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Tissue Plasminogen Activator Enhances the Hypoxia/reoxygenation-induced Impairment of the Blood–brain Barrier in a Primary Culture of Rat Brain Endothelial Cells

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Abstract

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.

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Acknowledgments

tPA was obtained as a generous gift from Kyowa Hakko Kogyo Co, Japan. We wish to thank Yoshisada Shibata, Maria A. Deli, Kunihiko Tanaka, Yasuko Yamashita, Yoshihiro Takaya, Shoji Horai, Yoichi Morofuji, Takanori Shimono, and Makiko Yamaguchi for their critical reviews of the manuscript and outstanding professional guidance.

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Authors and Affiliations

  1. Department of Neurosurgery, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki, 852-8501, Japan

    Takeshi Hiu, Kentaro Hayashi, Naoki Kitagawa, Keisuke Tsutsumi, Junichi Kawakubo, Masaru Honda, Kazuhiko Suyama & Izumi Nagata

  2. Department of Pharmacoloy, Nagasaki University Graduate School of Biomedical Sciences, 1-12-4 Sakamoto, Nagasaki, 852-8523, Japan

    Sinsuke Nakagawa & Masami Niwa

  3. BBB Laboratory, PharmaCo-Cell Co. Ltd, 1-12-4 Sakamoto, Nagasaki, 852-8523, Japan

    Sinsuke Nakagawa & Masami Niwa

Authors
  1. Takeshi Hiu
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  2. Sinsuke Nakagawa
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  3. Kentaro Hayashi
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  4. Naoki Kitagawa
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  5. Keisuke Tsutsumi
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  6. Junichi Kawakubo
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  7. Masaru Honda
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  8. Kazuhiko Suyama
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  9. Izumi Nagata
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  10. Masami Niwa
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Correspondence to Takeshi Hiu.

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Hiu, T., Nakagawa, S., Hayashi, K. et al. Tissue Plasminogen Activator Enhances the Hypoxia/reoxygenation-induced Impairment of the Blood–brain Barrier in a Primary Culture of Rat Brain Endothelial Cells. Cell Mol Neurobiol 28, 1139–1146 (2008). https://doi.org/10.1007/s10571-008-9294-x

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  • DOI: https://doi.org/10.1007/s10571-008-9294-x

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