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Published online before print June 17, 2008

0031-6997/08/6002-196-209$7.00
Pharmacol Rev 60:196-209, 2008

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Modulation of P-Glycoprotein at the Blood-Brain Barrier: Opportunities to Improve Central Nervous System Pharmacotherapy

David S. Miller, Björn Bauer and Anika M. S. Hartz

Laboratory of Pharmacology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina (D.S.M., B.B., A.M.S.H.); and College of Pharmacy (B.B.) and Medical School (A.M.S.H.), University of Minnesota, Duluth, Minnesota

Abstract
I. Introduction
II. The Blood-Brain Barrier
    A. The Structural/Physical Barrier
    B. The Selective/Biochemical Barrier
III. P-glycoprotein, a Critical Element of the Selective/Biochemical Barrier
IV. Modulation of P-Glycoprotein Transport Activity
    A. In the Periphery
    B. At the Blood-Brain Barrier
        1. Ligand-Activated Nuclear Receptors.
        2. Inflammation.
        3. Oxidative Stress/Ischemia.
        4. Seizures.
        5. Brain Cancer.
        6. HIV-1.
        7. Neurodegenerative Diseases.
V. Perspectives
Pharmacotherapy of central nervous system (CNS) disorders (e.g., neurodegenerative diseases, epilepsy, brain cancer, and neuro-AIDS) is limited by the blood-brain barrier. P-glycoprotein, an ATP-driven, drug efflux transporter, is a critical element of that barrier. High level of expression, luminal membrane location, multispecificity, and high transport potency make P-glycoprotein a selective gatekeeper of the blood-brain barrier and thus a primary obstacle to drug delivery into the brain. As such, P-glycoprotein limits entry into the CNS for a large number of prescribed drugs, contributes to the poor success rate of CNS drug candidates, and probably contributes to patient-to-patient variability in response to CNS pharmacotherapy. Modulating P-glycoprotein could therefore improve drug delivery into the brain. Here we review the current understanding of signaling mechanisms responsible for the modulation of P-glycoprotein activity/expression at the blood-brain barrier with an emphasis on recent studies from our laboratories. Using intact brain capillaries from rats and mice, we have identified multiple extracellular and intracellular signals that regulate this transporter; several signaling pathways have been mapped. Three pathways are triggered by elements of the brain's innate immune response, one by glutamate, one by xenobiotic-nuclear receptor (pregnane X receptor) interactions, and one by elevated β-amyloid levels. Signaling is complex, with several pathways sharing common signaling elements [tumor necrosis factor (TNF) receptor 1, endothelin (ET) B receptor, protein kinase C, and nitric-oxide synthase), suggesting a regulatory network. Several pathways include autocrine/paracrine elements, involving release of the proinflammatory cytokine, TNF-{alpha}, and the polypeptide hormone, ET-1. Finally, several steps in signaling are potential therapeutic targets that could be used to modulate P-glycoprotein activity in the clinic.

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






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