Understanding the Functions of Endogenous and Exogenous Tissue-Type Plasminogen Activator During Stroke
- Other version(s) of this article
You are viewing the most recent version of this article. Previous versions:
Alteplase (Actilyse or Activase) is the gold standard acute treatment of ischemic stroke1 and receives attention for hematoma resolution in hemorrhagic stroke. The active principle of Alteplase is the recombinant form of an endogenous protease, tissue-type plasminogen activator (tPA). Its intravascular thrombolytic activity is well known, but less are its multifaceted functions in the central nervous system (CNS). Endogenous tPA is not only released in the blood by endothelial cells but also expressed by many cells within the brain parenchyma (online-only Data Supplement), and it can act on all cell types of the brain virtually. Endogenous tPA has been involved in an ever-increasing number of brain functions, of which several are highly relevant during and after stroke. Importantly, knowledge on the mechanisms of action of endogenous tPA may hold true for recombinant tPA.
In this review, we provide an up-to-date overview of the current knowledge on the enzymatic or cytokine-like effects of action of tPA in the CNS, its various molecular substrates or receptors, focusing on the processes occurring during and after ischemic or hemorrhagic stroke, including excitotoxicity, apoptosis, blood–brain barrier breakdown, inflammation, axonal damage, and demyelination.
tPA Is More Than a Fibrinolytic Enzyme
tPA is a mosaic protease of 527 amino acids consisting of 5 distinct modules: a Finger domain, an epidermal growth factor (EGF)–like domain, 2 kringle domains (K1 and K2), and a serine protease proteolytic domain. Through these domains, tPA can interact with a variety of binding proteins and receptors in the brain parenchyma, thus extending its functions above the conversion of plasminogen into plasmin (Figure 1).
Figure 1. Main cellular and molecular targets of tissue-type plasminogen activator in the central nervous system. BBB indicates blood–brain barrier, EGFR, epidermal growth factor receptor; LRP, low-density lipoprotein receptor–related protein; NMDAR, N-methyl-d-aspartate receptors; and PDGFR, platelet-derived growth factor receptor.
tPA is not fibrinolytic by itself. To promote fibrinolysis, tPA activates fibrin-bound plasminogen into plasmin. The binding of plasminogen to fibrin is a necessary step to change its closed conformation to an open form, allowing its cleavage by tPA.2 The Finger domain of tPA is involved in its binding to fibrin and is necessary to promote fibrinolytic activity at low plasminogen activator concentrations.3 In the brain, the Finger domain, by interacting with low-density lipoprotein receptor–related proteins (LRPs), supports blood–brain barrier (BBB) crossing,4 astrocytic clearance,5 or microglial activation.6,7
The EGF-like domain shows homology with EGF and is accordingly thought to mediate the trophic and mitogenic functions of tPA in the brain.8–11 O-glycosylation of the EGF-like domain has been shown to promote the hepatic recapture of tPA.12
The role of the K1 domain in the brain is poorly investigated, but its high mannose-type glycosylation could be involved in uptake processes as shown on liver endothelial cells via mannose receptors.13 Because of the presence of loops and of a lysine binding site, the K2 domain binds to various proteins in the blood and in the brain parenchyma, including the platelet-derived growth factor-CC,14 N-methyl-d-aspartate receptors (NMDARs)15 or high mobility group box-1 protein.16 In the K2 domain, the Asn184 glycosylation site segregates 2 tPA variants (type I is fully glycosylated, whereas type II lacks glycosylation),17 which may exert different functions although this remains to be investigated. Interestingly, desmoteplase, the thrombolytic agent used in Desmoteplase in Acute Ischemic Stroke (DIAS) clinical trials, derived from a bat salivary gland, is closely related to tPA but lacks a K2 domain18 and is accordingly devoid of toxic actions, likely because of the inability to interact with NMDARs.19,20 Also, the specific amino acids involved in the backbone structure of the lysine binding site are also key in the ability of tPA to promote excitotoxicity on neurons.21
The catalytic domain supports the functions of tPA dependent on its protease activity. A specific cleavage at the Arg275-Ile276 peptide bound converts the single-chain form to the 2-chain form, maintained by a disulphide bound. In contrast to the other members of the chymotrypsin family of serine proteases, tPA is active in both its single- and 2-chain forms. However, some functions of tPA are specific to 1 form: for example, only the single-chain form of tPA can promote NMDAR-driven neurotoxicity.22
Role of tPA on the BBB Permeability
Strong experimental and clinical evidence link tPA to BBB damage, with subsequent risks of edema and bleeding23–25 (Figures 1 and 2). Several mechanisms may contribute to tPA-induced alteration of BBB permeability. These mechanisms are exacerbated with time of oxygen–glucose deprivation and delay to reperfusion.25 In endothelial cells, tPA induces the synthesis of metalloproteinases, matrix metalloproteinase-9 and matrix metalloproteinase-3, which in turn contribute to enhanced BBB permeability and intracranial bleeding.26,27 In perivascular astrocytes, tPA induces the shedding of LRPs,28 which activates nuclear factor-κB29 and Akt30 pathways leading to the expression of matrix metalloproteinase-9,31 which finally promotes the detachment of astrocyte end-feet processes.28 tPA can also alter the BBB by activating the platelet-derived growth factor-CC pathway on perivascular astrocytes14,32 (Figures 1 and 2). tPA also contributes to cleavage of the monocyte chemoattractant protein 1 (officially known as C-C motif chemokine 2), leading to a disruption of tight-junctions and thus to BBB leakage.33 It is important to note that the role of plasmin generation in the effect of tPA on the BBB remains controversial, as recently deeply reviewed.25 All these mechanisms have mainly been associated with BBB leakage and which of them is/are involved in hemorrhagic transformation remains unclear. The extent of ischemia is likely critical to determine whether BBB leakage will convert to bleeding. The delay of tPA administration is also suspected to influence the occurrence of bleeding but this lacks clinical evidence.
Figure 2. Mechanisms of tissue-type plasminogen activator (tPA) action on blood–brain barrier (BBB) breakdown. In endothelial cells, tPA activates nuclear factor (NF)-κB signaling through low-density lipoprotein receptor–related protein (LRP) to induce the synthesis of metalloproteinases matrix metalloproteinase (MMP)-9 and MMP-3, which in turn contribute to enhanced BBB permeability and intracranial bleeding. In perivascular astrocytes, tPA induces the shedding of LRPs, which activates NF-κB and Akt pathways, induces the expression of MMP-9 by perivascular astrocytes, which finally promotes the detachment of astrocyte end-feet processes. tPA effect on perivascular astrocytes can also be mediated by activating the platelet-derived growth factor (PDGF) pathway.
