ArticleStroke2012
An activated protein C analog with reduced anticoagulant activity extends the therapeutic window of tissue plasminogen activator for ischemic stroke in rodents.
Article in Stroke, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 44 papers, 1 of them a synthesis that pooled it.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
44 citing papers in PubMed, 1 synthesis or guideline pooled it, 65 citations in OpenAlex.
- Antithrombotic Agents for tPA-Induced Cerebral Hemorrhage: A Systematic Review and Meta-Analysis of Preclinical Studies.Journal of the American Heart Association · 2020Pooled it
- Trial
- Selecting Patients for Intra-Arterial Therapy in the Context of a Clinical Trial for Neuroprotection.Stroke · 2016Trial
- Phase 1 safety, tolerability and pharmacokinetics of 3K3A-APC in healthy adult volunteers.Current pharmaceutical design · 2013Trial
- In vivo neuroprotection in ischemic stroke by activated protein C requires β-arrestin 2.Blood vessels, thrombosis & hemostasis · 2025Article
- Therapeutic management of ischemic stroke.Naunyn-Schmiedeberg's archives of pharmacology · 2024Review
- Protection of ischemic white matter and oligodendrocytes in mice by 3K3A-activated protein C.The Journal of experimental medicine · 2022Article
- 3K3A-Activated Protein C Protects the Blood-Brain Barrier and Neurons From Accelerated Ischemic Injury Caused by Pericyte Deficiency in Mice.Frontiers in neuroscience · 2022Article
- Neuroprotection in Acute Ischemic Stroke: A Battle Against the Biology of Nature.Frontiers in neurology · 2022Review
- Emerging neuroprotective strategies for the treatment of ischemic stroke: An overview of clinical and preclinical studies.Experimental neurology · 2021Review
- Stroke Treatment With PAR-1 Agents to Decrease Hemorrhagic Transformation.Frontiers in neurology · 2021Review
- Activated Mesenchymal Stem Cells Induce Recovery Following Stroke Via Regulation of Inflammation and Oligodendrogenesis.Journal of the American Heart Association · 2020Article
- Neuroprotection and vasculoprotection using genetically targeted protease-ligands.Brain research · 2019Article
- Pericyte loss leads to circulatory failure and pleiotrophin depletion causing neuron loss.Nature neuroscience · 2019Article
- tPA Helpers in the Treatment of Acute Ischemic Stroke: Are They Ready for Clinical Use?Journal of stroke · 2019Review
- TRIM9-Mediated Resolution of Neuroinflammation Confers Neuroprotection upon Ischemic Stroke in Mice.Cell reports · 2019Article
- β-arrestin-2 in PAR-1-biased signaling has a crucial role in endothelial function via PDGF-β in stroke.Cell death & disease · 2019Article
- 3K3A-activated protein C blocks amyloidogenic BACE1 pathway and improves functional outcome in mice.The Journal of experimental medicine · 2019Article
- PAR1 biased signaling is required for activated protein C in vivo benefits in sepsis and stroke.Blood · 2018Article
- Early administration of pyrrolidine dithiocarbamate extends the therapeutic time window of tissue plasminogen activator in a male rat model of embolic stroke.Journal of neuroscience research · 2018Article
Corrections and comments
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Authors and funding
7 authors at 3 institutions in 1 country.
Funding
Abstract
background and purposeTissue plasminogen activator (tPA) is the only approved therapy for acute ischemic stroke. However, tPA has a brief therapeutic window. Its side effects include intracerebral bleeding and neurotoxicity. Therefore, a combination therapy with tPA and agents that can extend the therapeutic window of tPA and/or counteract its side effects are warranted. Here, we studied whether 3K3A-APC, a neuroprotective analog of activated protein C with reduced anticoagulant activity, can enhance the therapeutic effects of tPA in models of ischemic stroke in rodents.
methodsHuman recombinant tPA (10 mg/kg), alone or in combination with human recombinant 3K3A-APC (2 mg/kg), was administered intravenously 4 hours after proximal or distal transient middle cerebral artery occlusion in mice and embolic stroke in rats. The 3K3A-APC was additionally administered for 3 to 4 consecutive days after stroke. The neuropathological and neurological analyses were performed at 1 to 7 days after stroke.
resultsIn all models, tPA alone had no effects on the infarct volume or behavior (ie, neurological score, foot-fault, forelimb asymmetry, adhesive removal) compared with vehicle. The tPA and 3K3A-APC combination therapy reduced the infarct volume 24 hours and 7 days after proximal or distal transient middle cerebral artery occlusion in mice and 7 days after embolic stroke in rats by 65%, 63%, and 52%, respectively, significantly (P<0.05) improved behavior and eliminated tPA-induced intracerebral microhemorrhages.
conclusionsThe 3K3A-APC extends the therapeutic window of tPA for ischemic stroke in rodents. Therefore, this combination therapy also should be considered for treating stroke in humans.
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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.