Abstract

Background: Hemorrhagic transformation, neurotoxicity, short treatment time windows, and other defects are considered as the major limitations for the thrombolytic therapy. This study is devoted to figure out whether Danhong injection (DHI) combined with tissue-plasminogen activator (t-PA) could extend the treatment time windows and ameliorate brain injury, hemorrhagic complication and BBB disruption after focal embolic stroke.Methods: In vitro, the combined concentrations of DHI and t-PA were added to wells reacted with plasminogen and D-Val-Leu-Lys-AMC. The optimum ratio of the combination of DHI plus t-PA was explored by detecting relative fluorescent. In vivo experiments, we firstly investigated the optimal dose of t-PA and Danhong injection for focal embolic stroke. The neurological deficit score, infarct volume and brain edema were assessed. Secondly, we proved that the combination group extended the thrombolytic window for treatment of focal embolic stroke. The neurological deficit score, infarct volume, brain edema and hemorrhagic complication were assessed, while levels of BAX, Bcl-2 and caspase-3 in brain tissue were analyzed by real-time polymerase chain reaction. Finally, to ask whether combination therapy with DHI plus t-PA protected the blood–brain barrier in a rat model of focal embolic stroke, neurological deficit score, ELISA, RT-PCR, western blot and fluorescence were used to detect the indicators of blood–brain barrier, such as tight junction protein, blood–brain barrier permeability and related gene expression.Results: In vitro, plasmin activity assays showed that the combination of t-PA with DHI at about 1:1.6 w/v ratio increased by almost 1.4-fold the plasmin-generating capability of t-PA. In vivo experiments, the results showed that the combination of Danhong injection (4 mL/kg) and t-PA (2.5 mg/kg) could extend the t-PA treatment time windows to 4.5 h. And the combination t-PA (2.5 mg/kg) with DHI (4 mL/kg) ameliorated neurological score, cerebral infarction, brain edema, brain hemorrhage, and BBB disruption.Conclusion: Combination therapy with Danhong injection (4 mL/kg) plus t-PA (2.5 mg/kg) could extend the t-PA treatment time windows to 4.5 h, ameliorate BBB disruption, reduce infarction, brain swelling and hemorrhage after ischemic stroke.

Highlights

  • Ischemic stroke is a leading cause of death, disability, and massive socioeconomic loss worldwide (Wang et al, 2014)

  • Equal activity of plasmin could be reached by different combinations with lower dose tissue plasminogen activator (t-PA) with Danhong injection (DHI), such as t-PA 10 μg/mL plus DHI 4 μL/mL, t-PA 5 μg/mL plus DHI 4 μL/mL, t-PA 2.5 μg/mL plus DHI 4 μL/mL

  • The data of assay indicated that the plasmingenerating capability of combining t-PA with DHI at 1:1.6 w/v ratio was increased by almost 1.4-fold of t-PA in vitro

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Summary

Introduction

Ischemic stroke is a leading cause of death, disability, and massive socioeconomic loss worldwide (Wang et al, 2014). It is imperative to seek combination therapies that will truly extend the treatment time window, while reducing the risk of t-PA-associated hemorrhagic transformation, and enhancing thrombolytic efficacy (Whiteley et al, 2014). For this perspective, Danhong injection may be a compelling candidate. This study is devoted to figure out whether Danhong injection (DHI) combined with tissue-plasminogen activator (t-PA) could extend the treatment time windows and ameliorate brain injury, hemorrhagic complication and BBB disruption after focal embolic stroke

Methods
Results
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