Tissue plasminogen activator enhances the hypoxia/reoxygenation-induced impairment of the blood-brain barrier in a primary culture of rat brain endothelial cells.
Hemorrhagic transformation is a major complication associated with tissue plasminogen activator (tPA) therapy for ischemic stroke. We studied the effect of tPA on the blood-brain barrier (BBB) function with our in vitro monolayer model generated using rat brain microvascular endothelial cells subjected either to normoxia or to hypoxia/reoxygenation (H/R) with or without the administration of tPA. The barrier function was evaluated by the transendothelial electrical resistance (TEER), the permeability of sodium fluorescein and Evans' blue-albumin (EBA), and the uptake of lucifer yellow (LY). The permeability of sodium fluorescein and EBA was used as an index of paracellular and transcellular transport, respectively. The administration of tPA increased the permeability of EBA and the uptake of LY under normoxia. It enhanced the increase in the permeability of both sodium fluorescein and EBA, the decrease in the TEER, and the disruption in the expression of ZO-1 under H/R conditions. Administration of tPA could cause an increase in the transcellular transport under normoxia, and both the transcellular and paracellular transport of the BBB under H/R conditions in vitro. Even in humans, tPA may lead to an opening of the BBB under non-ischemic conditions and have an additional effect on the ischemia-induced BBB disruption.
Hiu
Takeshi
T
Department of Neurosurgery, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan. thiu-nagasaki@umin.ac.jp
Nakagawa
Sinsuke
S
Hayashi
Kentaro
K
Kitagawa
Naoki
N
Tsutsumi
Keisuke
K
Kawakubo
Junichi
J
Honda
Masaru
M
Suyama
Kazuhiko
K
Nagata
Izumi
I
Niwa
Masami
M
D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000473:pathology*; D015687:Cell Hypoxia / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D017097:Electric Impedance; D042783:Endothelial Cells / Q000187:drug effects* / Q000473:pathology*; D019793:Fluorescein / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D007546:Isoquinolines / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D010100:Oxygen / Q000494:pharmacology*; D010539:Permeability / Q000187:drug effects; D010750:Phosphoproteins / Q000378:metabolism; D051381:Rats; D013997:Time Factors; D010959:Tissue Plasminogen Activator / Q000008:administration & dosage / Q000494:pharmacology*; D062826:Zonula Occludens-1 Protein
D007546:Isoquinolines; D008565:Membrane Proteins; D010750:Phosphoproteins; C569042:TJP1 protein, human; C569044:Tjp1 protein, rat; D062826:Zonula Occludens-1 Protein; C017475:lucifer yellow; D010959:Tissue Plasminogen Activator; D010100:Oxygen; D019793:Fluorescein