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

Author:

Buttmann Mathias,Lorenz Alexander,Weishaupt Andreas,Rieckmann Peter

Abstract

Abstract3‐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 μmol/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‐α or interleukin‐1β. 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.

Publisher

Wiley

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