In vivo activation of human pregnane X receptor tightens the blood-brain barrier to methadone through P-glycoprotein up-regulation
The ATP-driven drug export pump, P-glycoprotein, is a primary gatekeeper of the blood-brain barrier and a major impediment to central nervous system (CNS) pharmacotherapy. Reducing P-glycoprotein activity dramatically increases penetration of many therapeutic drugs into the CNS. We used a transgenic mouse expressing human PXR (hPXR) to determine the consequences of increased blood-brain barrier P-glycoprotein […]
Rapid modulation of P-glycoprotein-mediated transport at the blood-brain barrier by tumor necrosis factor-alpha and lipopolysaccharide
We demonstrate a link between the brain’s innate immune response and functional regulation of P-glycoprotein. We show that exposing brain capillaries to the inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha), activated a TNF-R1 receptor, released ET-1, activated ET(B) receptor signaling, and essentially abolished P-glycoprotein-mediated transport. Bacterial lipopolysaccharide, a potent activator of the brain’s innate immune response, […]
Rapid regulation of P-glycoprotein at the blood-brain barrier by endothelin-1
We measured specific transport [(3′-oxo-4-butenyl-4-methyl-threonine(1), (valine(2)) cyclosporin (PSC833)-sensitive] of the fluorescent cyclosporin A derivative [N-epsilon(4-nitrobenzofurazan-7-yl)-D-Lys(8)]-cyclosporin A (NBDL-CSA) into the lumens of isolated rat brain capillaries using confocal microscopy and quantitative image analysis. Luminal NBDL-CSA accumulation was rapidly and reversibly reduced in a concentration-dependent manner by 0.1 to 100 nM endothelin-1 (ET-1). In this concentration range, […]
Pregnane X receptor up-regulation of P-glycoprotein expression and transport function at the blood-brain barrier
We report for the first time that pregnane X receptor (PXR) is expressed in rat brain capillaries. Moreover, exposing isolated capillaries to the PXR ligands pregnenolone-16alpha-carbonitrile (PCN) and dexamethasone increased p-glycoprotein expression and p-glycoprotein-specific transport of a fluorescent cyclosporine A derivative into capillary lumens. Dosing rats with PCN and dexamethasone increased p-glycoprotein expression in liver […]
Restoring blood-brain barrier P-glycoprotein reduces brain amyloid-beta in a mouse model of Alzheimer’s disease
We demonstrate that the ATP-driven pump, P-glycoprotein, specifically mediates efflux transport of Aβ from mouse brain capillaries into the vascular space, thus identifying a critical component of the Aβ brain efflux mechanism. We demonstrate in a transgenic mouse model of AD [human amyloid precursor protein (hAPP)-overexpressing mice; Tg2576 strain] that brain capillary P-glycoprotein expression and […]
Seizure-induced up-regulation of P-glycoprotein at the blood-brain barrier through glutamate and cyclooxygenase-2 signaling
We tested the hypothesis that seizures increase brain extracellular glutamate, which signals through an N-methyl-d-aspartate (NMDA) receptor and cyclooxygenase-2 (COX-2) in brain capillaries to increase blood-brain barrier P-glycoprotein expression. Consistent with this hypothesis, exposing isolated rat or mouse brain capillaries to glutamate for 15 to 30 min increased P-glycoprotein expression and transport activity hours later. […]
Tumor necrosis factor alpha and endothelin-1 increase P-glycoprotein expression and transport activity at the blood-brain barrier
We examined 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 […]