Inhibition of hypoxia-induced increase of blood-brain barrier permeability by YC-1 through the antagonism of HIF-1alpha 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-1alpha 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-1alpha accumulation and VEGF production, which in turn protect BBB from injury caused by hypoxia.
Yeh
Wei-Lan
WL
Department of pharmacology, College of Medicine, National Taiwan University, 1, Sec. 1, Jen-Ai Road, Taipei, Taiwan.
Lu
Dah-Yuu
DY
Lin
Chun-Jung
CJ
Liou
Houng-Chi
HC
Fu
Wen-Mei
WM
D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects*; D015687:Cell Hypoxia; D002478:Cells, Cultured; D006152:Cyclic GMP / Q000502:physiology; D017869:Cyclic GMP-Dependent Protein Kinases / Q000502:physiology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007191:Indazoles / Q000494:pharmacology*; D007511:Ischemia / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000032:analysis; D010539:Permeability; D010750:Phosphoproteins / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000517:prevention & control; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis*; D062826:Zonula Occludens-1 Protein
C497444:Hif1a protein, rat; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007191:Indazoles; D008565:Membrane Proteins; D010750:Phosphoproteins; C569044:Tjp1 protein, rat; D042461:Vascular Endothelial Growth Factor A; D062826:Zonula Occludens-1 Protein; C090937:3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole; D017869:Cyclic GMP-Dependent Protein Kinases; D006152:Cyclic GMP