Abstract
The ATP-driven drug efflux pump, P-glycoprotein, is a critical and selective element of the blood-brain barrier and a primary impediment to pharmacotherapy of central nervous system (CNS) disorders. Thus, an understanding of how P-glycoprotein function is regulated has the potential to improve CNS therapy. We recently demonstrated rapid (minutes) and reversible inactivation of P-glycoprotein in rat brain capillaries signaled through tumor necrosis factor-α (TNF-α) and endothelin-1 (ET-1), components of the brain's innate immune response. In this study, we examined the longer-term consequences of continuous exposure of rat brain capillaries to low levels of TNF-α and ET-1. Exposing brain capillaries to TNF-α or ET-1 caused a rapid decrease in P-glycoprotein transport activity with no change in transporter protein expression. This was followed by a 2- to 3-h plateau at the low activity level and then by a sharp increase in both transport activity and protein expression. After 6 h, transport activity and transporter protein expression was double that of control samples. TNF-α signaled through TNF-R1, which in turn caused ET release and action through ETA and ETB receptors, nitric-oxide synthase, protein kinase C and nuclear factor-κB (NF-κB) and finally increased P-glycoprotein expression and transport activity. Assuming similar effects occur in vivo, the present results imply a tightening of the selective blood-brain barrier with chronic inflammation and thus reduced efficacy of CNS-acting drugs that are P-glycoprotein substrates. Moreover, involvement of NF-κB raises the possibility that other effectors acting through this transcription factor may have similar effects on this key blood-brain barrier transporter.
Footnotes
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This research was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences.
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Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.
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doi:10.1124/mol.106.029512.
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ABBREVIATIONS: CNS, central nervous system; TNF-α, tumor necrosis factor-α; IL, interleukin; LPS, lipopolysaccharide; TNF-R1, TNF receptor 1; ET-1, endothelin-1; ETB, endothelin receptor B; NOS, nitric-oxide synthase; PKC, protein kinase C; TLR4, toll-like receptor 4; NF-κB, nuclear factor-κB; RES-701-1, cyclic (Gly1-Asp9) (Gly-Asn-Trp-His-Gly-Thr-Ala-Pro-Asp-Trp-Phe-Phe-Asn-Tyr-Tyr-Trp); JKC-301, d-aspartyl-propyl-d-isoleucyl-leucyl-d-tryptophan; SN50, H-Ala-Ala-Val-Ala-Leu-Leu-Pro-Ala-Val-Leu-Leu-Ala-Leu-Leu-Ala-Pro-Val-Gln-Arg-Lys-Arg-Gln-Lys-Leu-Met-Pro-OH; SN50M, H-Ala-Ala-Val-Ala-Leu-Leu-Pro-Ala-Val-Leu-Leu-Ala-Pro-Val-Glu-Arg-Asn-Gly-Gln-Lys-Leu-Met-Pro-OH; BIM, bisindolylmaleimide I; PMA, phorbol 12-myristate 13-acetate; PBS, phosphate-buffered saline; BSA, bovine serum albumin; NBD-CSA, [N-ϵ-(4-nitrobenzofurazan-7-yl)-d-Lys8]cyclosporin A; PSC833, valspodar; MK571, 3-[[3-[2-(7-chloroquinolin-2-yl)vinyl]phenyl]-(2-dimethylcarbamoylethylsulfanyl)methylsulfanyl] propionic acid; Mrp, multidrug-resistance associated protein; ECE, endothelin-converting enzyme; l-NMMA, NG-monomethyl-l-arginine; SNP, sodium nitroprusside.
- Received August 1, 2006.
- Accepted November 28, 2006.
- The American Society for Pharmacology and Experimental Therapeutics
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