Published Online
on April 25, 2005

A more recent version of this article appeared on May 3, 2005

This Article Full Text (PDF) All Versions of this Article: 111/17/2241    most recent 01.CIR.0000163542.48611.A2v1 Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Benchenane, K. Articles by Vivien, D. Search for Related Content PubMed PubMed Citation Articles by Benchenane, K. Articles by Vivien, D. Pubmed/NCBI databases Gene GEO Profiles HomoloGene UniGene Compound via MeSH Substance via MeSH Related Collections Acute Cerebral Infarction Other imaging Thrombolysis Other Vascular biology

Submitted on June 8, 2004
Revised on November 30, 2004
Accepted on December 3, 2004

Tissue-Type Plasminogen Activator Crosses the Intact Blood-Brain Barrier by Low-Density Lipoprotein Receptor-Related Protein-Mediated Transcytosis

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

From the INSERM-Avenir "tPA in the working brain" (K.B., C.A., M.F.-M., J.P.L.-A., D.V.) and UMR-CNRS 6185 (J.C., A.N., E.T.M., D.T.), Université de Caen, GIP Cyceron, Caen, France; Departments of Cell Biology and Physiology (G.B.), Washington University School of Medicine, St. Louis, Mo; and Laboratoire de Physiopathologie de la Barrière Hémato-Encéphalique (V.B., J.B., R.C.), Faculté des sciences Jean Perrin, Université d’Artois, Lens, France.

^* To whom correspondence should be addressed. E-mail: d.vivien{at}neuro.unicaen.fr.

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

Key words: plasminogen activators • stroke • brain • endothelium • thrombolysis

This article has been cited by other articles:

				B. D. Roussel, R. Macrez, A. Jullienne, V. Agin, E. Maubert, L. Dauphinot, M.-C. Potier, L. Plawinski, H. Castel, Y. Hommet, et al. Age and albumin D site-binding protein control tissue plasminogen activator levels: neurotoxic impact Brain, August 1, 2009; 132(8): 2219 - 2230. [Abstract] [Full Text] [PDF]

				H. Yuan, K. M. Vance, C. E. Junge, M. T. Geballe, J. P. Snyder, J. R. Hepler, M. Yepes, C.-M. Low, and S. F. Traynelis The Serine Protease Plasmin Cleaves the Amino-terminal Domain of the NR2A Subunit to Relieve Zinc Inhibition of the N-Methyl-D-aspartate Receptors J. Biol. Chem., May 8, 2009; 284(19): 12862 - 12873. [Abstract] [Full Text] [PDF]

				C. Zhang, J. An, D. K. Strickland, and M. Yepes The Low-Density Lipoprotein Receptor-Related Protein 1 Mediates Tissue-Type Plasminogen Activator-Induced Microglial Activation in the Ischemic Brain Am. J. Pathol., February 1, 2009; 174(2): 586 - 594. [Abstract] [Full Text] [PDF]

				N. Lebeurrier, S. Launay, R. Macrez, E. Maubert, H. Legros, A. Leclerc, S. P. Jamin, J.-Y. Picard, S. Marret, V. Laudenbach, et al. Anti-Mullerian-hormone-dependent regulation of the brain serine-protease inhibitor neuroserpin J. Cell Sci., October 15, 2008; 121(20): 3357 - 3365. [Abstract] [Full Text] [PDF]

				J. An, C. Zhang, R. Polavarapu, X. Zhang, X. Zhang, and M. Yepes Tissue-type plasminogen activator and the low-density lipoprotein receptor-related protein induce Akt phosphorylation in the ischemic brain Blood, October 1, 2008; 112(7): 2787 - 2794. [Abstract] [Full Text] [PDF]

				R. Polavarapu, J. An, C. Zhang, and M. Yepes Regulated Intramembrane Proteolysis of the Low-Density Lipoprotein Receptor-Related Protein Mediates Ischemic Cell Death Am. J. Pathol., May 1, 2008; 172(5): 1355 - 1362. [Abstract] [Full Text] [PDF]

				C. Orset, R. Macrez, A. R. Young, D. Panthou, E. Angles-Cano, E. Maubert, V. Agin, and D. Vivien Mouse Model of In Situ Thromboembolic Stroke and Reperfusion Stroke, October 1, 2007; 38(10): 2771 - 2778. [Abstract] [Full Text] [PDF]

				X. Zhang, R. Polavarapu, H. She, Z. Mao, and M. Yepes Tissue-Type Plasminogen Activator and the Low-Density Lipoprotein Receptor-Related Protein Mediate Cerebral Ischemia-Induced Nuclear Factor-{kappa}B Pathway Activation Am. J. Pathol., October 1, 2007; 171(4): 1281 - 1290. [Abstract] [Full Text] [PDF]

				E. E. Benarroch Tissue plasminogen activator: Beyond thrombolysis Neurology, August 21, 2007; 69(8): 799 - 802. [Full Text] [PDF]

				J. Paul, S. Strickland, and J. P. Melchor Fibrin deposition accelerates neurovascular damage and neuroinflammation in mouse models of Alzheimer's disease J. Exp. Med., August 6, 2007; 204(8): 1999 - 2008. [Abstract] [Full Text] [PDF]

				R. Polavarapu, M. C. Gongora, H. Yi, S. Ranganthan, D. A. Lawrence, D. Strickland, and M. Yepes Tissue-type plasminogen activator-mediated shedding of astrocytic low-density lipoprotein receptor-related protein increases the permeability of the neurovascular unit Blood, April 15, 2007; 109(8): 3270 - 3278. [Abstract] [Full Text] [PDF]

				J. P. Lopez-Atalaya, B. D. Roussel, C. Ali, E. Maubert, K.-U. Petersen, V. Berezowski, R. Cecchelli, C. Orset, and D. Vivien Recombinant Desmodus rotundus Salivary Plasminogen Activator Crosses the Blood-Brain Barrier Through a Low-Density Lipoprotein Receptor-Related Protein-Dependent Mechanism Without Exerting Neurotoxic Effects Stroke, March 1, 2007; 38(3): 1036 - 1043. [Abstract] [Full Text] [PDF]

				K. Benchenane, H. Castel, M. Boulouard, R. Bluthe, M. Fernandez-Monreal, B. D. Roussel, J. P. Lopez-Atalaya, S. Butt-Gueulle, V. Agin, E. Maubert, et al. Anti-NR1 N-terminal-domain vaccination unmasks the crucial action of tPA on NMDA-receptor-mediated toxicity and spatial memory J. Cell Sci., February 15, 2007; 120(4): 578 - 585. [Abstract] [Full Text] [PDF]

				U. Schaefer, T. Machida, S. Vorlova, S. Strickland, and R. Levi The plasminogen activator system modulates sympathetic nerve function J. Exp. Med., September 4, 2006; 203(9): 2191 - 2200. [Abstract] [Full Text] [PDF]