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First published on May 18, 2007; DOI: 10.1124/mol.107.036418

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Received for publication March 27, 2007.
Revised May 18, 2007.
Accepted for publication May 18, 2007.

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

WEI-LAN YEH 1, DAH-YUU LU 1, CHUN-JUNG LIN 2, HOUNG-CHI LIOU 1, WEN-MEI FU 3*

1 Department of pharmacology, College of Medicine, National Taiwan University 2 Graduate Istitute of Pharmaceutical Science, College of Medicine, National Taiwan University 3 College of Medicine, National Taiwan University

* Address correspondence to: E-mail: wenmei{at}ha.mc.ntu.edu.tw

Abstract

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 YC-1, 3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole, 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 FITC-dextran in cell culture inserts. It was found that the decrease and disorganization of tight junction protein 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 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.


Key words: Fluorescence techniques, Immunocytochemistry, Ischemia/Reperfusion


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W.-L. Yeh, C.-J. Lin, and W.-M. Fu
Enhancement of Glucose Transporter Expression of Brain Endothelial Cells by Vascular Endothelial Growth Factor Derived from Glioma Exposed to Hypoxia
Mol. Pharmacol., January 1, 2008; 73(1): 170 - 177.
[Abstract] [Full Text] [PDF]


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