Effects of tPA on NMDAR-Mediated Signaling and Subsequent Neuronal Outcome
Several studies have shown that inhibitors of tPA in the CNS can protect neurons against toxicity induced by the overactivation of NMDARs.34–36 This suggested that tPA can promote neurotoxicity by acting on NMDARs. The mechanism of action of tPA on NMDARs has been a subject of debate37,38 (Figures 1 and 3), turning around 3 main questions: Is it proteolytic or nonproteolytic? Does it require plasmin generation? Is a coreceptor involved?
Figure 3. Mechanisms of tissue-type plasminogen activator (tPA) modulation of N-methyl-d-aspartate receptor (NMDAR) signaling. 1. Synthesized as a single-chain tPA (sc-tPA), tPA can be processed in its 2-chain form (tc-tPA) by plasmin and plasmin-like proteases. Both forms can activate plasminogen (plg) into plasmin (plm). 2. Both tPA (direct effect) and plasmin/matrix metalloproteinase (MMP) generated by tPA (indirect effect) can interact and cleave NMDARs. 3. Interaction with NMDAR may require previous binding to type 1 low-density lipoprotein receptor–related protein (LRP-1). 4. Different NMDA subunits can be cleaved. Depending on the composition in subtypes of GluN2 subunit (GluN2a-d), different effects (detailed in the figure) can be achieved.
It is now established that the enhancement of NMDAR signaling by tPA depends on its proteolytic activity.22,39,40 Both plasmin-dependent and plasmin-independent mechanisms have been reported to sustain the potentiation of NMDAR signaling by tPA,37,41,42 but the most recent studies agree that it can occur independently of plasminogen activation.22,39,43,44
LRP can act as a coreceptor for tPA. Indeed, tPA would act on a nonplasminogen substrate, engaging LRP receptors, which in turn would enhance Ca2+ downstream of NMDARs.45 Whether tPA requires LRP to enhance NMDAR signals could depend on the type of neurons (hippocampal versus cortical), their state of maturation, the kinetic of tPA application or on the action of astrocytes.39,44,46 Interestingly, in PC12 and N2a neuron-like cells, tPA may signal through a complex containing NMDAR, LPR1, and Trk receptors.46
tPA interacts with the GluN1 subunit of NMDARs, and as already mentioned, this interaction involves the lysine binding site of tPA K2 domain.15,21 Accordingly, desmoteplase, a variant of tPA lacking the K2 domain, does not interact with NMDAR and does not promote NMDAR signaling in cortical cultures.18–20 Several groups reported that the cleavage of the amino-terminal domain of GluN1 subunit is necessary for enhancement of NMDAR signaling by tPA (Figure 3),47,48 whereas others did not detect tPA-dependent cleavage of GluN1, despite enhancement of NMDAR function by exogenous tPA in cortical cultures.45 Plasmin generated by tPA has also been reported to cleave NMDARs, specifically the GluN2 subunit (Figure 3) at 2 sites: Lys317 on GluN2A, which relieves Zn2+ inhibition (Zn2+ is a negative allosteric modulator of NMDAR) and thereby increases NMDAR function,49 and Arg67 on GluN2B, which increases sensitivity of the NMDAR to the coagonist of NMDARs, glycine.50
A recent study showed that only single-chain tPA can promote NMDAR signaling and neurotoxicity in cortical neurons, as well as late phase of long-term potentiation (LTP) in hippocampal neurons.22 Of note, Actilyse is a mix of single-chain recombinant tPA (90%) and 2-chain recombinant tPA (10%).22
Studies in transgenic mice overexpressing tPA in neurons (T4 transgenic mice) suggested that tPA can also have neuroprotective effects9,44 through a mechanism that is also dependent on the activation of NMDARs and independent on plasmin. The fact that tPA induces toxic or protective effects in neurons could depend on the different subtypes of GluN subunits involved, as well as on their location (synaptic versus extrasynaptic). In fact, exogenous tPA promotes neurotoxicity on cortical neurons by activating extrasynaptic GluN2D-containing NMDARs51,52 but leads to a neuroprotective effect by activating synaptic GluN2A-containing NMDARs.53 tPA may also have opposite effects depending on its concentration, with low concentrations of tPA being protective,53 and higher concentrations being deleterious,22,46 which suggests that there are multiple receptors for tPA with distinct affinities or coreceptors.
Interestingly, tPA can enhance NMDAR activity not only in neurons but also in brain endothelial cells.54,55 tPA also seems to play role in neurovascular coupling, an effect involving NMDARs, but the actual mechanisms involved need to be investigated further.56,57
Effects of tPA on Apoptosis
Several in vitro studies reported antiapoptotic effects of tPA on neurons10,28,58 and oligodendrocytes progenitors.8 Despite the heterogeneity of the toxic paradigms used in these different studies, they all show that this effect of tPA occurs independently of its proteolytic activity, through the so-called cytokine- or growth factor–like effect. A consensus also emerges around the necessary activation of PI3K/Akt pathway for neuroprotection by tPA.8,10,59 Two candidates have been proposed as the receptors mediating the antiapoptotic effects of tPA: annexin II and EGF receptor (Figure 2). Annexin II mediates these nonproteolytic effects of tPA in neurons (but the participation of EGF receptor was not addressed),59 whereas EGF receptor does so in oligodendrocytes progenitors (but the participation of annexin II was not addressed).8 Through this antiapoptotic effect on oligodendrocytes, tPA sustains the protection of the white matter after experimental ischemic stroke.8
In contrast to its reported antiapoptotic effects, tPA was shown to play proapoptotic effects on neurons,60 an effect possibly involving NMDARs and counteracted by the anticoagulant serine protease, activated protein C.61 However, the mechanisms through which this antiapoptotic effect occurs remain rather controversial.60–62 The state of maturation of neurons critically influences whether the effects of tPA are neurotoxic or neuroprotective. Indeed, during cortical development, tPA is toxic to neurons in deep layers (which are mature) through an NMDAR-dependent effect, whereas it protects neurons against apoptosis in superficial layers (which are immature) through an EGF receptor–dependent effect.63 Thus, it seems that the target of the antiapoptotic effects of tPA is generally immature cells, such as developing neurons or oligodendrocyte progenitors.
