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Atorvastatin partially prevents an inflammatory barrier breakdown of cultured human brain endothelial cells at a pharmacologically relevant concentration

Mathias Buttmann, Alexander Lorenz, Andreas Weishaupt, Peter Rieckmann
Journal of Neurochemistry 2007, 102 (4): 1001-8
17442054
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.

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