Platelet-targeted thrombolysis for treatment of acute ischemic stroke.
Mice
Animals
Ischemic Stroke
/ complications
Infarction, Middle Cerebral Artery
/ complications
Tissue Distribution
Thrombolytic Therapy
/ adverse effects
Fibrinolytic Agents
/ therapeutic use
Stroke
/ etiology
Urokinase-Type Plasminogen Activator
Thrombosis
/ drug therapy
Platelet Glycoprotein GPIIb-IIIa Complex
Journal
Blood advances
ISSN: 2473-9537
Titre abrégé: Blood Adv
Pays: United States
ID NLM: 101698425
Informations de publication
Date de publication:
28 02 2023
28 02 2023
Historique:
accepted:
09
04
2022
received:
29
11
2021
pubmed:
29
4
2022
medline:
25
2
2023
entrez:
28
4
2022
Statut:
ppublish
Résumé
Thrombolysis with tissue-type plasminogen activator (tPA) remains the main treatment for acute ischemic stroke. Nevertheless, tPA intervention is limited by a short therapeutic window, low recanalization rates, and a risk of intracranial hemorrhage (ICH), highlighting the clinical demand for improved thrombolytic drugs. We examined a novel thrombolytic agent termed "SCE5-scuPA," comprising a single-chain urokinase plasminogen activator (scuPA) fused with a single-chain antibody (SCE5) that targets the activated glycoprotein IIb/IIIa platelet receptor, for its effects in experimental stroke. SCE5-scuPA was first tested in a whole blood clot degradation assay to show the benefit of platelet-targeted thrombolysis. The tail bleeding time, blood clearance, and biodistribution were then determined to inform the use of SCE5-scuPA in mouse models of photothrombotic stroke and middle cerebral artery occlusion against tenecteplase. The impacts of SCE5-scuPA on motor function, ICH, blood-brain barrier (BBB) integrity, and immunosuppression were evaluated. Infarct size was measured by computed tomography imaging and magnetic resonance imaging. SCE5-scuPA enhanced clot degradation ex vivo compared with its nonplatelet-targeting control. The maximal SCE5-scuPA dose that maintained hemostasis and a rapid blood clearance was determined. SCE5-scuPA administration both before and 2 hours after photothrombotic stroke reduced the infarct volume. SCE5-scuPA also improved neurologic deficit, decreased intracerebral blood deposits, preserved the BBB, and alleviated immunosuppression poststroke. In middle cerebral artery occlusion, SCE5-scuPA did not worsen stroke outcomes or cause ICH, and it protected the BBB. Our findings support the ongoing development of platelet-targeted thrombolysis with SCE5-scuPA as a novel emergency treatment for acute ischemic stroke with a promising safety profile.
Identifiants
pubmed: 35482909
pii: 485108
doi: 10.1182/bloodadvances.2021006691
pmc: PMC9984306
doi:
Substances chimiques
Fibrinolytic Agents
0
Urokinase-Type Plasminogen Activator
EC 3.4.21.73
Platelet Glycoprotein GPIIb-IIIa Complex
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
561-574Informations de copyright
© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.
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