tPA and Cerebral Inflammatory Processes
tPA can promote microglial activation (Figure 1), independently of plasminogen activation, and via its finger domain interacting with microglial LRP and annexin II.6,7,64 A study using cell-specific tPA knockout mice challenged with kainate injection in the hippocampus revealed a regulatory loop in which neuron-derived tPA activates microglia, which in turn produces additional tPA. This microglia-derived tPA has autocrine, self-proliferative effects on microglia, and paracrine, neurotoxic effects.65 Data also indicate that annexin II may act in concert with the lectin galectin-1, which has previously been described as a receptor for tPA outside the CNS,66 to induce microglial activation by activating extracellular signal-regulated kinases 1/2 and c-Jun N-terminal kinase pathways and inflammatory responses by activating the Akt pathway.7 Interestingly, in the context of ischemia-reperfusion, plasmin67 and tPA68 have been reported to contribute to neutrophil and leukocyte infiltrations of reperfused tissue. Interestingly, tPA was suggested to have a biphasic action: first, via plasmin and matrix metalloproteinase, the activation would promote neutrophil transmigration and BBB injuries, and then would favor tPA extravasation in the brain, amplifying neutrophil recruitment via nonproteolytic activation of mast cells and lipid mediator release.68 Similarly, in in vitro models of BBB, tPA was reported to contribute to the adhesion and transmigration of monocytes and T lymphocytes, an effect prevented by blockage of the tPA–NMDAR interaction or of the LRP.54,69
Dare are sparse, and additional studies are warranted to determine the actual influence of tPA on brain inflammatory processes.
Role of tPA in Axonal Damage and Regeneration
Fibrin deposits within the CNS can lead to axonal damage and limited capacities of axonal regeneration. tPA might prevent both side effects of fibrin deposits.70 In fact, tPA is a key regulator of cellular migration and extension of cellular processes during development, by promoting the degradation of extracellular matrix (ECM) and cell adhesions. Similarly, tPA can promote the formation of new axonal varicosities during regenerative processes after axon degeneration.71 In general, the activation of plasmin by tPA results in the degradation of the ECM toward a more permissive environment for axonal growth. More specifically, in models of spinal cord injury, tPA action on axonal regeneration was shown to involve the degradation of chondroitin sulfate proteoglycans,72,73 a set of ECM proteins with inhibitory action on axon regrowth. Accordingly, tPA activates the chondroitin sulfate proteoglycan–degrading protease, a disintegrin and metalloprotease with thrombospondin domains-4, thus promoting axonal growth and functional recovery.74 These effects of tPA could be amplified by the fact that tPA, through its proteolytic activity, can facilitate the migration of macrophages, which in turn may locally release proteases that can degrade ECM components.75 Unfortunately, because of a low percentage of white matter in the brain of a rodent, these pathways remain poorly investigated in stroke models.
tPA Is Involved in Neuronal Plasticity
Via its ability to activate plasminogen and to regulate metabolism of the ECM, particularly at the growth cone,76 tPA is surely a crucial regulator of neuronal growth and motility. Indeed, tPA-dependent plasminogen activation was first demonstrated in neuronal cell lines, suggesting that it may have roles in neuronal growth.77–79 tPA-mediated neuronal plasticity thus, at least in part, occurs via facilitation of structural changes by degradation of the ECM to establish new or reinforce existing synapses.80–82 These effects on neuronal plasticity underline the link between tPA and LTP. Indeed, experimentally induced LTP rapidly induces the transcription of tPA in hippocampal neurons via an NMDAR-dependent mechanism.83 Accordingly, the treatment of hippocampal slices with tPA enhances the late phase of LTP84. Furthermore, transgenic mice overexpressing tPA show an enhanced and prolonged hippocampal LTP,85 whereas tPA knockout mice show reduced hippocampal86 and corticostriatal87 LTP. There are several other mechanisms by which tPA can promote synaptic plasticity. These include binding to and the activation of LRP, leading to protein kinase A activation.88 Also, recent data show a link between tPA and the neurotrophin brain-derived neurotrophic factor (BDNF) in hippocampal LTP. In hippocampal neurons, tPA, plasminogen, and pro-BDNF are copackaged in dense-core granules that can be efficiently recruited into active spines and can undergo activity-dependent release.89 Plasmin, generated by tPA, is necessary for late phase of LTP and cleaves pro-BDNF to its active form mBDNF90 that is known to promote the conversion of early to late hippocampal LTP.91 In agreement with this, a study92 demonstrated that high-frequency stimulation of hippocampal neurons leads to neuronal secretion of tPA, concomitant with an increase in extracellular mBDNF.
tPA, in particular single-chain tPA, could also promote LTP via its ability to enhance NMDAR signaling.21
To sum up, tPA (of neuronal and astrocytic origin)93 might promote poststroke recovery, via both plasmin-dependent effects (ECM degradation and BDNF activation) and plasmin-independent effects (activation of LRP-induced pathways and enhancement of NMDAR signaling).
Conclusions and Prospects
Research of the past 20 years has changed our image of tPA from a protease with vascular functions to a protease/cytokine with key roles in the brain parenchyma. Compelling evidence shows that tPA exerts multiple and sometimes opposite effects in the CNS, depending on the target cell type and the surrounding environment. Recent advances have explained this variety of effects by the different mechanisms of action of tPA, which are supported by its 5 functional domains and their interaction with their respective binding partners. In animal models of stroke, tPA is mainly reported to display deleterious effects, by promoting excitotoxicity and by enhancing BBB permeability. By contrast, in addition to fibrinolysis, tPA could also have beneficial effects after stroke, as it was reported to display oligotrophic and neurotrophic functions and to promote axonal regeneration and brain plasticity.
Several adjunctive therapies have been investigated in preclinical models to counteract the possible deleterious effects of tPA after stroke. For instance, thanks to the ever-increasing knowledge on how tPA might be noxious, such strategies include among other, coadministration of tPA with an antibody targeting the effect of tPA on NMDAR signaling,94 with annexin-2 to prevent BBB damages,95 with activated protein C96 or progesterone97 to prevent bleeding. Although efficient in preclinical models, the transfer to the clinic of these candidates remains to be established. However, with our ongoing improvement in the comprehension of the molecular mechanisms of action of tPA, as shown in the present review, one can truly expect an optimization of the clinical use of tPA.
