In vitro and in vivo study of dolichyl phosphate on the efflux activity of P‐glycoprotein at the blood–brain barrier

2013 ◽  
Vol 31 (8) ◽  
pp. 828-835 ◽  
Author(s):  
Bian‐Sheng Ji ◽  
Juan Cen ◽  
Lu Liu ◽  
Ling He
Keyword(s):  
Blood Brain Barrier ◽  
Brain Barrier ◽  
In Vivo Study ◽  
P Glycoprotein ◽  
Dolichyl Phosphate ◽  
Blood Brain

scholarly journals Comparative vulnerability of PET radioligands to partial inhibition of P-glycoprotein at the blood-brain barrier: A criterion of choice?

2021 ◽  
pp. 0271678X2110454
Author(s):  
Louise Breuil ◽  
Solène Marie ◽  
Sébastien Goutal ◽  
Sylvain Auvity ◽  
Charles Truillet ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Pet Imaging ◽  
Brain Barrier ◽  
Maximal Response ◽  
Half Maximum ◽  
Partial Inhibition ◽  
P Glycoprotein ◽  
Blood Brain

Only partial deficiency/inhibition of P-glycoprotein (P-gp, ABCB1) function at the blood-brain barrier (BBB) is likely to occur in pathophysiological situations or drug-drug interactions. This raises questions regarding the sensitivity of available PET imaging probes to detect moderate changes in P-gp function at the living BBB. In vitro, the half-maximum inhibitory concentration (IC50) of the potent P-gp inhibitor tariquidar in P-gp-overexpressing cells was significantly different using either [11C]verapamil (44 nM), [11C] N-desmethyl-loperamide (19 nM) or [11C]metoclopramide (4 nM) as substrate probes. In vivo PET imaging in rats showed that the half-maximum inhibition of P-gp-mediated efflux of [11C]metoclopramide, achieved using 1 mg/kg tariquidar ( in vivo IC50 = 82 nM in plasma), increased brain exposure by 2.1-fold for [11C]metoclopramide (p < 0.05, n = 4) and 2.4-fold for [11C]verapamil (p < 0.05, n = 4), whereby cerebral uptake of the “avid” substrate [11C] N-desmethyl-loperamide was unaffected (p > 0.05, n = 4). This comparative study points to differences in the “vulnerability” to P-gp inhibition among radiolabeled substrates, which were apparently unrelated to their “avidity” (maximal response to P-gp inhibition). Herein, we advocate that partial inhibition of transporter function, in addition to complete inhibition, should be a primary criterion of evaluation regarding the sensitivity of radiolabeled substrates to detect moderate but physiologically-relevant changes in transporter function in vivo.

An in vitro and in vivo study of peptide-functionalized nanoparticles for brain targeting: The importance of selective blood–brain barrier uptake

2017 ◽  
Vol 13 (3) ◽  
pp. 1289-1300 ◽  
Author(s):  
Gerard H. Bode ◽  
Gregory Coué ◽  
Christian Freese ◽  
Karin E. Pickl ◽  
Maria Sanchez-Purrà ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Brain Barrier ◽  
In Vivo Study ◽  
Brain Targeting ◽  
Functionalized Nanoparticles ◽  
Blood Brain

scholarly journals Activation of PKC Isoform βI at the Blood–Brain Barrier Rapidly Decreases P-Glycoprotein Activity and Enhances Drug Delivery to the Brain

2010 ◽  
Vol 30 (7) ◽  
pp. 1373-1383 ◽  
Author(s):  
Robert R Rigor ◽  
Brian T Hawkins ◽  
David S Miller
Keyword(s):  
Rat Brain ◽  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Brain Capillaries ◽  
P Glycoprotein ◽  
Blood Brain ◽  
Tnf Α ◽  
The Brain

