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

Karim Benchenane Vincent Berezowski 1 Carine Ali 2 Monica Fernandez-Monreal José P. Lopez-Atalaya Julien Brillault 3, 4 Julien Chuquet André Nouvelot Eric T. Mackenzie 5 Guojun Bu Roméo Cecchelli 1 Omar Touzani 5 Denis Vivien 2
1 LBHE - Laboratoire de Physiopathologie de la Barrière Hémato-Encéphalique
2 Sérine protéases et physiopathologie de l'unité neurovasculaire
3 Pharmacologie des anti-infectieux
4 Université de Poitiers - Faculté de Médecine et de Pharmacie
5 NMST - Neurodégénérescence : modèles et stratégies thérapeutiques
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.
Keywords : Plasminogen activators Stroke Brain Endothelium Thrombolysis
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Journal articles
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https://hal-univ-artois.archives-ouvertes.fr/hal-00542121
Contributor : Wilfried Déplanques <>
Submitted on : Wednesday, December 1, 2010 - 4:38:02 PM
Last modification on : Wednesday, May 15, 2019 - 10:30:04 AM

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Karim Benchenane, Vincent Berezowski, Carine Ali, Monica Fernandez-Monreal, José P. Lopez-Atalaya, et al.. Tissue-type plasminogen activator crosses the intact blood-brain barrier by low-density lipoprotein receptor–related protein-mediated transcytosis. Circulation, American Heart Association, 2005, p. 2241-2249. ⟨hal-00542121⟩

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