A challenging question is whether these effects can be exerted by exogenous recombinant tPA, injected to patients in an attempt to achieve reperfusion. Overall, Alteplase improves the outcome of patients with stroke,1 despite variable efficiencies of reperfusion, as a function of the cause, size, and location of the clot, as well as the time-to-treatment delay.98–100 Clinical evidence of the occurrence of tPA effects shown in animal models is challenging, but it is worth mentioning that after ischemic stroke, exogenous tPA was independently associated with seizure occurrence (a mechanism that involves tPA)101 and a worse outcome at 3 months in this seizure subgroup of patients.102 In addition, brain imaging studies evidenced that exogenous tPA indeed promotes BBB leakage in patients with stroke.24
Similar questions can be asked in the context of hemorrhagic stroke, for which hematoma evacuation with tPA seems safe and efficient,103 while first preclinical evidence supports proedema, proinflammatory, and proneurotoxic effects in addition to hematoma resolution.104–108
Disclosures
None.
Footnotes
References
- 1. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke.N Engl J Med. 1995; 333:1581–7.CrossrefMedlineGoogle Scholar
- 2.
Flemmig M, Melzig MF . Serine-proteases as plasminogen activators in terms of fibrinolysis.J Pharm Pharmacol. 2012; 64:1025–1039.CrossrefMedlineGoogle Scholar - 3.
Larsen GR, Henson K, Blue Y . Variants of human tissue-type plasminogen activator. Fibrin binding, fibrinolytic, and fibrinogenolytic characterization of genetic variants lacking the fibronectin finger-like and/or the epidermal growth factor domains.J Biol Chem. 1988; 263:1023–1029.MedlineGoogle Scholar - 4.
Benchenane K, Berezowski V, Ali C, Fernández-Monreal M, López-Atalaya JP, Brillault J, . Tissue-type plasminogen activator crosses the intact blood-brain barrier by low-density lipoprotein receptor-related protein-mediated transcytosis.Circulation. 2005; 111:2241–2249.LinkGoogle Scholar - 5.
Cassé F, Bardou I, Danglot L, Briens A, Montagne A, Parcq J, . Glutamate controls tPA recycling by astrocytes, which in turn influences glutamatergic signals.J Neurosci. 2012; 32:5186–5199.CrossrefMedlineGoogle Scholar - 6.
Siao CJ, Tsirka SE . Tissue plasminogen activator mediates microglial activation via its finger domain through annexin II.J Neurosci. 2002; 22:3352–3358.CrossrefMedlineGoogle Scholar - 7.
Pineda D, Ampurdanés C, Medina MG, Serratosa J, Tusell JM, Saura J, . Tissue plasminogen activator induces microglial inflammation via a noncatalytic molecular mechanism involving activation of mitogen-activated protein kinases and Akt signaling pathways and AnnexinA2 and Galectin-1 receptors.Glia. 2012; 60:526–540.CrossrefMedlineGoogle Scholar - 8.
Correa F, Gauberti M, Parcq J, Macrez R, Hommet Y, Obiang P, . Tissue plasminogen activator prevents white matter damage following stroke.J Exp Med. 2011; 208:1229–1242.CrossrefMedlineGoogle Scholar - 9.
Haile WB, Wu J, Echeverry R, Wu F, An J, Yepes M . Tissue-type plasminogen activator has a neuroprotective effect in the ischemic brain mediated by neuronal TNF-α.J Cereb Blood Flow Metab. 2012; 32:57–69.CrossrefMedlineGoogle Scholar - 10.
Liot G, Roussel BD, Lebeurrier N, Benchenane K, López-Atalaya JP, Vivien D, . Tissue-type plasminogen activator rescues neurones from serum deprivation-induced apoptosis through a mechanism independent of its proteolytic activity.J Neurochem. 2006; 98:1458–1464.CrossrefMedlineGoogle Scholar - 11.
Ortiz-Zapater E, Peiró S, Roda O, Corominas JM, Aguilar S, Ampurdanés C, . Tissue plasminogen activator induces pancreatic cancer cell proliferation by a non-catalytic mechanism that requires extracellular signal-regulated kinase ½ activation through epidermal growth factor receptor and annexin A2.Am J Pathol. 2007; 170:1573–1584.CrossrefMedlineGoogle Scholar - 12.
Hajjar KA, Reynolds CM . alpha-Fucose-mediated binding and degradation of tissue-type plasminogen activator by HepG2 cells.J Clin Invest. 1994; 93:703–710.CrossrefMedlineGoogle Scholar - 13.
Kuiper J, Van’t Hof A, Otter M, Biessen EA, Rijken DC, van Berkel TJ . Interaction of mutants of tissue-type plasminogen activator with liver cells: effect of domain deletions.Biochem J. 1996; 313(Pt 3):775–780.CrossrefMedlineGoogle Scholar - 14.
Fredriksson L, Li H, Fieber C, Li X, Eriksson U . Tissue plasminogen activator is a potent activator of PDGF-CC.EMBO J. 2004; 23:3793–3802.CrossrefMedlineGoogle Scholar - 15.
Lopez-Atalaya JP, Roussel BD, Levrat D, Parcq J, Nicole O, Hommet Y, . Toward safer thrombolytic agents in stroke: molecular requirements for NMDA receptor-mediated neurotoxicity.J Cereb Blood Flow Metab. 2008; 28:1212–1221.CrossrefMedlineGoogle Scholar - 16.
Roussel BD, Mysiorek C, Rouhiainen A, Jullienne A, Parcq J, Hommet Y, . HMGB-1 promotes fibrinolysis and reduces neurotoxicity mediated by tissue plasminogen activator.J Cell Sci. 2011; 124(Pt 12):2070–2076.CrossrefMedlineGoogle Scholar - 17.
Rathore YS, Rehan M, Pandey K, Sahni G, Ashish . First structural model of full-length human tissue-plasminogen activator: a SAXS data-based modeling study.J Phys Chem B. 2012; 116:496–502.CrossrefMedlineGoogle Scholar - 18.
Schleuning WD . Vampire bat plasminogen activator DSPA-alpha-1 (desmoteplase): a thrombolytic drug optimized by natural selection.Haemostasis. 2001; 31:118–122.MedlineGoogle Scholar - 19.
Liberatore GT, Samson A, Bladin C, Schleuning WD, Medcalf RL . Vampire bat salivary plasminogen activator (desmoteplase): a unique fibrinolytic enzyme that does not promote neurodegeneration.Stroke. 2003; 34:537–543.LinkGoogle Scholar - 20.
López-Atalaya JP, Roussel BD, Ali C, Maubert E, Petersen KU, Berezowski V, . Recombinant Desmodus rotundus salivary plasminogen activator crosses the blood-brain barrier through a low-density lipoprotein receptor-related protein-dependent mechanism without exerting neurotoxic effects.Stroke. 2007; 38:1036–1043.LinkGoogle Scholar - 21.
