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Inhibition of Hypoxia-Induced Increase of Blood-Brain Barrier Permeability by YC-1 through the Antagonism of HIF-1 Accumulation and VEGF Expression

Department of Pharmacology (W.-L.Y., D.-Y.L., H.-C.L., W.-M.F.) and Graduate Institute of Pharmaceutical Science (C.-J.L.), College of Medicine, National Taiwan University, Taipei, Taiwan

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 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 accumulation and VEGF production, which in turn protect BBB from injury caused by hypoxia.

Received for publication March 27, 2007.

Accepted for publication May 18, 2007.

Address correspondence to: Wen-Mei Fu, Department of pharmacology, College of Medicine, National Taiwan University, 1, Sec. 1, Jen-Ai Road, Taipei, Taiwan., E-mail: wenmei{at}ntu.edu.tw

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