title: Atorvastatin partially prevents an inflammatory barrier breakdown of cultured human brain endothelial cells at a pharmacologically relevant concentration.
abstract: 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (i.e. statins) are currently under clinical investigation as a prophylactic immunomodulatory treatment for neurological diseases where an inflammatory disruption of the blood-brain barrier plays a pathogenic role. Here, we investigated whether atorvastatin pre-treatment modulates inflammatory-induced barrier dysfunction of cultured human brain microvascular endothelial cells (HBMEC). Pre-treatment of immortalized HBMEC with atorvastatin (50 nmol/L to 1 micromol/L) dose-dependently prevented an inflammatory up-regulation of monocyte chemoattractant protein-1/CCL2 but not of interleukin-8/CXCL8 and intercellular adhesion molecule-1 expression by tumor necrosis factor-alpha or interleukin-1beta. It antagonized an inflammatory up-regulation of claudin-3 expression while zonula occludens-1 and occludin protein levels remained unaltered. Like immortalized HBMEC, primary HBMEC also showed a reduction of claudin-3 and of inducible CCL2 expression following atorvastatin pre-treatment. On a functional level, atorvastatin pre-treatment of HBMEC strongly and dose-dependently reduced adhesion of activated T lymphocytes to pre-activated primary endothelium. Atorvastatin effects could partially be abolished by parallel mevalonate treatment. These anti-inflammatory effects of atorvastatin were observed already at a pharmacologically relevant concentration of 50 nmol/L. Our results obtained with human brain endothelial cells demonstrate how statins may partially prevent an inflammatory-mediated blood-brain barrier breakdown in humans.
authors: Department of Neurology, Julius-Maximilians-University, Würzburg, Germany. m.buttmann@uni-wuerzburg.de
authors: Mathias
authors: M
authors: Buttmann
authors: Alexander
authors: A
authors: Lorenz
authors: Andreas
authors: A
authors: Weishaupt
authors: Peter
authors: P
authors: Rieckmann
mesh_terms: D000069059:Atorvastatin; D001921:Brain / Q000166:cytology*; D002470:Cell Survival; D002478:Cells, Cultured; D018925:Chemokines / Q000378:metabolism; D062465:Claudin-3; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D042783:Endothelial Cells / Q000187:drug effects*; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005434:Flow Cytometry / Q000379:methods; D005786:Gene Expression Regulation / Q000187:drug effects; D006538:Heptanoic Acids / Q000494:pharmacology*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D053583:Interleukin-1beta / Q000633:toxicity; D008565:Membrane Proteins / Q000378:metabolism; D011758:Pyrroles / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000633:toxicity
chemical_list: C568122:CLDN3 protein, human; D018925:Chemokines; D062465:Claudin-3; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D053583:Interleukin-1beta; D008565:Membrane Proteins; D011758:Pyrroles; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1; D000069059:Atorvastatin