Parcq J, Bertrand T, Baron AF, Hommet Y, Anglès-Cano E, Vivien D . Molecular requirements for safer generation of thrombolytics by bioengineering the tissue-type plasminogen activator A chain.J Thromb Haemost. 2013; 11:539–546.CrossrefMedlineGoogle Scholar - 22.
Parcq J, Bertrand T, Montagne A, Baron AF, Macrez R, Billard JM, . Unveiling an exceptional zymogen: the single-chain form of tPA is a selective activator of NMDA receptor-dependent signaling and neurotoxicity.Cell Death Differ. 2012; 19:1983–1991.CrossrefMedlineGoogle Scholar - 23.
Yepes M, Roussel BD, Ali C, Vivien D . Tissue-type plasminogen activator in the ischemic brain: more than a thrombolytic.Trends Neurosci. 2009; 32:48–55.CrossrefMedlineGoogle Scholar - 24.
Kassner A, Roberts TP, Moran B, Silver FL, Mikulis DJ . Recombinant tissue plasminogen activator increases blood-brain barrier disruption in acute ischemic stroke: an MR imaging permeability study.AJNR Am J Neuroradiol. 2009; 30:1864–1869.CrossrefMedlineGoogle Scholar - 25.
Niego B, Medcalf RL . Plasmin-dependent modulation of the blood-brain barrier: a major consideration during tPA-induced thrombolysis?J Cereb Blood Flow Metab. 2014; 34:1283–1296.CrossrefMedlineGoogle Scholar - 26.
Wang X, Lee SR, Arai K, Lee SR, Tsuji K, Rebeck GW, . Lipoprotein receptor-mediated induction of matrix metalloproteinase by tissue plasminogen activator.Nat Med. 2003; 9:1313–1317.CrossrefMedlineGoogle Scholar - 27.
Suzuki Y, Nagai N, Yamakawa K, Kawakami J, Lijnen HR, Umemura K . Tissue-type plasminogen activator (t-PA) induces stromelysin-1 (MMP-3) in endothelial cells through activation of lipoprotein receptor-related protein.Blood. 2009; 114:3352–3358.CrossrefMedlineGoogle Scholar - 28.
Polavarapu R, Gongora MC, Yi H, Ranganthan S, Lawrence DA, Strickland D, . Tissue-type plasminogen activator-mediated shedding of astrocytic low-density lipoprotein receptor-related protein increases the permeability of the neurovascular unit.Blood. 2007; 109:3270–3278.CrossrefMedlineGoogle Scholar - 29.
Zhang X, Polavarapu R, She H, Mao Z, Yepes M . Tissue-type plasminogen activator and the low-density lipoprotein receptor-related protein mediate cerebral ischemia-induced nuclear factor-kappaB pathway activation.Am J Pathol. 2007; 171:1281–1290.CrossrefMedlineGoogle Scholar - 30.
An J, Zhang C, Polavarapu R, Zhang X, Zhang X, Yepes M . Tissue-type plasminogen activator and the low-density lipoprotein receptor-related protein induce Akt phosphorylation in the ischemic brain.Blood. 2008; 112:2787–2794.CrossrefMedlineGoogle Scholar - 31.
Wang S, Lee SR, Guo SZ, Kim WJ, Montaner J, Wang X, . Reduction of tissue plasminogen activator-induced matrix metalloproteinase-9 by simvastatin in astrocytes.Stroke. 2006; 37:1910–1912.LinkGoogle Scholar - 32.
Su EJ, Fredriksson L, Geyer M, Folestad E, Cale J, Andrae J, . Activation of PDGF-CC by tissue plasminogen activator impairs blood-brain barrier integrity during ischemic stroke.Nat Med. 2008; 14:731–737.CrossrefMedlineGoogle Scholar - 33.
Yao Y, Tsirka SE . Monocyte chemoattractant protein-1 and the blood-brain barrier.Cell Mol Life Sci. 2014; 71:683–697.CrossrefMedlineGoogle Scholar - 34.
Docagne F, Nicole O, Marti HH, MacKenzie ET, Buisson A, Vivien D . Transforming growth factor-beta1 as a regulator of the serpins/t-PA axis in cerebral ischemia.FASEB J. 1999; 13:1315–1324.CrossrefMedlineGoogle Scholar - 35.
Buisson A, Nicole O, Docagne F, Sartelet H, Mackenzie ET, Vivien D . Up-regulation of a serine protease inhibitor in astrocytes mediates the neuroprotective activity of transforming growth factor beta1.FASEB J. 1998; 12:1683–1691.CrossrefMedlineGoogle Scholar - 36.
Zhang Z, Zhang L, Yepes M, Jiang Q, Li Q, Arniego P, . Adjuvant treatment with neuroserpin increases the therapeutic window for tissue-type plasminogen activator administration in a rat model of embolic stroke.Circulation. 2002; 106:740–745.LinkGoogle Scholar - 37.
Matys T, Strickland S . Tissue plasminogen activator and NMDA receptor cleavage.Nat Med. 2003; 9:371–2.CrossrefMedlineGoogle Scholar - 38.
Vivien D, Fernandez-Monreal M, Nicole O, Buisson A . Reply to “Tissue plasminogen activator and NMDA receptor cleavage”.Nat Med. 2003; 9:372.CrossrefGoogle Scholar - 39.
Echeverry R, Wu J, Haile WB, Guzman J, Yepes M . Tissue-type plasminogen activator is a neuroprotectant in the mouse hippocampus.J Clin Invest. 2010; 120:2194–2205.CrossrefMedlineGoogle Scholar - 40.
Armstead WM, Riley J, Cines DB, Higazi AA . tPA contributes to impairment of ATP and Ca sensitive K channel mediated cerebrovasodilation after hypoxia/ischemia through upregulation of ERK MAPK.Brain Res. 2011; 1376:88–93.CrossrefMedlineGoogle Scholar - 41.
Nicole O, Docagne F, Ali C, Margaill I, Carmeliet P, MacKenzie ET, . The proteolytic activity of tissue-plasminogen activator enhances NMDA receptor-mediated signaling.Nat Med. 2001; 7:59–64.CrossrefMedlineGoogle Scholar - 42.
Pawlak R, Strickland S . Tissue plasminogen activator and seizures: a clot-buster’s secret life.J Clin Invest. 2002; 109:1529–1531.CrossrefMedlineGoogle Scholar - 43.
Samson AL, Medcalf RL . Tissue-type plasminogen activator: a multifaceted modulator of neurotransmission and synaptic plasticity.Neuron. 2006; 50:673–678.CrossrefMedlineGoogle Scholar - 44.
