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

Int J Biol Macromol. 2023 Dec 7:128618. doi: 10.1016/j.ijbiomac.2023.128618. Online ahead of print.ABSTRACTAdministration of recombinant tPA (rtPA, or a trade name Alteplase®) is an FDA-approved therapy for acute ischemic stroke (AIS), but often 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 a mutant variant of uPA serine protease domain, human serum albumin, and cyclic RGD peptide. PAItrap4 efficiently targets and inhibits PAI-1 on activated platelets, while also possessing a long half-life in vivo. Our results demonstrate that PAItrap4 effectively counteracts the inhibitory effects of PAI-1 on rtPA, thus 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 th...
Source: International Journal of Biological Macromolecules - Category: Biochemistry Authors: Source Type: research