Inhibition of Hypoxia-Induced Increase of Blood-Brain Barrier Permeability by Yc-1 through the Antagonism of Hif-1 Alpha Accumulation and Vegf Expression

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-1 alpha 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-1 alpha accumulation and VEGF production, which in turn protect BBB from injury caused by hypoxia