Wu F, Wu J, Nicholson AD, Echeverry R, Haile WB, Catano M, . Tissue-type plasminogen activator regulates the neuronal uptake of glucose in the ischemic brain.J Neurosci. 2012; 32:9848–9858.CrossrefMedlineGoogle Scholar - 45.
Samson AL, Nevin ST, Croucher D, Niego B, Daniel PB, Weiss TW, . Tissue-type plasminogen activator requires a co-receptor to enhance NMDA receptor function.J Neurochem. 2008; 107:1091–1101.MedlineGoogle Scholar - 46.
Mantuano E, Lam MS, Gonias SL . LRP1 assembles unique co-receptor systems to initiate cell signaling in response to tissue-type plasminogen activator and myelin-associated glycoprotein.J Biol Chem. 2013; 288:34009–34018.CrossrefMedlineGoogle Scholar - 47.
Kvajo M, Albrecht H, Meins M, Hengst U, Troncoso E, Lefort S, . Regulation of brain proteolytic activity is necessary for the in vivo function of NMDA receptors.J Neurosci. 2004; 24:9734–9743.CrossrefMedlineGoogle Scholar - 48.
Macrez R, Bezin L, Le Mauff B, Ali C, Vivien D . Functional occurrence of the interaction of tissue plasminogen activator with the NR1 Subunit of N-methyl-D-aspartate receptors during stroke.Stroke. 2010; 41:2950–2955.LinkGoogle Scholar - 49.
Yuan H, Vance KM, Junge CE, Geballe MT, Snyder JP, Hepler JR, . The serine protease plasmin cleaves the amino-terminal domain of the NR2A subunit to relieve zinc inhibition of the N-methyl-D-aspartate receptors.J Biol Chem. 2009; 284:12862–12873.CrossrefMedlineGoogle Scholar - 50.
Ng KS, Leung HW, Wong PT, Low CM . Cleavage of the NR2B subunit amino terminus of N-methyl-D-aspartate (NMDA) receptor by tissue plasminogen activator: identification of the cleavage site and characterization of ifenprodil and glycine affinities on truncated NMDA receptor.J Biol Chem. 2012; 287:25520–25529.CrossrefMedlineGoogle Scholar - 51.
Jullienne A, Montagne A, Orset C, Lesept F, Jane DE, Monaghan DT, . Selective inhibition of GluN2D-containing N-methyl-D-aspartate receptors prevents tissue plasminogen activator-promoted neurotoxicity both in vitro and in vivo.Mol Neurodegener. 2011; 6:68.CrossrefMedlineGoogle Scholar - 52.
Baron A, Montagne A, Cassé F, Launay S, Maubert E, Ali C, . NR2D-containing NMDA receptors mediate tissue plasminogen activator-promoted neuronal excitotoxicity.Cell Death Differ. 2010; 17:860–871.CrossrefMedlineGoogle Scholar - 53.
Wu F, Echeverry R, Wu J, An J, Haile WB, Cooper DS, . Tissue-type plasminogen activator protects neurons from excitotoxin-induced cell death via activation of the ERK1/2-CREB-ATF3 signaling pathway.Mol Cell Neurosci. 2013; 52:9–19.CrossrefMedlineGoogle Scholar - 54.
Reijerkerk A, Kooij G, van der Pol SM, Leyen T, Lakeman K, van Het Hof B, . The NR1 subunit of NMDA receptor regulates monocyte transmigration through the brain endothelial cell barrier.J Neurochem. 2010; 113:447–453.CrossrefMedlineGoogle Scholar - 55.
Mali RS, Cheng M, Chintala SK . Plasminogen activators promote excitotoxicity-induced retinal damage.FASEB J. 2005; 19:1280–1289.CrossrefMedlineGoogle Scholar - 56.
Su EJ, Fredriksson L, Schielke GP, Eriksson U, Lawrence DA . Tissue plasminogen activator-mediated PDGF signaling and neurovascular coupling in stroke.J Thromb Haemost. 2009; 7(suppl 1):155–158.CrossrefMedlineGoogle Scholar - 57.
Park L, Gallo EF, Anrather J, Wang G, Norris EH, Paul J, . Key role of tissue plasminogen activator in neurovascular coupling.Proc Natl Acad Sci U S A. 2008; 105:1073–1078.CrossrefMedlineGoogle Scholar - 58.
Flavin MP, Zhao G . Tissue plasminogen activator protects hippocampal neurons from oxygen-glucose deprivation injury.J Neurosci Res. 2001; 63:388–394.CrossrefMedlineGoogle Scholar - 59.
Lee HY, Hwang IY, Im H, Koh JY, Kim YH . Non-proteolytic neurotrophic effects of tissue plasminogen activator on cultured mouse cerebrocortical neurons.J Neurochem. 2007; 101:1236–1247.CrossrefMedlineGoogle Scholar - 60.
Flavin MP, Zhao G, Ho LT . Microglial tissue plasminogen activator (tPA) triggers neuronal apoptosis in vitro.Glia. 2000; 29:347–354.CrossrefMedlineGoogle Scholar - 61.
Liu D, Cheng T, Guo H, Fernández JA, Griffin JH, Song X, Zlokovic BV . Tissue plasminogen activator neurovascular toxicity is controlled by activated protein C.Nat Med. 2004; 10:1379–83.CrossrefMedlineGoogle Scholar - 62.
Medina MG, Ledesma MD, Domínguez JE, Medina M, Zafra D, Alameda F, . Tissue plasminogen activator mediates amyloid-induced neurotoxicity via Erk1/2 activation.EMBO J. 2005; 24:1706–1716.CrossrefMedlineGoogle Scholar - 63.
Henry VJ, Lecointre M, Laudenbach V, Ali C, Macrez R, Jullienne A, . High t-PA release by neonate brain microvascular endothelial cells under glutamate exposure affects neuronal fate.Neurobiol Dis. 2013; 50:201–208.CrossrefMedlineGoogle Scholar - 64.
Zhang C, An J, Haile WB, Echeverry R, Strickland DK, Yepes M . Microglial low-density lipoprotein receptor-related protein 1 mediates the effect of tissue-type plasminogen activator on matrix metalloproteinase-9 activity in the ischemic brain.J Cereb Blood Flow Metab. 2009; 29:1946–1954.CrossrefMedlineGoogle Scholar - 65.
Siao CJ, Fernandez SR, Tsirka SE . Cell type-specific roles for tissue plasminogen activator released by neurons or microglia after excitotoxic injury.J Neurosci. 2003; 23:3234–3242.CrossrefMedlineGoogle Scholar - 66.
