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Clot injection technique affects thrombolytic efficacy in a rat embolic stroke model: implications for translaboratory collaborations.

ABSTRACT: Current recommendations encourage the use of embolic stroke (ES) models and replication of results across laboratories in preclinical research. Since such endeavors employ different surgeons, we sought to ascertain the impact of injection technique on outcome and response to thrombolysis in an ES model. Embolic stroke was induced in Male Wistar Kyoto rats (n=166) by a fast or a slow clot injection (CI) technique. Saline or recombinant tissue plasminogen activator (rtPA) was given at 1 hour after stroke. Flow rate curves were assessed in 24 animals. Cerebral perfusion was assessed using laser Doppler flowmetry. Edema corrected infarct volume, hemispheric swelling, hemorrhagic transformation, and neurologic outcome were assessed at 24 hours after stroke. Clot burden was estimated in a subset of animals (n=40). Slow CI resulted in significantly smaller infarct volumes (P=0.024) and better neurologic outcomes (P=0.01) compared with fast CI at 24 hours. Unexpectedly, rtPA treatment attenuated infarct size in fast (P<0.001) but not in slow CI experiments (P=0.382), possibly related to reperfusion injury as indicated by greater hemorrhagic transformation (P<0.001) and hemispheric swelling (P<0.05). Outcome and response to thrombolysis after ES are operator dependent, which needs to be considered when comparing results obtained from different laboratories.

SUBMITTER: Marinescu M

PROVIDER: S-EPMC3982093 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description: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.

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Clot injection technique affects thrombolytic efficacy in a rat embolic stroke model: implications for translaboratory collaborations.

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