Table 1.
Reported effects of tPA on challenged neurons.
| Reference | Model(s) | tPA | Mechanism(s) | |
|---|---|---|---|---|
| Beneficial | ||||
| Kim et al., 1999 | In vitro: cortical cultures exposure to 300 mM zinc (mice) | Exogenous 10 μg/ml | Independently of its proteolytic action, tPA attenuated zinc-induced cell death | |
| In vivo: kainate injection (10 mg/kg) in rats | Intracerebroventricular tPA 1 mg/ml | tPA attenuated kainate seizure-induced neuronal death in the hippocampus | ||
| Flavin and Zhao, 2001 |
In vitro: OGD, 2.5 h Cultured hippocampal neurons from rats (DIV 7–10) |
Exogenous 1,000 IU | tPA protects neurons from oxygen glucose deprivation (OGD) by a non-proteolytic action | |
| Centonze et al., 2002 | Ex vivo: striatal neurons WT and tPA –/– mice subjected to OGD | Endogenous | tPA enhanced ischemia-induced neuronal damage by facilitating apoptosis rather than necrosis | |
| Yi et al., 2004 |
In vitro: mixed cortical cell cultures (mice) Treatment: zinc (35 μmol/l) |
Exogenous 10 μg/ml | tPA attenuated zinc-induced neuronal death, independently of its proteolytic activity | |
| Head et al., 2009 |
In vitro: primary cultures of neurons (DIV 5–21) exposed to 1.4% isoflurane for 4 h In vivo: 1.4% isoflurane (anesthetic mediated neurotoxicity in mice) |
Exogenous 0.03–3 μg/ml | Isoflurane induced apoptosis at DIV 5 (but not DIV 14 or DIV 21) in cultured neurons tPA decreases isoflurane-induced cell death in primary cultures of neurons (DIV 5) Isoflurane-induced neurotoxicity in the developing rodent brain is mediated by reduced tPA synaptic release and enhanced proBDNF/p75NTR-mediated apoptosis | |
| Echeverry et al., 2010 | In vitro: cultures of hippocampal neurons (OGD conditions for 30 min (preconditioning) or not, followed 24 h later by incubation under OGD conditions for 55 min) | Endogenous (tPA KO mice) and exogenous (0–1 μM) | Treatment after OGD (early preconditionning). Beneficial effect of tPA involving a LRP1 dependent signaling pathway and independent of its proteolytic activity. Treatment 24 h after OGD (delayed preconditioning): beneficial effect of tPA via a NMDA-dependent signaling pathway (activation of pAkt), and activation of plasmin |
|
| Wu et al., 2012 | In vitro: cultures of cortical neurons (55 min OGD and then exposed 10 min later to a second episode of hypoxia (10 min OGD, post-conditioning)) | Endogenous (transgenic mice T4) | Decrease of the activation of mTor- HIFα, involving NMDAR | |
| Wu et al., 2013a |
In vivo: excitotoxin-induced neuronal death T4 mice and WT Intrastriatal injection of NMDA (50 mM) |
T4 mice or IV 1 mg/Kg on WT mice | tPA protected the brain from excitotoxin-induced cell death Dose-dependent effect of tPA on NMDA-induced neuronal death – 5 and 10 nM beneficial – 100 at 500 nM deleterious |
|
| (1) The neuroprotective effect of tPA was mediated by activation of synaptic GluN2A containing NMDAR via a plasminogen-independent mechanism (2) ERK activation mediated the protective effect of tPA against excitotoxin-induced neuronal death |
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| In vitro: cerebral cortical neurons (mice) NMDA induced neuronal death (50 M) | Exogenous 5–500 nM | (3) tPA activated the ERK -CREB-Atf3 pathway (4) Atf3-mediated the protective effect of tPA against excitotoxin-induced neuronal death |
||
