TY - JOUR T1 - Inhibition of Hypoxia-Induced Increase of Blood-Brain Barrier Permeability by YC-1 through the Antagonism of HIF-1α Accumulation and VEGF Expression JF - Molecular Pharmacology JO - Mol Pharmacol SP - 440 LP - 449 DO - 10.1124/mol.107.036418 VL - 72 IS - 2 AU - Wei-Lan Yeh AU - Dah-Yuu Lu AU - Chun-Jung Lin AU - Houng-Chi Liou AU - Wen-Mei Fu Y1 - 2007/08/01 UR - http://molpharm.aspetjournals.org/content/72/2/440.abstract N2 - Cerebral microvascular endothelial cells form the anatomical basis of the blood-brain barrier (BBB), and the tight junctions of the BBB are critical for maintaining brain homeostasis and low permeability. Ischemia/reperfusion is known to damage the tight junctions of BBB and lead to permeability changes. Here we investigated the protective role of 3-(5′-hydroxymethyl-2′-furyl)-1-benzylindazole (YC-1), against chemical hypoxia and hypoxia/reoxygenation (H/R)-induced BBB hyperpermeability using adult rat brain endothelial cell culture (ARBEC). YC-1 significantly decreased CoCl2- and H/R-induced hyperpermeability of fluorescein isothiocyanate (FITC)-dextran in cell culture inserts. It was found that the decrease and disorganization of tight junction protein zonular occludens-1 (ZO-1) in response to CoCl2, and H/R was antagonized by YC-1. The protection of YC-1 may result from the inhibition of HIF-1α accumulation and production of its downstream target vascular endothelial growth factor (VEGF). VEGF alone significantly increased FITC-dextran permeability and down-regulated mRNA and protein levels of ZO-1 in ARBECs. We further used animal model to examine the effect of YC-1 on BBB permeability after cerebral ischemia/reperfusion. It was found that YC-1 significantly protected the BBB against ischemia/reperfusion-induced injury. Taken together, these results indicate that YC-1 may inhibit HIF-1α accumulation and VEGF production, which in turn protect BBB from injury caused by hypoxia. ER -