Tissue-type plasminogen activator crosses the intact blood-brain barrier by low-density lipoprotein receptor-related protein-mediated transcytosis

Karim Benchenane, Vincent Berezowski, Carine Ali, Mónica Fernández-Monreal, José P. López-Atalaya, Julien Brillault, Julien Chuquet, André Nouvelot, Eric T. MacKenzie, Guojun Bu, Roméo Cecchelli, Omar Touzani, Denis Vivien

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144 Scopus citations

Abstract

Background - Accumulating evidence demonstrates a critical involvement of tissue-type plasminogen activator (tPA) in pathological and physiological brain conditions. Determining whether and how vascular tPA can cross the blood-brain barrier (BBB) to enter the brain is thus important, not only during stroke but also in physiological conditions. Methods and Results - In the present work, we provide evidence in vivo that intravenous injection of tPA increases NMDA-induced striatal lesion in the absence of BBB leakage. Accordingly, we show that tPA crosses the BBB both after excitotoxic lesion and in control conditions. Indeed, vascular injected tPA can be detected within the brain parenchyma and in the cerebrospinal fluid. By using an in vitro model of BBB, we have confirmed that tPA can cross the intact BBB. Its passage was blocked at 4°C, was saturable, and was independent of its proteolytic activity. We have shown that tPA crosses the BBB by transcytosis, mediated by a member of the LDL receptor-related protein family. Conclusions - We demonstrate that blood-derived tPA can reach the brain parenchyma without alteration of the BBB. The molecular mechanism of the passage of tPA from blood to brain described here could represent an interesting target to improve thrombolysis in stroke.

Original languageEnglish (US)
Pages (from-to)2241-2249
Number of pages9
JournalCirculation
Volume111
Issue number17
DOIs
StatePublished - May 3 2005

Keywords

  • Brain
  • Endothelium
  • Plasminogen activators
  • Stroke
  • Thrombolysis

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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    Benchenane, K., Berezowski, V., Ali, C., Fernández-Monreal, M., López-Atalaya, J. P., Brillault, J., Chuquet, J., Nouvelot, A., MacKenzie, E. T., Bu, G., Cecchelli, R., Touzani, O., & Vivien, D. (2005). Tissue-type plasminogen activator crosses the intact blood-brain barrier by low-density lipoprotein receptor-related protein-mediated transcytosis. Circulation, 111(17), 2241-2249. https://doi.org/10.1161/01.CIR.0000163542.48611.A2