| Wu et al., 2013b | In vitro: cultures of cortical neurons (OGD 55 min) | Endogenous (transgenic mice T4) | Adaptation to metabolic stress – AMPK activation involving NMDAR | |
| Henry et al., 2013 | Ex vivo: cortical brain slices from postnatal P10 mice | Exogenous (20 μg/mL) | tPA significantly reduced caspase-3 activity In superficial layers (less mature), tPA alone inhibited apoptosis via EGFR |
|
| No effects | ||||
| Vandenberghe et al., 1998 |
In vitro: spinal cords cultures of mice tPA –/– and WT (DIV 10–12) Kainate-induced death of motoneurons (20 and 100 μM for 24 h) |
Endogenous | tPA did not affect the vulnerability of cultured neurons to kainite | |
| Tucker et al., 2000 |
In vivo: primary cultures of rat cortical neurons Treatment: Aβ (16 or 25 μM) and plasminogen (30 nM) |
Exogenous 10 μg/ml | tPA required plasminogen to inhibit Aβ toxicity and to block Aβ deposition Degradation of Aβ fibrils is dependent on tPA and Plg proteolytic activity |
|
| Flavin and Zhao, 2001 |
In vitro: cultured hippocampal neurons from rats (DIV 7–10) ± NMDA 10 μM |
Exogenous 1,000 IU | tPA resulted in a modest exaggeration of this injury | |
| Yi et al., 2004 |
In vitro: mixed cortical cell cultures (mice) Treatment: NMDA (30 μmol/l) |
Exogenous 10 μg/ml | Calcium-mediated neuronal death was not attenuated by tPA | |
| Deleterious | ||||
| Tsirka et al., 1995 | In vivo: kainate induced neuronal death | Mouse tPA –/– | Endogenous | tPA is required to promote neuronal degeneration |
| Mouse WT | 120 μg tPA for 3 days (intra-parenchymal) | |||
| Wang et al., 1999 | In vitro: PC12 cells and primary cultures of cortical neurons (rats; DIV 12–14) | Exogenous 50 μg/ml | tPA significantly increased hemoglobin-induced cell death | |
| Flavin and Zhao, 2001 | In vitro: cultured hippocampal neurons on rats (DIV 7–10) ± plasminogen | Exogenous 100 IU | Proteolytic action | |
| Nicole et al., 2001 | In vitro: mixed cortical cultures or near-pure neuronal cultures (mice) | Exogenous 0.2–20 μg/ml | tPA failed to modify the neurotoxicity induced by the exposure to a non-NMDA agonist (kainate) | |
| Excitotoxicity: NMDA (10 or 12.5 μM) or 50 μM kainate Calcium imaging |
The catalytic activity of tPA enhanced neuronal death induced by exposure to NMDA tPA cleaves the GluN1 subunit of the NMDAR |
|||
| In vivo: NMDA induced excitotoxic lesions (rats) (50 nmol) | Exogenous 3.0 μg (intra-parenchymal) | |||
| Gabriel et al., 2003 |
In vitro: cultured cortical neurons (mice) Mixed cortical cultures of neurons and astrocytes (mice) |
Apoptosis: serum deprivation (DIV 7)Nifedipine (50 μM, DIV 14) Excitotoxicity (DIV 13–14) 12.5 μM of NMDA |
Endogenous | TGF-α rescued neurons from NMDA-induced excitotoxicity in mixed cultures through inhibition of tPA activity, involving PAI-1 overexpression by an ERK-dependent pathway in astrocytes |
| Liberatore et al., 2003 | In vivo: kainate-induced excitotoxicity on tPA –/– and WT mice (1.5 nmol of kainate) | Exogenous 1.85 μmol/L | Infusion of tPA into tPA –/– mice restored sensitivity to kainate-mediated neurotoxicity and activation of microglia | |
| In vivo: NMDA-induced excitotoxicity in mice (50 mmol/L NMDA) | Exogenous 46 μmol/L | tPA increased the lesion volumes induced by NMDA injection into the striatum | ||
| Liot et al., 2004 | In vitro: pure cultures of mouse cortical neurons exposed to NMDA (12.5 μmol/L) | Exogenous 20 μg/ml | Proteolytic activity | |
| Liu et al., 2004 |
In vitro: primary neuronal cultures (mice; DIV 14) NMDA treatment–induced apoptosis in neurons |
