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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Campos, Christopher R. Cannon, Ronald E. Hawkins, Brian T. Miller, David S. Peart, John C. |
| Description | Author Affiliation: Cannon RE ( Laboratory of Toxicology and Pharmacology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA. cannon1@niehs.nih.gov); |
| Abstract | P-glycoprotein, an ATP-driven drug efflux pump, is a major obstacle to the delivery of small-molecule drugs across the blood-brain barrier and into the CNS. Here we test a unique signaling-based strategy to overcome this obstacle. We used a confocal microscopy-based assay with isolated rat brain capillaries to map a signaling pathway that within minutes abolishes P-glycoprotein transport activity without altering transporter protein expression or tight junction permeability. This pathway encompasses elements of proinflammatory- (TNF-α) and sphingolipid-based signaling. Critical to this pathway was signaling through sphingosine-1-phosphate receptor 1 (S1PR1). In brain capillaries, S1P acted through S1PR1 to rapidly and reversibly reduce P-glycoprotein transport activity. Sphingosine reduced transport by a sphingosine kinase-dependent mechanism. Importantly, fingolimod (FTY720), a S1P analog recently approved for treatment of multiple sclerosis, also rapidly reduced P-glycoprotein activity; similar effects were found with the active, phosphorylated metabolite (FTY720P). We validated these findings in vivo using in situ brain perfusion in rats. Administration of S1P, FTY720, or FTY729P increased brain uptake of three radiolabeled P-glycoprotein substrates, $^{3}H-verapamil$ (threefold increase), $^{3}H-loperamide$ (fivefold increase), and $^{3}H-paclitaxel$ (fivefold increase); blocking S1PR1 abolished this effect. Tight junctional permeability, measured as brain $^{14}C-sucrose$ accumulation, was not altered. Therefore, targeting signaling through S1PR1 at the blood-brain barrier with the sphingolipid-based drugs, FTY720 or FTY720P, can rapidly and reversibly reduce basal P-glycoprotein activity and thus improve delivery of small-molecule therapeutics to the brain. |
| ISSN | 00278424 |
| e-ISSN | 10916490 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Issue Number | 39 |
| Volume Number | 109 |
| Language | English |
| Publisher | National Academy of Sciences |
| Publisher Date | 2012-09-01 |
| Publisher Place | United States |
| Access Restriction | Open |
| Subject Keyword | Blood-Brain Barrier Metabolism Drug Delivery Systems Lysophospholipids Nerve Tissue Proteins P-Glycoprotein Signal Transduction Physiology Sphingolipids Sphingosine Analogs & Derivatives Animals Biological Transport, Active Drug Effects Calcium Channel Blockers Pharmacology Capillaries Cytology Fingolimod Hydrochloride Immunosuppressive Agents Organophosphates Propylene Glycols Rats, Sprague-Dawley Receptors, Lysosphingolipid Tight Junctions Tumor Necrosis Factor-alpha Verapamil Research Support, N.I.H., Intramural Multidisciplinary |
| Content Type | Text |
| Resource Type | Article |
| Subject | Multidisciplinary |
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