P‐glycoprotein trafficking at the blood–brain barrier altered by peripheral inflammatory hyperalgesia

McCaffrey, Gwen; Staatz, William D.; Sanchez-Covarrubias, Lucy; Finch, Jessica D.; Demarco, Kristen; Laracuente, Mei Li; Ronaldson, Patrick T.; Davis, Thomas P.

doi:10.1111/j.1471-4159.2012.07831.x

Cited by 71 publications

(87 citation statements)

References 68 publications

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“…Alterations in caveolar protein or lipid composition will impact signaling events during PIP including PgP activation. Each of these trafficking events may contribute to the PgP activity increase during PIP we reported previously 11 and provide an explanation for the physiological observation that CNS morphine efficacy decreases after PIP. 5 The combination of an increase in PgP at the endothelial cell luminal surface concomitant with a decrease in PgP in the nuclear compartment after PIP suggests we are measuring a protein trafficking event.…”

Section: Discussionsupporting

confidence: 57%

“…Use of an acute PIP model, 3 h after a carrageenan (CAR) injection in the rat paw compared with a saline (SAL)-injected control, allows us to measure post-translational PgP alterations in vivo. Our previous studies using this model indicate that PIP increases PgP activity in BBB endothelial cells 11 concomitant with decreased morphine efficacy and accumulation in the brain. 5 PIP also causes a redistribution of PgP in BBB endothelial membrane fractions.…”

Section: Introductionmentioning

confidence: 91%

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P-glycoprotein traffics from the nucleus to the plasma membrane in rat brain endothelium during inflammatory pain

Tome

Herndon

Schaefer

et al. 2016

J Cereb Blood Flow Metab

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P-glycoprotein (PgP), a drug efflux pump in blood-brain barrier endothelial cells, is a major clinical obstacle for effective central nervous system drug delivery. Identifying PgP regulatory pathways that can be exploited clinically is critical for improving central nervous system drug delivery. We previously found that PgP activity increases in rat brain microvessels concomitant with decreased central nervous system drug delivery in response to acute peripheral inflammatory pain. In the current study, we tested the hypothesis that PgP traffics to the luminal plasma membrane of the microvessel endothelial cells from intracellular stores during peripheral inflammatory pain. Using immunofluorescence microscopy, we detected PgP in endothelial cell nuclei and in the luminal plasma membrane in control animals. Following peripheral inflammatory pain, luminal PgP staining increased while staining in the nucleus decreased. Biochemical analysis of nuclear PgP content confirmed our visual observations. Peripheral inflammatory pain also increased endothelial cell luminal staining of polymerase 1 and transcript release factor/cavin1 and serum deprivation response protein/cavin2, two caveolar scaffold proteins, without changing caveolin1 or protein kinase C delta binding protein/cavin3 location. Our data (a) indicate that PgP traffics from stores in the nucleus to the endothelial cell luminal membrane in response to peripheral inflammatory pain; (b) provide an explanation for our previous observation that peripheral inflammatory pain inhibits central nervous system drug uptake; and (c) suggest a novel regulatory mechanism for PgP activity in rat brain. KeywordsCaveolin1, P-glycoprotein, protein kinase C delta binding protein/cavin3, polymerase 1 and transcript release factor/ cavin1, serum deprivation response protein/cavin2, trafficking

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Section: Discussionsupporting

confidence: 57%

Section: Introductionmentioning

confidence: 91%

P-glycoprotein traffics from the nucleus to the plasma membrane in rat brain endothelium during inflammatory pain

Tome

Herndon

Schaefer

et al. 2016

J Cereb Blood Flow Metab

View full text Add to dashboard Cite

show abstract

“…It is possible that mediators released during the course of these diseases (e.g., inflammatory cytokines, chemokines, ROS) may have affected BBB transporter expression in these subjects. As demonstrated by our group, presence of a pathologic stressor in the periphery can have dramatic effects on BBB transporter expression and, subsequently, CNS drug delivery (Hau et al, 2004;Seelbach et al, 2007;Lochhead et al, 2012;McCaffrey et al, 2012). Therefore, these proteomic data cannot be interpreted to suggest that OATP family members are absent from the human BBB or that these transporters do not represent viable targets for optimization of CNS drug delivery.…”

Section: A Blood-brain Barriermentioning

confidence: 90%

Targeted Drug Delivery to Treat Pain and Cerebral Hypoxia

Ronaldson

Davis

2013

Pharmacol Rev

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“…Accumulated research suggests that P-gp affects CNS drug uptake in a plethora of diseases including inflammation, pain, epilepsy, HIV, brain cancer (Seelbach et al, 2007; McCaffrey et al, 2012; Miller et al, 2008; Zhang et al, 2012) and cerebral ischemia (Spudich et al, 2006; Miller et al, 2008 and Thompson & Ronaldson in the current volume). These data support a role for P-gp in treatment response.…”

Section: Inhibition Of Brain Barrier Efflux Transportersmentioning

confidence: 97%

P-glycoprotein Trafficking as a Therapeutic Target to Optimize CNS Drug Delivery

Davis

Sanchez-Covarubias

Tome

2014

Advances in Pharmacology

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The primary function of the blood-brain barrier (BBB) /neurovascular unit is to protect the CNS from potentially harmful xenobiotic substances and maintain CNS homeostasis. Restricted access to the CNS is maintained via a combination of tight junction proteins as well as a variety of efflux and influx transporters that limits the transcellular and paracellular movement of solutes. Of the transporters identified at the BBB, P-glycoprotein (P-gp) has emerged as the transporter that is the greatest obstacle to effective CNS drug delivery. In this chapter we provide data to support intracellular protein trafficking of P-gp within cerebral capillary microvessels as a potential target for improved drug delivery. We show that pain induced changes in P-gp trafficking are associated with changes in P-gp’s association with caveolin-1, a key scaffolding/trafficking protein that co-localizes with P-gp at the luminal membrane of brain microvessels. Changes in co-localization with the phosphorylated and non-phosphorylated forms of caveolin-1, by pain, are accompanied by dynamic changes in the distribution, relocalization and activation of P-gp “pools” between microvascular endothelial cell subcellular compartments. Since redox sensitive processes may be involved in signaling disassembly of higher order structures of P-gp, we feel that manipulating redox signaling, via specific protein targeting at the BBB, may protect disulfide bond integrity of P-gp reservoirs and control trafficking to the membrane surface providing improved CNS drug delivery. The advantage of therapeutic drug “relocalization” of a protein is that the physiological impact can be modified, temporarily or long term, despite pathology-induced changes in gene transcription.

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P‐glycoprotein trafficking at the blood–brain barrier altered by peripheral inflammatory hyperalgesia

Cited by 71 publications

References 68 publications

P-glycoprotein traffics from the nucleus to the plasma membrane in rat brain endothelium during inflammatory pain

P-glycoprotein traffics from the nucleus to the plasma membrane in rat brain endothelium during inflammatory pain

Targeted Drug Delivery to Treat Pain and Cerebral Hypoxia

P-glycoprotein Trafficking as a Therapeutic Target to Optimize CNS Drug Delivery

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