P-glycoprotein trafficking as a therapeutic target to optimize CNS drug delivery

Thomas P Davis, Lucy Sanchez-Covarubias, Margaret E Tome

Research output: Contribution to journalArticle

24 Scopus citations

Abstract

The primary function of the blood-brain barrier (BBB)/neurovascular unit is to protect the central nervous system (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 colocalizes with P-gp at the luminal membrane of brain microvessels. Changes in colocalization with the phosphorylated and nonphosphorylated 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.

Original languageEnglish (US)
Pages (from-to)25-44
Number of pages20
JournalAdvances in Pharmacology
Volume71
DOIs
Publication statusPublished - 2014

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Keywords

  • ATP-binding cassette transporter
  • Blood-brain barrier
  • Drug delivery
  • Neurovascular unit
  • P-glycoprotein
  • Peripheral inflammatory pain
  • Protein trafficking
  • Reactive oxygen species
  • Redox-sensitive protein pools

ASJC Scopus subject areas

  • Pharmacology

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