Hsp90 inhibition protects brain endothelial cells against LPS-induced injury.

Abstract

Dysfunction of the blood-brain barrier (BBB) endothelium increases infiltration of lymphocytes and innate immune cells in the brain, leading to the development of neurological disorders. Heat shock protein 90 (Hsp90) inhibitors are anti-inflammatory agents and P53 inducers, which reduce the production of reactive oxygen species (ROS) in a diverse variety of human tissues. In this study, we investigate the effects of those compounds in LPS-induced brain endothelial inflammation, by utilizing human cerebral microvascular endothelial cells (hCMEC/D3). Our results suggest that Hsp90 inhibitors suppress inflammation by inhibiting the LPS-induced signal transducer and activator of transcription 3 (STAT3); and P38 activation. Moreover, those compounds reduce the P53 suppressors murine double minute 2 (MDM2) and murine double minute 4 (MDM4). Immunoglobulin heavy chain binding protein/glucose-regulated protein 78 (BiP/Grp78)-a key element of endothelial barrier integrity-was also increased by Hsp90 inhibition. Hence, we conclude that application of Hsp90 inhibitors in diseases related to BBB dysfunction may deliver a novel therapeutic possibility in the affected population.