Tissue plasminogen activator prevents white matter damage following stroke

Abstract

Tissue plasminogen activator protects white matter from stroke-induced lesions via the EGF-like domain and independent of proteolytic activity by promoting oligodendrocyte survival.

Stressed neurons protect themselves by a tissue-type plasminogen activator-mediated EGFR-dependent mechanism

“…These data are in agreement with a previous demonstration that tPA may have EGFR-dependent oligotrophic activity. 6 Activation of NMDAR has been suggested as a possible mechanism of tPA-dependent neuroprotection following OGD in cortical neurons, 20 but we did not confirm these results in our present model. This may be explained by the use of different strategies to block tPA-dependent NMDAR signaling, that is, MK-801 as a broad antagonist of NMDAR on one hand and an antibody previously characterized to specifically prevent the tPA-dependent potentiation of NMDAR signaling without affecting their basal activity 30 on the other hand.…”

“…1 Neurons and glial cells are also a source of tPA in the brain parenchyma, 2 where it can act either as a plasminogen-dependent or -independent enzyme, a cytokine-like molecule or a neuromodulator to control neuronal plasticity, survival and death. [3][4][5] Substrates, binding proteins or receptors for tPA, other than plasminogen, include the epidermal growth factor receptor (EGFR), 6 the platelet derived growth factor-C, 7 the low-density lipoprotein receptor-related protein (LRP), 8 the annexin-II, 9 the chemokine macrophage chemoattractant protein 1 10 and the N-methyl-D-aspartate receptor (NMDAR). 11 In some cases, the recruitment of coreceptors might be necessary for tPA to exert its action.…”

“…12 Several studies showed that tPA can promote neurotoxicity, 5,13 especially by an overactivation of NMDARs. 8,11,[14][15][16] However, tPA may also display prosurvival properties on neurons and oligodendrocytes 4,6,[17][18][19][20] involving either an EGFR-dependent signaling, 6 binding to Annexin-II 18 or active NMDARs. 20 Interestingly, although the proneurotoxic effects of tPA were reported for exogenous tPA 11,21 or based on data obtained from tPA-deficient mice, 13 neurotrophic effects were mainly reported for endogenous tPA 19 or from experiments performed on tPA overexpressing animals.…”

GluN2D Subunit-Containing NMDA Receptors Control Tissue Plasminogen Activator-Mediated Spatial Memory

“…Accordingly, tPA has been implicated in numerous behaviors, including various forms of learning and emotional behaviors (Seeds et al, 1995;Madani et al, 1999;Calabresi et al, 2000;Pawlak et al, 2002Pawlak et al, , 2003Seeds et al, 2003;Benchenane et al, 2007). Apart from these physiological functions, tPA was reported to influence neuronal, oligodendrocytic, and endothelial death/survival after excitotoxic, apoptotic, and/or inflammatory challenges (Chen and Strickland 1997;Wang et al, 1998;Nicole et al, 2001;Liu et al, 2004a;Liot et al, 2006;Correa et al, 2011).…”

A bloody brake on myelin repair

“…This leads to the formation of large fibrin complexes, which are equivalent to blood clots. Moreover, tissue plasminogen activator protein, which is routinely given to people who have had an ischaemic stroke to promote the breakdown of fibrin-containing blood clots, inhibits the death of oligodendrocytes 9 and promotes axonal regeneration 10 . One must assume that these factors, like fibrinogen, access the brain in the absence of a functional BBB, and have roles in determining the success or failure of myelin repair.…”