Exogenous 20 μg/ml | tPA potentiated apoptosis in mouse cortical neurons treated with N-methyl-D-aspartate (NMDA) by shifting the apoptotic pathway | |
| Benchenane et al., 2005 | In vivo: striatal excitotoxic lesions (rats; NMDA 50 nmol) | Exogenous IV 1 mg/kg | tPA potentiated excitotoxic lesions | |
| Lebeurrier et al., 2005 | In vivo: excitotoxic lesions in mice induced by NMDA (10 nmol in striatum or 20 nmol in cortex) | Endogenous | Overexpression of neuroserpin in the brain parenchyma might limit the deleterious effect of tPA on NMDAR-mediated neuronal death | |
| In vitro: neuronal cortical cultures from mice | Serum deprivation (DIV 7) | |||
| Treatment: neuroserpin (0.5–1 μM) | Excitotoxic paradigms (DIV 13–14) NMDA (12.5 μmol/l) AMPA (10 μmol/l) Calcium videomicroscopy |
|||
| Medina et al., 2005 | In vitro: mouse neuroblastoma N2a cells; primary cultures of hippocampal neurons tPA –/– or WT (mouse) | Exogenous 20 μg/ml | tPA induced Erk1/2 activation in neurons (independently of plasmin), tau phosphorylation and promoted A-beta mediated apoptosis tPA treatments induced GSK3 activation, tau hyperphosphorylation, microtubule destabilization and apoptosis in hippocampal neurons |
|
| Benchenane et al., 2007 |
In vivo studies: Excitotoxic lesions in mice performed by injection of NMDA (10 nmol) into the striatum In vivo studies: permanent MCAO in mice |
Exogenous 1 mg/kg |
Immunization against the NTD of the GluN1 subunit of NMDAR prevented the neurotoxic effect of endogenous and exogenous tPA | |
| López-Atalaya et al., 2007 | In vivo: striatal excitotoxic lesions (rats; 50 nmol) | Exogenous IV 1 mg/kg | tPA increased lesion volumes induced by NMDA (+40%) | |
| López-Atalaya et al., 2008 | In vitro: pure neuronal cultures (mice) | Excitotoxicity (NMDA 10 μmol/L) Calcium videomicroscopy (NMDA 12.5–100 μmol/L) |
Exogenous 0.3 μmol/L | Interaction of tPA with GluN1 led to a subsequent potentiation of NMDA-induced calcium influx and neurotoxicity |
| Wiegler et al., 2008 |
In vitro: hippocampal slices from P12 rats (OGD 30 min) Treatment: c-Jun N-terminal kinase inhibitor (XG-102; 12 nM 6 h after OGD) |
Exogenous 0.9 μg/ml | Addition of tPA after OGD enhanced neuronal death in CA1 and XG-102 administration reduced neuronal death, alone or in the presence of tPA | |
| Sun et al., 2009 |
In vitro: cultured dopaminergic neuroblasts (rat; N27 line) Treatments: aprotinine (200 KIU/ml), 𝜀-aminocaproic acid (2 mM), EGRck (Glu–Gly–Arg–CH2Cl, 100 mg/ml), FPRck (Phe–Pro–Arg–CH2Cl, 100 mg/ml), bivalirudin (20 mg/ml) |
Exogenous 10–20 μg/ml | tPA induced N27 neuroblast cell death. Aprotinin and other protease inhibitors led to an inhibition of tPA-mediated neurotoxicity Aprotinin, FPRck, and EGRck directly antagonized the proteolytic activity of tPA, whereas 𝜀-aminocaproic acid inhibited the binding of tPA to lysine residues on the cell surface |
|
| Baron et al., 2010 | In vitro study: cortical and hippocampal neurons from mice (DIV 7 or DIV 12–14). Excitotoxic neuronal death (NMDA 50 μM) | Exogenous 20 μg/ml | Catalytic tPA promoted NMDAR-induced Erk(1/2) MAPK activation tPA failed to potentiate excitotoxicity of hippocampal neurons lacking GluN2D tPA exacerbated neurotoxicity through GluN2D-containing NMDAR via Erk 1/2 |
|
| In vivo: excitotoxic lesions. Male Swiss mice Hippocampal or cortical bilateral injections of NMDA | Exogenous IV 10 mg/kg | |||
