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Abstract
In the central nervous system, tissue-type plasminogen activator (tPA) has been associated with both pro-death and prosurvival actions on neurons. In most cases, this has been related to exogenous tPA. In the present study, we addressed the influence of endogenous tPA. We first observed an increased transcription of tPA following either in vivo global brain ischemia in rats or in vitro oxygen glucose deprivation (OGD) on mice and rats hippocampal slices. Hippocampal slices from tPA-deficient mice were more sensitive to OGD than wild-type slices. Pharmacological approaches targeting the known receptors of tPA revealed that only the inhibition of phosphorylation of epidermal growth factor receptors (EGFRs) prevented the neuroprotective effect of endogenous tPA. This study shows that ischemic hippocampal neurons overproduce endogenous tPA as an intend to protect themselves from ischemic death, by a mechanism involving an activation of EGFRs. Thus, strategies contributing to promote either endogenous production of tPA or its associated EGFR-linked signaling pathway may have beneficial effects following brain injuries such as stroke.
Highlights
Activator is critical for the control of hemostasis
This study shows that ischemic hippocampal neurons overproduce endogenous type plasminogen activator (tPA) as an intend to protect themselves from ischemic death, by a mechanism involving an activation of epidermal growth factor receptor (EGFR)
Prosurvival and proneurotoxic effects of tPA involve mechanisms that are beyond its ability to activate plasminogen into plasmin, including modulation of N-methyl-D-aspartate receptor (NMDAR)-dependent signaling,[11] lipoprotein receptor-related protein (LRP)-mediated PSD95 activation,[16] annexin-II-dependent processes.[9]
Summary
Activator (tPA) is critical for the control of hemostasis. When secreted in the vascular lumen by endothelial cells, tPA promotes fibrinolysis via the conversion of fibrin-bound plasminogen into plasmin.[1]. 60 nM) promote neuronal death induced by NMDA exposure[11] or oxygen glucose deprivation (OGD),[23] whereas lower doses of tPA (below 10 nM) are neuroprotective following OGD.[20] Despite the heterogeneity of both the experimental models and the toxic paradigms used in these different studies, they all showed that the prosurvival effects of tPA can occur independently of its proteolytic activity,[4,17] through a so-called ‘cytokine’ or ‘growth factor’-like effect. Our data reveal that global cerebral ischemia leads to an overexpression of tPA in hippocampal neurons, and that endogenous tPA is neuroprotective via an EGFR-dependent mechanism
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