ArticleBlood advances2024
Improving stroke outcomes in hyperglycemic mice by modulating tPA/NMDAR signaling to reduce inflammation and hemorrhages.
Article in Blood advances, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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Who cites it
10 citing papers in PubMed, 11 citations in OpenAlex.
- Effects of Antioxidant DI-3-N-Butylphthalide on Hemorrhagic Transformation Assessed by Propensity Score Matching in a Real-World Thrombolyzed Ischemic Stroke Patient Setting.Translational stroke research · 2026Article
- Ischemic stroke: molecular mechanisms of blood-brain barrier dysfunction and opportunities for drug development.Fluids and barriers of the CNS · 2026Review
- N-Methyl-D-aspartate receptors: structure, signaling and roles in atherosclerosis.Journal of translational medicine · 2026Review
- Decompressive Craniectomy Decreases Neuroinflammation after Ischemic Stroke in Mice.Translational stroke research · 2026Article
- Toward improved thrombolysis in ischemic stroke: targeting nonfibrin components.Research and practice in thrombosis and haemostasis · 2026Review
- Engineered nanoconjugates for simultaneous detection and degradation of stroke-associated microthrombi.Theranostics · 2026Article
- Restoring brain barriers: an innovative approach for treating neurological disorders.Fluids and barriers of the CNS · 2025Review
- Voclosporin promotes neurological function recovery by inhibiting inflammation and maintaining blood-brain barrier integrity following rtPA reperfusion after MCAO in mice.Inflammopharmacology · 2025Article
- Serum anti-NMDA receptor antibodies are linked to memory impairment 12 months after stroke.Molecular psychiatry · 2025Article
- A sweet deal: blocking NMDAR for safer t-PA in diabetes.Blood advances · 2024Article
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Authors and funding
15 authors at 3 institutions in 1 country.
Funding
Abstract
abstractThe pharmacological intervention for ischemic stroke hinges on intravenous administration of the recombinant tissue-type plasminogen activator (rtPA, Alteplase/Actilyse) either as a standalone treatment or in conjunction with thrombectomy. However, despite its clinical significance, broader use of rtPA is constrained because of the risk of hemorrhagic transformations (HTs). Furthermore, the presence of diabetes or chronic hyperglycemia is associated with an elevated risk of HT subsequent to thrombolysis. This detrimental impact of tPA on the neurovascular unit in patients with hyperglycemia has been ascribed to its capacity to induce endothelial N-methyl-D-aspartate receptor (NMDAR) signaling, contributing to compromised blood-brain barrier integrity and neuroinflammatory processes. In a mouse model of thromboembolic stroke with chronic hyperglycemia, we assessed the effectiveness of rtPA and N-acetylcysteine (NAC) as thrombolytic agents. We also tested the effect of blocking tPA/NMDAR signaling using a monoclonal antibody, Glunomab. Magnetic resonance imaging, speckle contrast imaging, flow cytometry, and behavioral tasks were used to evaluate stroke outcomes. In hyperglycemic animals, treatment with rtPA resulted in lower recanalization rates and increased HTs. Conversely, NAC treatment reduced lesion sizes while mitigating HTs. After a single administration, either in standalone or combined with rtPA-induced thrombolysis, Glunomab reduced brain lesion volumes, HTs, and neuroinflammation after stroke, translating into improved neurological outcomes. Additionally, we demonstrated the therapeutic efficacy of Glunomab in combination with NAC or as a standalone strategy in chronic hyperglycemic animals. Counteracting tPA-dependent endothelial NMDAR signaling limits ischemic damages induced by both endogenous and exogenous tPA, including HTs and inflammatory processes after ischemic stroke in hyperglycemic animals.
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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.