Oxygen glucose deprivation switches the transport of tPA across the blood-brain barrier from an LRP-dependent to an increased LRP-independent process
Stroke. 2005-05-01; 36(5): 1059-1064
DOI: 10.1161/01.STR.0000163050.39122.4f
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BACKGROUND AND PURPOSE: Despite uncontroversial benefit from its thrombolytic
activity, the documented neurotoxic effect of tissue plasminogen activator (tPA)
raises an important issue: the current emergency stroke treatment might not be
optimum if exogenous tPA can enter the brain and thus add to the deleterious
effects of endogenous tPA within the cerebral parenchyma. Here, we aimed at
determining whether vascular tPA crosses the blood-brain barrier (BBB) during
cerebral ischemia, and if so, by which mechanism.
METHODS: First, BBB permeability was assessed in vivo by measuring Evans Blue
extravasation following intravenous injection at 0 or 3 hours after middle
cerebral artery electrocoagulation in mice. Second, the passage of vascular tPA
was investigated in an in vitro model of BBB, subjected or not to oxygen and
glucose deprivation (OGD).
RESULTS: We first demonstrated that after focal permanent ischemia in mice, the
BBB remains impermeable to Evans Blue in the early phase (relative to the
therapeutic window of tPA), whereas at later time points massive Evans Blue
extravasation occurs. Then, the passage of tPA during these 2 phases, was
investigated in vitro and we show that in control conditions, tPA crosses the
intact BBB by a low-density lipoprotein (LDL) receptor-related protein
(LRP)-dependent transcytosis, whereas OGD leads to an exacerbation of tPA
passage, which switches to a LRP-independent process.
CONCLUSIONS: We evidence 2 different mechanisms through which vascular tPA can
reach the brain parenchyma, depending on the state of the BBB. As discussed,
these data show the importance of taking the side effects of blood-derived tPA
into account and offer a basis to improve the current thrombolytic strategy.