Confocal imaging of xenobiotic transport across the blood-brain barrier.
The brain capillary endothelium is a formidable barrier to entry of foreign chemicals into the central nervous system (CNS). For the most part it poorly distinguishes between therapeutics and neurotoxins and thus the blood-brain barrier both protects the brain from toxic chemicals and limits our ability to treat a variety of CNS disorders. Two elements underlie the barrier function of the brain capillary endothelium: 1). a physical barrier comprised of tight junctions, which form an effective seal to intercellular diffusion, and the cells themselves, which exhibit a low rate of endocytosis, and 2). a metabolic/active barrier, comprised of specific membrane transporters expressed by the endothelial cells. We have recently developed an experimental system based on confocal microscopy to study mechanisms of transport in freshly isolated brain capillaries. Here I review studies demonstrating a major role for the ATP-driven, xenobiotic export pump, p-glycoprotein, in barrier function and recent experiments showing that transient inhibition of pump function can have substantial benefit for chemotherapy in an animal model of brain cancer.
Laboratory of Pharmacology and Chemistry, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina 27709, USA. miller@niehs.nih.gov
David S
DS
Miller
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D001693:Biological Transport, Active / Q000502:physiology; D001812:Blood-Brain Barrier / Q000378:metabolism* / Q000502:physiology; D004358:Drug Therapy / Q000379:methods; D006801:Humans; D018613:Microscopy, Confocal / Q000379:methods*; D015262:Xenobiotics / Q000493:pharmacokinetics*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D015262:Xenobiotics