期刊
MOLECULAR PHARMACOLOGY
卷 71, 期 3, 页码 667-675出版社
AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS
DOI: 10.1124/mol.106.029512
关键词
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资金
- Intramural NIH HHS Funding Source: Medline
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-alpha (TNF-alpha) 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-alpha and ET-1. Exposing brain capillaries to TNF-alpha 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-alpha signaled through TNFR1, which in turn caused ET release and action through ET A and ET B receptors, nitric-oxide synthase, protein kinase C and nuclear factor-kappa B (NF-kappa 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-kappa B raises the possibility that other effectors acting through this transcription factor may have similar effects on this key blood-brain barrier transporter.
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