Tissue-type plasminogen activator crosses the intact blood-brain barrier by low-density lipoprotein receptor-related protein-mediated transcytosis
Circulation. 2005-05-03; 111(17): 2241-2249
DOI: 10.1161/01.CIR.0000163542.48611.A2
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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 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.