ArticleMolecular and cellular neurosciences2013
Tissue-type plasminogen activator protects neurons from excitotoxin-induced cell death via activation of the ERK1/2-CREB-ATF3 signaling pathway.
Article in Molecular and cellular neurosciences, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 43 papers.
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Who cites it
43 citing papers in PubMed, 68 citations in OpenAlex.
- Tissue Plasminogen Activator as an Approved Strategy for Ischemic Stroke: A Review of tPA's Structure, Mechanism of Action and the Novel Targeting Methods.Journal of molecular neuroscience : MN · 2025Review
- New Wine in an Old Bottle: tPA for Ischemic Stroke Management.Translational stroke research · 2025Article
- The Janus face of endogenous neuronal tPA: promoting self-protection and worsening the death of neighboring neurons.Cell death & disease · 2024Article
- Glucocorticoid-Responsive Tissue Plasminogen Activator (tPA) and Its Inhibitor Plasminogen Activator Inhibitor-1 (PAI-1): Relevance in Stress-Related Psychiatric Disorders.International journal of molecular sciences · 2023Review
- Tissue-type plasminogen activator induces conditioned receptive field plasticity in the mouse auditory cortex.iScience · 2023Article
- Activating Transcription Factor 3 Diminishes Ischemic Cerebral Infarct and Behavioral Deficit by Downregulating Carboxyl-Terminal Modulator Protein.International journal of molecular sciences · 2023Article
- NMDA Receptor C-Terminal Domain Signalling in Development, Maturity, and Disease.International journal of molecular sciences · 2022Review
- Targeting NMDA Receptors at the Neurovascular Unit: Past and Future Treatments for Central Nervous System Diseases.International journal of molecular sciences · 2022Review
- Thrombolysis by PLAT/tPA increases serum free IGF1 leading to a decrease of deleterious autophagy following brain ischemia.Autophagy · 2022Article
- High fat diet-induced brain damaging effects through autophagy-mediated senescence, inflammation and apoptosis mitigated by ginsenoside F1-enhanced mixture.Journal of ginseng research · 2022Article
- Two-Chains Tissue Plasminogen Activator Unifies Met and NMDA Receptor Signalling to Control Neuronal Survival.International journal of molecular sciences · 2021Article
- Plasminogen Activators in Neurovascular and Neurodegenerative Disorders.International journal of molecular sciences · 2021Review
- Assessment of recombinant tissue plasminogen activator (rtPA) toxicity in cultured neural cells and subsequent treatment with poly-arginine peptide R18D.Neurochemical research · 2020Article
- The role of endogenous tissue-type plasminogen activator in neuronal survival after ischemic stroke: friend or foe?Cellular and molecular life sciences : CMLS · 2019Review
- Monoacylglycerol Lipase Inhibitor is Safe when Combined with Delayed r-tPA Administration in Treatment of Stroke.Inflammation · 2018Article
- Tissue-type plasminogen activator protects the postsynaptic density in the ischemic brain.Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism · 2018Article
- Worse Outcome in Stroke Patients Treated with rt-PA Without Early Reperfusion: Associated Factors.Translational stroke research · 2018Article
- PAI1 blocks NMDA receptor-mediated effects of tissue-type plasminogen activator on cell signaling and physiology.Journal of cell science · 2018Article
- Subacute intranasal administration of tissue plasminogen activator improves stroke recovery by inducing axonal remodeling in mice.Experimental neurology · 2018Article
- Activation of cell surface GRP78 decreases endoplasmic reticulum stress and neuronal death.Cell death and differentiation · 2017Article
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Authors and funding
8 authors at 3 institutions in 2 countries.
Funding
Abstract
The release of the serine proteinase tissue-type plasminogen activator (tPA) from cerebral cortical neurons has a neuroprotective effect in the ischemic brain. Because excitotoxicity is a basic mechanism of ischemia-induced cell death, here we investigated the effect of tPA on excitotoxin-induced neuronal death. We report that genetic overexpression of neuronal tPA or treatment with recombinant tPA renders neurons resistant to the harmful effects of an excitotoxic injury in vitro and in vivo. We found that at concentrations found in the ischemic brain, tPA interacts with synaptic but not extrasynaptic NMDARs. This effect is independent of tPA's proteolytic properties and leads to a rapid and transient phosphorylation of the extracellular signal regulated kinases1/2 (ERK1/2), with ERK1/2-mediated activation of the cAMP response element binding protein (CREB) and induction of the neuroprotective CREB-regulated activating transcription factor 3 (Atf3). In line with these observations, Atf3 down-regulation abrogates the protective effect of tPA against excitotoxin-induced neuronal death. Our data indicate that tPA preferentially activates synaptic NMDARs via a plasminogen-independent mechanism turning on a cell signaling pathway that protects neurons from the deleterious effects of excitotoxicity.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.