ◽  
Gbenga G. Sofowora ◽  
John P. Donahue ◽  
Usha B. Nair ◽  
Grant R. Wilkinson ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Pupil Diameter ◽  
Ex Vivo ◽  
Area Under The Curve ◽  
Brain Barrier ◽  
Double Blind ◽  
P Glycoprotein ◽  
Blood Brain ◽  
Double Blind Crossover Study

Background Loperamide, a potent opioid, has been used as an in vivo probe to assess P-glycoprotein activity at the blood-brain barrier, because P-glycoprotein inhibition allows loperamide to cross the blood-brain barrier and exert its central opioid effects. In humans, studies with nonselective and moderately potent inhibitors resulted in mild opioid effects but were confounded by the concurrent inhibition of loperamide's metabolism. The authors studied the effect of the highly selective, potent P-glycoprotein inhibitor tariquidar on loperamide's central opioid effects. Methods In a randomized, double-blind, crossover study, nine healthy subjects received on 2 study days oral loperamide (32 mg) followed by an intravenous infusion of either tariquidar (150 mg) or placebo. Central opioid effects (pupil diameter, sedation) were measured for 12 h, and blood samples were drawn up to 48 h after drug administration to determine plasma loperamide concentrations and ex vivo P-glycoprotein activity in T lymphocytes. Values for pupil diameter and loperamide concentrations were plotted over time, and the areas under the curves on the tariquidar and placebo study day were compared within each subject. Results Tariquidar did not significantly affect loperamide's central effects (median reduction in pupil diameter area under the curve, 6.9% [interquartile range, -1.4 to 12.1%]; P = 0.11) or plasma loperamide concentrations (P = 0.12) but profoundly inhibited P-glycoprotein in lymphocytes by 93.7% (95% confidence interval, 92.0-95.3%). Conclusion These results suggest that despite full inhibition of lymphocyte P-glycoprotein, the selective P-glycoprotein inhibitor tariquidar does not potentiate loperamide's opioid brain effects in humans.

scholarly journals Dynamic Analysis of the Blood-Brain Barrier Disruption in Experimental Stroke Using Time Domain in Vivo Fluorescence Imaging

2008 ◽  
Vol 7 (6) ◽  
pp. 7290.2008.00025 ◽  
Author(s):  
Abedelnasser Abulrob ◽  
Eric Brunette ◽  
Jacqueline Slinn ◽  
Ewa Baumann ◽  
Danica Stanimirovic
Keyword(s):  
Optical Imaging ◽  
Contrast Enhancement ◽  
Blood Brain Barrier ◽  
Time Domain ◽  
Near Infrared ◽  
Ex Vivo ◽  
Brain Barrier ◽  
Experimental Stroke ◽  
Blood Brain

The blood-brain barrier (BBB) disruption following cerebral ischemia can be exploited to deliver imaging agents and therapeutics into the brain. The aim of this study was (a) to establish novel in vivo optical imaging methods for longitudinal assessment of the BBB disruption and (b) to assess size selectivity and temporal patterns of the BBB disruption after a transient focal ischemia. The BBB permeability was assessed using in vivo time domain near-infrared optical imaging after contrast enhancement with either free Cy5.5 (1 kDa) or Cy5.5 conjugated with bovine serum albumin (BSA) (67 kDa) in mice subjected to either 60- or 20-minute transient middle cerebral artery occlusion (MCAO) and various times of reperfusion (up to 14 days). In vivo imaging observations were corroborated by ex vivo brain imaging and microscopic analyses of fluorescent tracer extravasation. The in vivo optical contrast enhancement with Cy5.5 was spatially larger than that observed with BSA-Cy5.5. Longitudinal studies after a transient 20-minute MCAO suggested a bilateral BBB disruption, more pronounced in the ipsilateral hemisphere, peaking at day 7 and resolving at day 14 after ischemia. The area differential between the BBB disruption for small and large molecules could potentially be useful as a surrogate imaging marker for assessing perinfarct tissues to which neuroprotective therapies of appropriate sizes could be delivered.

scholarly journals Ex vivo Evans blue assessment of the blood brain barrier in three breast cancer brain metastasis models

2014 ◽  
Vol 144 (1) ◽  
pp. 93-101 ◽  
Author(s):  
John Do ◽  
Deshka Foster ◽  
Corinne Renier ◽  
Hannes Vogel ◽  
Sahar Rosenblum ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Brain Metastasis ◽  
Blood Brain Barrier ◽  
Evans Blue ◽  
Ex Vivo ◽  
Brain Barrier ◽  
Blood Brain ◽  
Breast Cancer Brain Metastasis ◽  
Metastasis Models
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