Rapid modulation of P-glycoprotein-mediated transport at the blood-brain barrier by tumor necrosis factor-α and lipopolysaccharide

Anika M.S. Hartz, Björn Bauer, Gert Fricker, David S. Miller

Research output: Contribution to journalArticlepeer-review

177 Scopus citations

Abstract

At the blood-brain barrier, P-glycoprotein, an ATP-driven drug efflux pump, selectively limits drug access to the brain parenchyma, impeding pharmacotherapy of a number of central nervous system (CNS) disorders. We previously used confocal imaging to demonstrate in isolated rat brain capillaries that endothelin-1 (ET-1), acting through an ETB receptor, NO synthase, and protein kinase C, rapidly and reversibly reduces P-glycoprotein transport function. In this study, we define a link between the brain's innate immune response and functional regulation of P-glycoprotein. We show that exposing brain capillaries to the inflammatory cytokine tumor necrosis factor-α (TNF-α), activated a TNF-R1 receptor, released ET-1, activated ETB receptor signaling, and essentially abolished P-glycoprotein-mediated transport. Bacterial lipopolysaccharide, a potent activator of the brain's innate immune response, reduced P-glycoprotein activity through TNF-α release, ET-1 release, and ETB receptor signaling. TNF-α and LPS effects had a rapid onset (minutes), were reversible, and did not involve changes in tight junctional permeability. These findings define a signaling pathway through which P-glycoprotein activity is acutely modulated. They show that this key component of the selective/active blood-brain barrier is an early target of cytokine signaling during the innate immune response and suggest ways to manipulate the barrier for improved CNS pharmacotherapy.

Original languageEnglish
Pages (from-to)462-470
Number of pages9
JournalMolecular Pharmacology
Volume69
Issue number2
DOIs
StatePublished - 2006

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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