Published Online
on April 25, 2005

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

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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

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