Modulation of P-glycoprotein Transport Activity in the Mouse Blood-Brain Barrier by Rifampin

2003 ◽  
Vol 306 (2) ◽  
pp. 556-562 ◽  
Author(s):  
Jian Zong ◽  
Gary M. Pollack
Keyword(s):  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Transport Activity ◽  
Mouse Blood ◽  
P Glycoprotein ◽  
Blood Brain ◽  
Glycoprotein Transport

scholarly journals Sphingolipids signal rapid loss of P‐glycoprotein transport activity at the blood‐brain barrier

2012 ◽  
Vol 26 (S1) ◽  
Author(s):  
David S. Miller ◽  
Christopher R. Campos ◽  
Brian T. Hawkins ◽  
Ronald Cannon
Keyword(s):  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Transport Activity ◽  
Rapid Loss ◽  
P Glycoprotein ◽  
Blood Brain ◽  
Glycoprotein Transport

scholarly journals Activating PKC-β1 at the blood—brain barrier reverses induction of P-glycoprotein activity by dioxin and restores drug delivery to the CNS

2011 ◽  
Vol 31 (6) ◽  
pp. 1371-1375 ◽  
Author(s):  
Xueqian Wang ◽  
Brian T Hawkins ◽  
David S Miller
Keyword(s):  
Drug Delivery ◽  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Transport Activity ◽  
Aryl Hydrocarbon ◽  
Kinase C ◽  
P Glycoprotein ◽  
Blood Brain ◽  
Glycoprotein Transport ◽  
The Brain

Upregulation of blood-brain barrier (BBB) P-glycoprotein expression causes central nervous system (CNS) pharmacoresistance. However, activation of BBB protein kinase C-β1 (PKC-β1) rapidly reduces basal P-glycoprotein transport activity. We tested whether PKC-β1 activation would reverse CNS drug resistance caused by dioxin acting through aryl hydrocarbon receptor. A selective PKC-β1 agonist abolished the increase in P-glycoprotein activity induced by dioxin in isolated rat brain capillaries and reversed the effect of dioxin on brain uptake of verapamil in dioxin-dosed rats. Thus, targeting BBB PKC-β1 may be an effective strategy to improve drug delivery to the brain, even in drug-resistant individuals.

scholarly journals Lysophosphatidic acid and amitriptyline signal through LPA1R to reduce P-glycoprotein transport at the blood–brain barrier

2017 ◽  
Vol 38 (5) ◽  
pp. 857-868 ◽  
Author(s):  
David B Banks ◽  
Gary NY Chan ◽  
Rebecca A Evans ◽  
David S Miller ◽  
Ronald E Cannon
Keyword(s):  
Blood Brain Barrier ◽  
Lysophosphatidic Acid ◽  
Brain Parenchyma ◽  
Tricyclic Antidepressant ◽  
Brain Barrier ◽  
Transgenic Rat ◽  
Transport Activity ◽  
P Glycoprotein ◽  
Blood Brain ◽  
Glycoprotein Transport

The blood–brain barrier is a microvascular network that (1) provides neuroprotection from metabolic and environmental toxins and (2) limits the delivery of therapeutics to the central nervous system (CNS). The ATP-binding cassette transporter P-glycoprotein contributes to the latter by actively pumping clinical substrates back into circulation before they can reach the brain parenchyma. Targeting P-glycoprotein has proven effective in increasing the delivery of therapeutics to their cerebral targets. We provide a novel mechanism to achieve this end in functioning, intact rat brain capillaries, whereby the bioactive phospholipid lysophosphatidic acid (LPA) and tricyclic antidepressant (TCA) amitriptyline reduce basal P-glycoprotein transport activity through a distinct lysophosphatidic acid 1 receptor-mediated signaling cascade that requires G-protein coupling, Src kinase, and ERK 1/2. Furthermore, we demonstrate the ability of LPA and TCA amitriptyline to decrease induced P-glycoprotein transport activity in a human SOD1 transgenic rat model of amyotrophic lateral sclerosis. This work may translate to new clinical strategies for increasing the cerebral penetration of therapeutics in patients suffering from CNS diseases marked by exacerbated pharmacoresistance.

St. John’s Wort Constituents Modulate P-glycoprotein Transport Activity at the Blood-Brain Barrier

2010 ◽  
Vol 27 (5) ◽  
pp. 811-822 ◽  
Author(s):  
Melanie Ott ◽  
Miriam Huls ◽  
Michael G. Cornelius ◽  
Gert Fricker
Keyword(s):  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Transport Activity ◽  
St John’S Wort ◽  
St John's Wort ◽  
P Glycoprotein ◽  
Blood Brain ◽  
Glycoprotein Transport

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 Expression, Up-Regulation, and Transport Activity of the Multidrug-Resistance Protein Abcg2 at the Mouse Blood-Brain Barrier

2004 ◽  
Vol 64 (9) ◽  
pp. 3296-3301 ◽  
Author(s):  
Salvatore Cisternino ◽  
Claire Mercier ◽  
Fanchon Bourasset ◽  
Françoise Roux ◽  
Jean-Michel Scherrmann
Keyword(s):  
Multidrug Resistance ◽  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Multidrug Resistance Protein ◽  
Transport Activity ◽  
Mouse Blood ◽  
Blood Brain ◽  
Resistance Protein

scholarly journals Mrp1 is Essential for Sphingolipid Signaling to P-Glycoprotein in Mouse Blood–Brain and Blood–Spinal Cord Barriers

2012 ◽  
Vol 33 (3) ◽  
pp. 381-388 ◽  
Author(s):  
Tara A Cartwright ◽  
Christopher R Campos ◽  
Ronald E Cannon ◽  
David S Miller
Keyword(s):  
Spinal Cord ◽  
Endothelial Cells ◽  
Transport Activity ◽  
Wild Type ◽  
Mouse Blood ◽  
P Glycoprotein ◽  
Blood Brain ◽  
Tnf Α ◽  
Glycoprotein Transport ◽  
Brain And Spinal Cord

At the blood–brain and blood–spinal cord barriers, P-glycoprotein, an ATP-driven drug efflux pump, is a major obstacle to central nervous system (CNS) pharmacotherapy. Recently, we showed that signaling through tumor necrosis factor-α (TNF-α), sphingolipids, and sphingosine-1-phosphate receptor 1 (S1PR1) rapidly and reversibly reduced basal P-glycoprotein transport activity in the rat blood–brain barrier. The present study extends those findings to the mouse blood–brain and blood–spinal cord barriers and, importantly, identifies multidrug resistance-associated protein 1 (Mrp1, Abcc1) as the transporter that mediates S1P efflux from brain and spinal cord endothelial cells. In brain and spinal cord capillaries isolated from wild-type mice, TNF-α, sphingosine, S1P, the S1PR agonist fingolimod (FTY720), and its active, phosphorylated metabolite, FTY720P, reduced P-glycoprotein transport activity; these effects were abolished by a specific S1PR1 antagonist. In brain and spinal cord capillaries isolated from Mrp1-null mice, neither TNF-α nor sphingosine nor FTY720 reduced P-glycoprotein transport activity. However, S1P and FTY720P had the same S1PR1-dependent effects on transport activity as in capillaries from wild-type mice. Thus, deletion of Mrp1 alone terminated endogenous signaling to S1PR1. These results identify Mrp1 as the transporter essential for S1P efflux from the endothelial cells and thus for inside-out S1P signaling to P-glycoprotein at the blood–brain and blood–spinal cord barriers.

Sign in / Sign up

Export Citation Format

Share Document