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

• Published in: Pharmacological reviews Vol. 60; no. 2; pp. 196 - 209
• Main Authors: Miller, David S, Bauer, Björn, Hartz, Anika M S
• Format: Journal Article
• Language: English
• Published: United States American Society for Pharmacology and Experimental Therapeutics 01.06.2008
• Subjects: Animals; ATP-Binding Cassette, Sub-Family B, Member 1 - metabolism; ATP-Binding Cassette, Sub-Family B, Member 1 - physiology; Biological Transport; Blood-Brain Barrier - metabolism; Brain - blood supply; Brain Ischemia - metabolism; Brain Neoplasms - metabolism; Central Nervous System Agents - pharmacology; Encephalitis - metabolism; HIV Infections - metabolism; Humans; Immunity, Innate; Microcirculation - metabolism; Neurodegenerative Diseases - metabolism; Seizures - metabolism; Signal Transduction
• ISSN: 0031-6997; 1521-0081
• DOI: 10.1124/pr.107.07109

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-α, 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.