| Guo et al., 2011 |
In vitro: mouse cortical neurons (DIV14) Neuronal apoptosis model |
Exogenous 20 μg/ml | The anticoagulant factor protein S (PS) protects mouse cortical neurons from tPA/NMDA induced injury. PS blocks the extrinsic apoptotic cascade | |
| Jullienne et al., 2011 |
In vitro: cortical and hippocampal neurons (mice; DIV 12–13) Excitotoxic neuronal death: NMDA (10 μM) Treatment: UBP145 (0.2 μM) |
Exogenous 20 μg/mL | tPA increased NMDA-mediated neurotoxicity in cortical neuronal cultures but not in hippocampal neuronal cultures UBP145 had no effect on NMDA-mediated neurotoxicity in hippocampal neurons but prevented tPA-induced potentiation of NMDA-mediated neurotoxicity in cortical neurons |
|
|
In vivo: cortical excitotoxic lesions NMDA (mice; 2.5 nmol) Treatment: UBP145 (0.05 nmol) |
Exogenous IV 10 mg/kg | Inhibition of GluN2D-containing NMDAR with UBP145 can fully prevent the pro-excitotoxic effect of intravenously administered tPA | ||
| Rodríguez-González et al., 2011 | In vitro: primary mixed cortical cell cultures from rats (OGD 150 min) | Exogenous 5 mg/mL | Treatment with tPA after OGD increased LDH release, active MMP-9, MCP-1, and MIP-2 Treatment with neuroserpin after OGD decreased LDH release and active MMP-9 |
|
| Roussel et al., 2011 |
In vitro: primary cultures of cortical neurons (mice; DIV 10) Excitotoxicity induced by 10 μM NMDA Treatment: HMGB-1 0.3 μM |
Exogenous 0.3 μM | HMGB-1 reversed the pro-neurotoxic effect of tPA HMGB-1 prevented tPA from potentiating NMDA-evoked Ca2+ influx |
|
| Ma et al., 2012 |
In vitro: cultures of cortical neurons (rats; OGD/R) Treatment: neuroserpin |
Endogenous | Neuroserpin protected neurons against OGD/R. mainly by inhibiting tPA-mediated acute neuronal excitotoxicity | |
| Montagne et al., 2012 |
In vitro: cortical cultures of neurons from mice (DIV 12–13) Treatment: memantine (1–10 μmol/L) |
Excitotoxicity NMDA (10 μmol/L) OGD (30 min) Calcium videomicroscopy NMDA (50 μmol/L) |
Exogenous 0.3 μmol/L | Memantine prevented the potentiation of excitotoxic neuronal death induced by rtPA Memantine prevented rtPA-exacerbated calcium influx through activated NMDAR |
|
In vitro: cultures of cortical neurons from mice (DIV 15–16) Excitotoxic neuronal death: NMDA 50 μM |
Exogenous 0.3 μM | In contrast to WT tPA, tPA mutants including deletion of the kringle 2 domain and point mutation of the LBS-containing kringle 2 domain did not promote NMDAR-mediated neurotoxicity | ||
| Parcq et al., 2012 | In vitro | Excitotoxicity induced by exposure of cortical neurons to NMDA (mice; 50 μM) at DIV 14 | Exogenous 0.3 μM | sc-tPA promoted NMDAR-mediated neurotoxicity through its proteolytic activity, tc-tPA did not sc-tPA promoted both NMDA-induced calcium influx and Erk (½) activation, tc-tPA did not |
| NMDA-induced calcium influx recorded from cultured cortical neurons (mice; DIV 12–14) exposed to NMDA (50 μM) | ||||
| In vivo | NMDA-induced excitotoxic brain lesions (NMDA 10 mM) | Exogenous 45 μM | ||
| Henry et al., 2013 | Ex vivo: cortical brain slices from postnatal P10 mice | Exogenous 20 μg/mL | In deeper layers (more mature), tPA was associated with glutamate-promoted neuronal necrosis | |
| Omouendze et al., 2013 |
In vivo: excitotoxic insult by intra-cortical injection of Ibotenate in rats PAI-1 or tPA –/– or WT Ex vivo: brain sections |
Endogenous or exogenous 20 μg/ml | Neonatal brain lesions | |