Roda O, Ortiz-Zapater E, Martínez-Bosch N, Gutiérrez-Gallego R, Vila-Perelló M, Ampurdanés C, . Galectin-1 is a novel functional receptor for tissue plasminogen activator in pancreatic cancer.Gastroenterology. 2009; 136:1379–90, e1.CrossrefMedlineGoogle Scholar - 67.
Reichel CA, Lerchenberger M, Uhl B, Rehberg M, Berberich N, Zahler S, . Plasmin inhibitors prevent leukocyte accumulation and remodeling events in the postischemic microvasculature.PLoS One. 2011; 6:e17229.CrossrefMedlineGoogle Scholar - 68.
Uhl B, Zuchtriegel G, Puhr-Westerheide D, Praetner M, Rehberg M, Fabritius M, . Tissue plasminogen activator promotes postischemic neutrophil recruitment via its proteolytic and nonproteolytic properties.Arterioscler Thromb Vasc Biol. 2014; 34:1495–1504.LinkGoogle Scholar - 69.
Wang J, Zhang X, Mu L, Zhang M, Gao Z, Zhang J, . t-PA acts as a cytokine to regulate lymphocyte-endothelium adhesion in experimental autoimmune encephalomyelitis.Clin Immunol. 2014; 152:90–100.CrossrefMedlineGoogle Scholar - 70.
Akassoglou K, Kombrinck KW, Degen JL, Strickland S . Tissue plasminogen activator-mediated fibrinolysis protects against axonal degeneration and demyelination after sciatic nerve injury.J Cell Biol. 2000; 149:1157–1166.CrossrefMedlineGoogle Scholar - 71.
Benarroch EE . Tissue plasminogen activator: beyond thrombolysis.Neurology. 2007; 69:799–802.CrossrefMedlineGoogle Scholar - 72.
Bukhari N, Torres L, Robinson JK, Tsirka SE . Axonal regrowth after spinal cord injury via chondroitinase and the tissue plasminogen activator (tPA)/plasmin system.J Neurosci. 2011; 31:14931–14943.CrossrefMedlineGoogle Scholar - 73.
Nolin WB, Emmetsberger J, Bukhari N, Zhang Y, Levine JM, Tsirka SE . tPA-mediated generation of plasmin is catalyzed by the proteoglycan NG2.Glia. 2008; 56:177–189.CrossrefMedlineGoogle Scholar - 74.
Lemarchant S, Pruvost M, Hébert M, Gauberti M, Hommet Y, Briens A, . tPA promotes ADAMTS-4-induced CSPG degradation, thereby enhancing neuroplasticity following spinal cord injury.Neurobiol Dis. 2014; 66:28–42.CrossrefMedlineGoogle Scholar - 75.
Ling C, Zou T, Hsiao Y, Tao X, Chen ZL, Strickland S, . Disruption of tissue plasminogen activator gene reduces macrophage migration.Biochem Biophys Res Commun. 2006; 349:906–912.CrossrefMedlineGoogle Scholar - 76.
Krystosek A, Seeds NW . Plasminogen activator release at the neuronal growth cone.Science. 1981; 213:1532–1534.CrossrefMedlineGoogle Scholar - 77.
Moonen G, Grau-Wagemans MP, Selak I . Plasminogen activator- plasmin system and neuronal migration.Nature. 1982; 298:753–755.CrossrefMedlineGoogle Scholar - 78.
Krystosek A, Seeds NW . Plasminogen activator secretion by granule neurons in cultures of developing cerebellum.Proc Natl Acad Sci U S A. 1981; 78:7810–7814.CrossrefMedlineGoogle Scholar - 79.
Seeds NW, Basham ME, Haffke SP . Neuronal migration is retarded in mice lacking the tissue plasminogen activator gene.Proc Natl Acad Sci U S A. 1999; 96:14118–14123.CrossrefMedlineGoogle Scholar - 80.
Neuhoff H, Roeper J, Schweizer M . Activity-dependent formation of perforated synapses in cultured hippocampal neurons.Eur J Neurosci. 1999; 11:4241–4250.CrossrefMedlineGoogle Scholar - 81.
Zhang Y, Kanaho Y, Frohman MA, Tsirka SE . Phospholipase D1-promoted release of tissue plasminogen activator facilitates neurite outgrowth.J Neurosci. 2005; 25:1797–1805.CrossrefMedlineGoogle Scholar - 82.
Nakagami Y, Abe K, Nishiyama N, Matsuki N . Laminin degradation by plasmin regulates long-term potentiation.J Neurosci. 2000; 20:2003–2010.CrossrefMedlineGoogle Scholar - 83.
Qian Z, Gilbert ME, Colicos MA, Kandel ER, Kuhl D . Tissue-plasminogen activator is induced as an immediate-early gene during seizure, kindling and long-term potentiation.Nature. 1993; 361:453–457.CrossrefMedlineGoogle Scholar - 84.
Baranes D, Lederfein D, Huang YY, Chen M, Bailey CH, Kandel ER . Tissue plasminogen activator contributes to the late phase of LTP and to synaptic growth in the hippocampal mossy fiber pathway.Neuron. 1998; 21:813–825.CrossrefMedlineGoogle Scholar - 85.
Madani R, Hulo S, Toni N, Madani H, Steimer T, Muller D, . Enhanced hippocampal long-term potentiation and learning by increased neuronal expression of tissue-type plasminogen activator in transgenic mice.EMBO J. 1999; 18:3007–3012.CrossrefMedlineGoogle Scholar - 86.
Huang YY, Bach ME, Lipp HP, Zhuo M, Wolfer DP, Hawkins RD, . Mice lacking the gene encoding tissue-type plasminogen activator show a selective interference with late-phase long-term potentiation in both Schaffer collateral and mossy fiber pathways.Proc Natl Acad Sci U S A. 1996; 93:8699–8704.CrossrefMedlineGoogle Scholar - 87.
Centonze D, Napolitano M, Saulle E, Gubellini P, Picconi B, Martorana A, . Tissue plasminogen activator is required for corticostriatal long-term potentiation.Eur J Neurosci. 2002; 16:713–721.CrossrefMedlineGoogle Scholar - 88.
Zhuo M, Holtzman DM, Li Y, Osaka H, DeMaro J, Jacquin M, . Role of tissue plasminogen activator receptor LRP in hippocampal long-term potentiation.J Neurosci. 2000; 20:542–549.CrossrefMedlineGoogle Scholar - 89.
