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


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 degrees 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.
Benchenane
Karim
K
INSERM-Avenir tPA in the working brain, Université de Caen, GIP Cyceron, Caen, France.
Berezowski
Vincent
V
Ali
Carine
C
Fernández-Monreal
Mónica
M
López-Atalaya
José P
JP
Brillault
Julien
J
Chuquet
Julien
J
Nouvelot
André
A
MacKenzie
Eric T
ET
Bu
Guojun
G
Cecchelli
Roméo
R
Touzani
Omar
O
Vivien
Denis
D
D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism*; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D003080:Cold Temperature; D026503:Low Density Lipoprotein Receptor-Related Protein-1 / Q000378:metabolism / Q000502:physiology*; D008297:Male; D016202:N-Methylaspartate / Q000008:administration & dosage; D020258:Neurotoxicity Syndromes / Q000209:etiology; D017395:Plasminogen Activator Inhibitor 1 / Q000008:administration & dosage; D021381:Protein Transport; D051381:Rats; D017207:Rats, Sprague-Dawley; D010959:Tissue Plasminogen Activator / Q000009:adverse effects* / Q000493:pharmacokinetics*
D026503:Low Density Lipoprotein Receptor-Related Protein-1; D017395:Plasminogen Activator Inhibitor 1; D016202:N-Methylaspartate; D010959:Tissue Plasminogen Activator