Tissue-Type Plasminogen Activator Crosses the Intact Blood-Brain Barrier by Low-Density Lipoprotein Receptor–Related Protein-Mediated Transcytosis

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 (Circulation. 2005;111:2241-2249.)

Anti-NR1 N-terminal-domain vaccination unmasks the crucial action of tPA on NMDA-receptor-mediated toxicity and spatial memory

“…Immunisation prevents tPA-induced exacerbation of excitotoxic neuronal death We previously reported that (1) tPA within the cerebral parenchyma, exacerbates excitotoxic neuronal death (Nicole et al, 2001), an effect demonstrated in vitro to result from a direct interaction with the NR1 subunit of NMDA receptors (Nicole et al, 2001;Fernandez-Monreal et al, 2004) and that (2) intravenously injected tPA (as performed in stroke patients) can penetrate the brain (Benchenane et al, 2005a;Benchenane et al, 2005b). Thus, we postulated that antibodies preventing the tPA-NR1 interaction might improve the current acute management of stroke.…”

Tissue-Type Plasminogen Activator has a Neuroprotective Effect in the Ischemic Brain Mediated by Neuronal TNF-α

“…Our data indicate that either endogenous tPA or treatment with rtPA, at doses not associated with the development of hemorrhagic complications, not only is not neurotoxic but instead induces ischemic tolerance. Because after tPA-induced neuroprotectionits intravenous administration rtPA reaches the brain parenchyma (Benchenane et al, 2005), we propose that besides its beneficial thrombolytic properties, treatment with rtPA may also have a neuroprotective effect in the ischemic brain. Our findings are in apparent conflict with those by others indicating that genetic deficiency of tPA is associated with a better neurological outcome after experimental cerebral ischemia (Wang et al, 1998;Nagai et al, 1999).…”

Tissue-Type Plasminogen Activator and the Low-Density Lipoprotein Receptor-Related Protein Mediate Cerebral Ischemia-Induced Nuclear Factor-κB Pathway Activation

“…11,12 In addition, some studies have demonstrated the passage of tPA from the intravascular space into the brain under ischemic and nonischemic conditions. 39,40 Because tPA is the only Food and Drug Administration-approved medication for the treatment of patients with acute ischemic stroke, 15 it is important to investigate the mechanisms of tPA's deleterious effects during cerebral ischemia.…”