Specific inhibition on PAI-1 reduces the dose of Alteplase for ischemic stroke treatment.

Abstract

Administration of recombinant tPA (rtPA, or trade name Alteplase®) is an FDA-approved therapy for acute ischemic stroke (AIS), but poses the risk of hemorrhagic complications. Recombinant tPA can be rapidly inactivated by the endogenous inhibitor, plasminogen activator inhibitor 1 (PAI-1). In this work, we study a novel treatment approach that combines a PAI-1 inhibitor, PAItrap4, with a reduced dose of rtPA to address the hemorrhagic concern of rtPA. PAItrap4 is a highly specific and very potent protein-based inhibitor of PAI-1, comprising of a variant of uPA serine protease domain, human serum albumin, and a cyclic RGD peptide. PAItrap4 efficiently targets and inhibits PAI-1 on activated platelets, and also possesses a long half-life in vivo. Our results demonstrate that PAItrap4 effectively counteracts the inhibitory effects of PAI-1 on rtPA, preserving rtPA activity based on amidolytic and clot lysis assays. In an in vivo murine stroke model, PAItrap4, together with low-dose rtPA, enhances the blood perfusion in the stroke-affected areas, reduces infarct size, and promotes neurological recovery in mice. Importantly, such treatment does not increase the amount of cerebral hemorrhage, thus reducing the risk of cerebral hemorrhage. In addition, PAItrap4 does not compromise the normal blood coagulation function in mice, demonstrating its safety as a therapeutic agent. These findings highlight this combination therapy as a promising alternative for the treatment of ischemic stroke, offering improved safety and efficacy.

• Authors: Yanyan Xu, Yinping Hu, Guangqian Wu, Lili Niu, Chao Fang, Yongkun Li, Longguang Jiang, Cai Yuan, Mingdong Huang
• Journal: International journal of biological macromolecules (Int J Biol Macromol) Vol. 257 Issue Pt 2 Pg. 128618 (Feb 2024) ISSN: 1879-0003 [Electronic] Netherlands
• PMID: 38070813 (Publication Type: Journal Article)
• Copyright: Copyright © 2023 Elsevier B.V. All rights reserved.

Chemical References

• Tissue Plasminogen Activator
• Plasminogen Activator Inhibitor 1
• Fibrinolytic Agents

Topics

• Humans
• Mice
• Animals
• Tissue Plasminogen Activator (pharmacology, therapeutic use)
• Plasminogen Activator Inhibitor 1
• Ischemic Stroke (complications, drug therapy)
• Stroke (drug therapy, complications)
• Cerebral Hemorrhage (complications, drug therapy)
• Fibrinolytic Agents (pharmacology, therapeutic use)