Development of a P-Glycoprotein Knockout Model in Rodents to Define Species Differences in its Functional Effect at the Blood–brain Barrier

2006 ◽  
Vol 95 (9) ◽  
pp. 1944-1953 ◽  
Author(s):  
Leanne Cutler ◽  
Colin Howes ◽  
Nigel J. Deeks ◽  
Tania L. Buck ◽  
Phil Jeffrey
Keyword(s):  
Blood Brain Barrier ◽  
Species Differences ◽  
Brain Barrier ◽  
Functional Effect ◽  
P Glycoprotein ◽  
Blood Brain ◽  
Knockout Model

scholarly journals Approaching Complete Inhibition of P-Glycoprotein at the Human Blood–Brain Barrier: An (R)-[11C]Verapamil PET Study

2015 ◽  
Vol 35 (5) ◽  
pp. 743-746 ◽  
Author(s):  
Martin Bauer ◽  
Rudolf Karch ◽  
Markus Zeitlinger ◽  
Cécile Philippe ◽  
Kerstin Römermann ◽  
...  
Keyword(s):  
Positron Emission Tomography ◽  
Blood Brain Barrier ◽  
Distribution Volume ◽  
Emission Tomography ◽  
Brain Barrier ◽  
Whole Brain ◽  
P Glycoprotein ◽  
Blood Brain ◽  
Positron Emission ◽  
Pet Scans

As P-glycoprotein (Pgp) inhibition at the blood–brain barrier (BBB) after administration of a single dose of tariquidar is transient, we performed positron emission tomography (PET) scans with the Pgp substrate ( R)-[11C]verapamil in five healthy volunteers during continuous intravenous tariquidar infusion. Total distribution volume ( VT) of ( R)-[11C]verapamil in whole-brain gray matter increased by 273 ± 78% relative to baseline scans without tariquidar, which was higher than previously reported VT increases. During tariquidar infusion whole-brain VT was comparable to VT in the pituitary gland, a region not protected by the BBB, which suggested that we were approaching complete Pgp inhibition at the human BBB.

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.

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