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Tumor Necrosis Factor and Endothelin-1 Increase P-Glycoprotein Expression and Transport Activity at the Blood-Brain Barrier

Laboratory of Pharmacology and Chemistry, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina

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- (TNF-) 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- and ET-1. Exposing brain capillaries to TNF- 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- signaled through TNF-R1, which in turn caused ET release and action through ET_A and ET_B receptors, nitric-oxide synthase, protein kinase C and nuclear factor-B (NF-B) 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-B raises the possibility that other effectors acting through this transcription factor may have similar effects on this key blood-brain barrier transporter.

Received for publication August 1, 2006.

Accepted for publication November 28, 2006.

Address correspondence to: Dr. David S. Miller, Laboratory of Pharmacology and Chemistry, National Institute of Environmental Health Sciences, National Institutes of Health, 111 TW Alexander Dr, PO Box 12233, MD F2–03, Research Triangle Park, NC 27709. E-mail: miller{at}niehs.nih.gov

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