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Rapid Modulation of P-Glycoprotein-Mediated Transport at the Blood-Brain Barrier by Tumor Necrosis Factor- and Lipopolysaccharide

Laboratory of Pharmacology and Chemistry, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina (A.M.S.H., B.B., D.S.M.); and Institute for Pharmacy and Molecular Biotechnology, University of Heidelberg, Heidelberg, Germany (A.M.S.H., G.F.)

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 ET_B 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- (TNF-), activated a TNF-R1 receptor, released ET-1, activated ET_B 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- release, ET-1 release, and ET_B receptor signaling. TNF- 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.

Address correspondence to: Dr. David S. Miller, Laboratory of Pharmacology and Chemistry, National Institute of Environmental Health Sciences, National Institutes of Health, 111 TW Alexander Drive, Research Triangle Park, NC 27709. E-mail: miller{at}niehs.nih.gov

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