TPA as an ‘interface’ between blood and brain

Abstract

Over the last decade, tPA has been implicated in a variety of brain functions. It is secreted from growth cones or extending neurites, it modulates neurite outgrowth and promotes neuronal migration. tPA has also been involved in physiological glutamatergic-dependent processes such as synaptic plasticity and long term potentiation. In addition, t-PA has been shown to play an important role in the pathogenesis of seizure, multiple sclerosis, trauma and ischemic brain injury. In a previous study, we have shown that the proteolytic activity of t-PA enhances the N-methyl-D-aspartate (NMDA) receptor-mediated signalling (Nicole et al., 2001). Here, we provide evidences that tPA is able to cross the intact blood brain barrier both in vitro and in vivo and that this mechanism is independent of its proteolytic activity and mediated by an interaction with a LDL-related receptor, LRP. Overall, these data suggest that blood-derived tPA could influence neuronal functioning. Accordingly, intravenous injection of tPA potentiates the NMDA-induced brain lesion in rats even in the absence of blood brain barrier leakage. As a model demonstrating that preventing the NMDA-dependent effect of tPA could improve the efficiency of thrombolysis in the treatment of stroke, we evidence that the blood-derived tPA failed to enhance NMDA-dependent signalling in a model of mice previously vaccinated with the amino-terminal domain (ATD) of NR1 subunit of the NMDA receptor. Thus, we propose a new concept suggesting that tPA is one of the key element of the interface between the blood and the brain parenchyma.