Signalling pathways influencing basal and H(2)O(2)-induced P-glycoprotein expression in endothelial cells derived from the blood-brain barrier

J Neurochem. 2003 Nov;87(4):1043-51. doi: 10.1046/j.1471-4159.2003.02061.x.


The drug transporter, P-glycoprotein (P-gp) on brain microvessel endothelium, influences movement of lipophilic substances in and out of the brain. Pathways regulating P-gp expression, both basal and hydrogen peroxide (H2O2)-induced, are here examined in primary cultured rat brain endothelial cells. Activation of extracellular-signal regulated kinases (ERK1/2), protein kinase C (PKC), the p46 isoform of stress-activated protein kinase (SAPK) and its downstream transcription factor, c-Jun, occurred in a time- and concentration-dependent manner following exposure of cells to H2O2 with concomitant increases in P-gp expression. Blockade of ERK activation with U0126, of PKC with Gö6976 and of SAPK with SP600125 decreased basal P-gp but did not abolish the H2O2-induced increase. Blockade of Akt with PI3-kinase inhibitor, LY294002, lowered basal P-gp and prevented the H2O2-induced increase. Inhibition of nuclear factor-kappaB (NF-kappaB), either by blocking dissociation from its inhibitory factor, IkappaB, with MG132 or its nuclear translocation with SN50 enhanced basal P-gp, obscuring the H2O2-induced increase. H2O2 itself produced no detectable activation of IkappaB, but inhibited that induced by 5 ng/mL tumour necrosis factor-alpha (TNF-alpha). P-gp expression may involve positive inputs from ERK1/2, SAPK, Akt and PKC and inhibitory influences of NF-kappaB. By depressing NF-kappaB signalling, H2O2 may still augment P-gp expression when ERK1/2, PKC or SAPK are inhibited.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / biosynthesis*
  • Animals
  • Blood-Brain Barrier / cytology
  • Blood-Brain Barrier / metabolism*
  • Brain / blood supply
  • Cells, Cultured
  • Endothelium, Vascular / cytology
  • Endothelium, Vascular / drug effects
  • Endothelium, Vascular / metabolism*
  • Enzyme Inhibitors / pharmacology
  • Gene Expression / drug effects
  • Hydrogen Peroxide / pharmacology*
  • Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • Mitogen-Activated Protein Kinases / metabolism
  • NF-kappa B / antagonists & inhibitors
  • NF-kappa B / metabolism
  • Oxidants / pharmacology
  • Peptides / pharmacology
  • Phosphoinositide-3 Kinase Inhibitors
  • Phosphorylation / drug effects
  • Protein Kinase C / antagonists & inhibitors
  • Protein Kinase C / metabolism
  • Protein Serine-Threonine Kinases*
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-akt
  • Proto-Oncogene Proteins c-jun / metabolism
  • Rats
  • Signal Transduction / drug effects
  • Signal Transduction / physiology*


  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Enzyme Inhibitors
  • NF-kappa B
  • Oxidants
  • Peptides
  • Phosphoinositide-3 Kinase Inhibitors
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-jun
  • SN50 peptide
  • Hydrogen Peroxide
  • Akt1 protein, rat
  • Protein Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Protein Kinase C
  • Mitogen-Activated Protein Kinases