ArticlePloS one2017
Tissue plasminogen activator mediates deleterious complement cascade activation in stroke.
Article in PloS one, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
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Who cites it
27 citing papers in PubMed, 38 citations in OpenAlex.
- Molecular determinants of STEC-HUS: from complement activation to microvascular thrombosis.Frontiers in immunology · 2026Article
- Review
- PA System in the Pathogenesis of Ischemic Stroke.Arteriosclerosis, thrombosis, and vascular biology · 2025Review
- The Role of the Complement System in Synaptic Pruning after Stroke.Aging and disease · 2024Review
- Tranexamic acid for haemostasis and beyond: does dose matter?Thrombosis journal · 2023Review
- Role of microRNA-34a in blood-brain barrier permeability and mitochondrial function in ischemic stroke.Frontiers in cellular neuroscience · 2023Review
- Hemorrhagic Transformation After Tissue Plasminogen Activator Treatment in Acute Ischemic Stroke.Cellular and molecular neurobiology · 2022Review
- Article
- Targeting Complement C3a Receptor to Improve Outcome After Ischemic Brain Injury.Neurochemical research · 2021Review
- Fibrinolysis: A Primordial System Linked to the Immune Response.International journal of molecular sciences · 2021Review
- Screening of serum protein biomarkers in hemorrhagic cerebral infarction by surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF-MS) technology.Annals of translational medicine · 2020Article
- C3a receptor antagonist therapy is protective with or without thrombolysis in murine thromboembolic stroke.British journal of pharmacology · 2020Article
- Complement-Dependent Synaptic Uptake and Cognitive Decline after Stroke and Reperfusion Therapy.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2020Article
- Inhibition of GSK3β and RIP1K Attenuates Glial Scar Formation Induced by Ischemic StrokeFrontiers in pharmacology · 2020Article
- Tissue-Type Plasminogen Activator and Tenecteplase-Mediated Increase in Blood Brain Barrier Permeability Involves Cell Intrinsic Complement.Frontiers in neurology · 2020Article
- The Role of Complement C3a Receptor in Stroke.Neuromolecular medicine · 2019Review
- Acetyl-11-keto-β-boswellic acid (AKBA) Attenuates Oxidative Stress, Inflammation, Complement Activation and Cell Death in Brain Endothelial Cells Following OGD/Reperfusion.Neuromolecular medicine · 2019Article
- The role of endogenous tissue-type plasminogen activator in neuronal survival after ischemic stroke: friend or foe?Cellular and molecular life sciences : CMLS · 2019Review
- C3a Receptor Inhibition Protects Brain Endothelial Cells Against Oxygen-glucose Deprivation/Reperfusion.Experimental neurobiology · 2019Article
- Therapeutic Modulation of the Complement Cascade in Stroke.Frontiers in immunology · 2019Review
Corrections and comments
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Authors and funding
5 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The use of intravenous tissue plasminogen activator (tPA) in the treatment of ischemic stroke is limited by its propensity to exacerbate brain edema and hemorrhage. The mechanisms underlying these deleterious effects of tPA remain incompletely understood. The purpose of this study was to delineate a pathway of tPA-mediated complement cascade activation in stroke and to determine whether complement inhibition ameliorates the adverse effects of post-ischemic tPA administration. We found that tPA promotes C3 cleavage both in vitro and in ischemic brain through a plasmin-mediated extrinsic pathway. Using cell culture models, we then showed that the C3a-receptor is strongly expressed on ischemic endothelium and that exogenous C3a dramatically enhances endothelial cell permeability. Next, we assessed the effect of tPA administration on brain edema and hemorrhage in a transient model of focal cerebral ischemia in C57BL/6 mice. We found that intravenous tPA exacerbates brain edema and hemorrhage in stroke, and that these effects are abrogated by a small-molecule antagonist of the C3a receptor. These findings establish for the first time that intravenous tPA dramatically upregulates complement cascade activation in ischemic brain and that pharmacologic complement inhibition protects against the adverse effects of tPA-mediated thrombolysis in stroke.
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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.