P-glycoprotein is an ATP (adenosine triphosphate)-driven drug efflux transporter that is highly expressed at the blood–brain barrier (BBB) and is a major obstacle to the pharmacotherapy of central nervous system diseases, including brain tumors, neuro-AIDS, and epilepsy. Previous studies have shown that P-glycoprotein transport activity in rat brain capillaries is rapidly reduced by the proinflammatory cytokine, tumor necrosis factor-α (TNF-α) acting through protein kinase C (PKC)-dependent signaling. In this study, we used isolated rat brain capillaries to show that the TNF-α-induced reduction of P-glycoprotein activity was prevented by a PKCβI/II inhibitor, LY333531, and mimicked by a PKCβI/II activator, 12-deoxyphorbol-13-phenylacetate-20-acetate (dPPA). Western blotting of brain capillary extracts with phospho-specific antibodies showed that dPPA activated PKCβI, but not PKCβII. Moreover, in intact rats, intracarotid infusion of dPPA potently increased brain accumulation of the P-glycoprotein substrate, [3H]-verapamil without compromising tight junction integrity. Thus, PKCβI activation selectively reduced P-glycoprotein activity both in vitro and in vivo. Targeting PKCβI at the BBB may prove to be an effective strategy for enhancing the delivery of small molecule therapeutics to the brain.

scholarly journals PEGylation of Reduced Graphene Oxide Induces Toxicity in Cells of the Blood–Brain Barrier: An in Vitro and in Vivo Study

2016 ◽  
Vol 13 (11) ◽  
pp. 3913-3924 ◽  
Author(s):  
Monique Culturato Padilha Mendonça ◽  
Edilene Siqueira Soares ◽  
Marcelo Bispo de Jesus ◽  
Helder José Ceragioli ◽  
Ângela Giovana Batista ◽  
...  
Keyword(s):  
Graphene Oxide ◽  
Reduced Graphene Oxide ◽  
Blood Brain Barrier ◽  
Brain Barrier ◽  
In Vivo Study ◽  
Blood Brain ◽  
Reduced Graphene ◽  
In Cells

In vivo and in vitro evidence for ATP-dependency of P-glycoprotein-mediated efflux of doxorubicin at the blood-brain barrier

1995 ◽  
Vol 49 (10) ◽  
pp. 1541-1544 ◽  
Author(s):  
Toshimasa Ohnishi ◽  
Ikumi Tamai ◽  
Koji Sakanaka ◽  
Atsushi Sakata ◽  
Tetsumori Yamashima ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Brain Barrier ◽  
P Glycoprotein ◽  
Blood Brain

Activation of PKC modulates blood-brain barrier endothelial cell permeability changes induced by hypoxia and posthypoxic reoxygenation

2005 ◽  
Vol 289 (5) ◽  
pp. H2012-H2019 ◽  
Author(s):  
Melissa A. Fleegal ◽  
Sharon Hom ◽  
Lindsay K. Borg ◽  
Thomas P. Davis
Keyword(s):  
Blood Brain Barrier ◽  
Paracellular Permeability ◽  
Cell Permeability ◽  
Brain Barrier ◽  
Cerebral Microvessels ◽  
Permeability Changes ◽  
Blood Brain ◽  
Brain Microvessel

The blood-brain barrier (BBB) is a metabolic and physiological barrier important for maintaining brain homeostasis. The aim of this study was to determine the role of PKC activation in BBB paracellular permeability changes induced by hypoxia and posthypoxic reoxygenation using in vitro and in vivo BBB models. In rat brain microvessel endothelial cells (RMECs) exposed to hypoxia (1% O2-99% N2; 24 h), a significant increase in total PKC activity was observed, and this was reduced by posthypoxic reoxygenation (95% room air-5% CO2) for 2 h. The expression of PKC-βII, PKC-γ, PKC-η, PKC-μ, and PKC-λ also increased following hypoxia (1% O2-99% N2; 24 h), and these protein levels remained elevated following posthypoxic reoxygenation (95% room air-5% CO2; 2 h). Increases in the expression of PKC-ε and PKC-ζ were also observed following posthypoxic reoxygenation (95% room air-5% CO2; 2 h). Moreover, inhibition of PKC with chelerythrine chloride (10 μM) attenuated the hypoxia-induced increases in [14C]sucrose permeability. Similar to what was observed in RMECs, total PKC activity was also stimulated in cerebral microvessels isolated from rats exposed to hypoxia (6% O2-94% N2; 1 h) and posthypoxic reoxygenation (room air; 10 min). In contrast, hypoxia (6% O2-94% N2; 1 h) and posthypoxic reoxygenation (room air; 10 min) significantly increased the expression levels of only PKC-γ and PKC-θ in the in vivo hypoxia model. These data demonstrate that hypoxia-induced BBB paracellular permeability changes occur via a PKC-dependent mechanism, possibly by differentially regulating the protein expression of the 11 PKC isozymes.

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