Lochner JE, Spangler E, Chavarha M, Jacobs C, McAllister K, Schuttner LC, . Efficient copackaging and cotransport yields postsynaptic colocalization of neuromodulators associated with synaptic plasticity.Dev Neurobiol. 2008; 68:1243–1256.CrossrefMedlineGoogle Scholar - 90.
Pang PT, Teng HK, Zaitsev E, Woo NT, Sakata K, Zhen S, . Cleavage of proBDNF by tPA/plasmin is essential for long-term hippocampal plasticity.Science. 2004; 306:487–491.CrossrefMedlineGoogle Scholar - 91.
Lu Y, Christian K, Lu B . BDNF: a key regulator for protein synthesis-dependent LTP and long-term memory?Neurobiol Learn Mem. 2008; 89:312–323.CrossrefMedlineGoogle Scholar - 92.
Nagappan G, Zaitsev E, Senatorov VV, Yang J, Hempstead BL, Lu B . Control of extracellular cleavage of ProBDNF by high frequency neuronal activity.Proc Natl Acad Sci U S A. 2009; 106:1267–1272.CrossrefMedlineGoogle Scholar - 93.
Li Y, Liu Z, Xin H, Chopp M . The role of astrocytes in mediating exogenous cell-based restorative therapy for stroke.Glia. 2014; 62:1–16.CrossrefMedlineGoogle Scholar - 94.
Macrez R, Obiang P, Gauberti M, Roussel B, Baron A, Parcq J, . Antibodies preventing the interaction of tissue-type plasminogen activator with N-methyl-D-aspartate receptors reduce stroke damages and extend the therapeutic window of thrombolysis.Stroke. 2011; 42:2315–2322.LinkGoogle Scholar - 95.
Wang X, Fan X, Yu Z, Liao Z, Zhao J, Mandeville E, . Effects of tissue plasminogen activator and annexin A2 combination therapy on long-term neurological outcomes of rat focal embolic stroke.Stroke. 2014; 45:619–622.LinkGoogle Scholar - 96.
Cheng T, Petraglia AL, Li Z, Thiyagarajan M, Zhong Z, Wu Z, . Activated protein C inhibits tissue plasminogen activator-induced brain hemorrhage.Nat Med. 2006; 12:1278–1285.CrossrefMedlineGoogle Scholar - 97.
Won S, Lee JH, Wali B, Stein DG, Sayeed I . Progesterone attenuates hemorrhagic transformation after delayed tPA treatment in an experimental model of stroke in rats: involvement of the VEGF-MMP pathway.J Cereb Blood Flow Metab. 2014; 34:72–80.CrossrefMedlineGoogle Scholar - 98.
Le Behot A, Gauberti M, Martinez De Lizarrondo S, Montagne A, . GpIbα-VWF blockade restores vessel patency by dissolving platelet aggregates formed under very high shear rate in mice.Blood. 2014; 123:3354–3363.CrossrefMedlineGoogle Scholar - 99.
Bhatia R, Hill MD, Shobha N, Menon B, Bal S, Kochar P, . Low rates of acute recanalization with intravenous recombinant tissue plasminogen activator in ischemic stroke: real-world experience and a call for action.Stroke. 2010; 41:2254–2258.LinkGoogle Scholar - 100.
Riedel CH, Zimmermann P, Jensen-Kondering U, Stingele R, Deuschl G, Jansen O . The importance of size: successful recanalization by intravenous thrombolysis in acute anterior stroke depends on thrombus length.Stroke. 2011; 42:1775–1777.LinkGoogle Scholar - 101.
Pawlak R, Melchor JP, Matys T, Skrzypiec AE, Strickland S . Ethanol-withdrawal seizures are controlled by tissue plasminogen activator via modulation of NR2B-containing NMDA receptors.Proc Natl Acad Sci U S A. 2005; 102:443–448.CrossrefMedlineGoogle Scholar - 102.
Alvarez V, Rossetti AO, Papavasileiou V, Michel P . Acute seizures in acute ischemic stroke: does thrombolysis have a role to play?J Neurol. 2013; 260:55–61.CrossrefMedlineGoogle Scholar - 103.
Mould WA, Carhuapoma JR, Muschelli J, Lane K, Morgan TC, McBee NA, . Minimally invasive surgery plus recombinant tissue-type plasminogen activator for intracerebral hemorrhage evacuation decreases perihematomal edema.Stroke. 2013; 44:627–34.LinkGoogle Scholar - 104.
Thiex R, Mayfrank L, Rohde V, Gilsbach JM, Tsirka SA . The role of endogenous versus exogenous tPA on edema formation in murine ICH.Exp Neurol. 2004; 189:25–32.CrossrefMedlineGoogle Scholar - 105.
Rohde V, Rohde I, Thiex R, Ince A, Jung A, Dückers G, . Fibrinolysis therapy achieved with tissue plasminogen activator and aspiration of the liquefied clot after experimental intracerebral hemorrhage: rapid reduction in hematoma volume but intensification of delayed edema formation.J Neurosurg. 2002; 97:954–962.CrossrefMedlineGoogle Scholar - 106.
Thiex R, Weis J, Krings T, Barreiro S, Yakisikli-Alemi F, Gilsbach JM, . Addition of intravenous N-methyl-D-aspartate receptor antagonists to local fibrinolytic therapy for the optimal treatment of experimental intracerebral hemorrhages.J Neurosurg. 2007; 106:314–320.CrossrefMedlineGoogle Scholar - 107.
Gaberel T, Montagne A, Lesept F, Gauberti M, Lemarchand E, Orset C, . Urokinase versus Alteplase for intraventricular hemorrhage fibrinolysis.Neuropharmacology. 2014; 85:158–165.CrossrefMedlineGoogle Scholar - 108.
Gaberel T, Macrez R, Gauberti M, Montagne A, Hebert M, Petersen KU, . Immunotherapy blocking the tissue plasminogen activator-dependent activation of N-methyl-D-aspartate glutamate receptors improves hemorrhagic stroke outcome.Neuropharmacology. 2013; 67:267–271.CrossrefMedlineGoogle Scholar
eLetters(0)
eLetters should relate to an article recently published in the journal and are not a forum for providing unpublished data. Comments are reviewed for appropriate use of tone and language. Comments are not peer-reviewed. Acceptable comments are posted to the journal website only. Comments are not published in an issue and are not indexed in PubMed. Comments should be no longer than 500 words and will only be posted online. References are limited to 10. Authors of the article cited in the comment will be invited to reply, as appropriate.
Comments and feedback on AHA/ASA Scientific Statements and Guidelines should be directed to the AHA/ASA Manuscript Oversight Committee via its Correspondence page.