scholarly journals Pinocembrin Protects Blood-Brain Barrier Function and Expands the Therapeutic Time Window for Tissue-Type Plasminogen Activator Treatment in a Rat Thromboembolic Stroke Model

2018 ◽  
Vol 2018 ◽  
pp. 1-13 ◽  
Author(s):  
YinZhong Ma ◽  
Li Li ◽  
LingLei Kong ◽  
ZhiMei Zhu ◽  
Wen Zhang ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Plasminogen Activator ◽  
Blood Brain Barrier ◽  
Time Window ◽  
Tissue Type ◽  
Stroke Model ◽  
Thromboembolic Stroke ◽  
Tissue Type Plasminogen Activator ◽  
Type Plasminogen Activator ◽  
Therapeutic Time Window

Tissue-type plasminogen activator (t-PA) remains the only approved therapy for acute ischemic stroke but has a restrictive treatment time window of 4.5 hr. Prolonged ischemia causes blood-brain barrier (BBB) damage and increases the incidence of hemorrhagic transformation (HT) secondary to reperfusion. In this study, we sought to determine the effect of pinocembrin (PCB; a pleiotropic neuroprotective agent) on t-PA administration-induced BBB damage in a novel rat thromboembolic stroke model. By assessing the leakage of Evans blue into the ischemic hemisphere, we demonstrated that PCB pretreatment 5 min before t-PA administration significantly reduced BBB damage following 2 hr, 4 hr, 6 hr, and even 8 hr ischemia. Consistently, PCB pretreatment significantly decreased t-PA infusion-resulting brain edema and infarction volume and improved the behavioral outcomes following 6 hr ischemia. Mechanistically, PCB pretreatment inhibited the activation of MMP-2 and MMP-9 and degradation of tight junction proteins (TJPs) occludin and claudin-5 in the ischemic hemisphere. Moreover, PCB pretreatment significantly reduced phosphorylation of platelet-derived growth factor receptor α (PDGFRα) as compared with t-PA alone. In an in vitro BBB model, PCB decreased transendothelial permeability upon hypoxia/aglycemia through inhibiting PDGF-CC secretion. In conclusion, we demonstrated that PCB pretreatment shortly before t-PA infusion significantly protects BBB function and improves neurological outcomes following prolonged ischemia beyond the regular 4.5 hr t-PA time window. PCB pretreatment may represent a novel means of increasing the safety and the therapeutic time window of t-PA following ischemic stroke.

scholarly journals Iron Overload Exacerbates the Risk of Hemorrhagic Transformation After tPA (Tissue-Type Plasminogen Activator) Administration in Thromboembolic Stroke Mice

Stroke ◽  
2018 ◽  
Vol 49 (9) ◽  
pp. 2163-2172 ◽  
Author(s):  
Isaac García-Yébenes ◽  
Alicia García-Culebras ◽  
Carolina Peña-Martínez ◽  
David Fernández-López ◽  
Jaime Díaz-Guzmán ◽  
...  
Keyword(s):  
Iron Overload ◽  
Plasminogen Activator ◽  
Hemorrhagic Transformation ◽  
Tissue Type ◽  
Thromboembolic Stroke ◽  
Tissue Type Plasminogen Activator ◽  
Type Plasminogen Activator

Abstract 1029: Stromelysin-1 is Critical For Intracranial Bleeding After Tissue-type plasminogen activator Treatment Of Stroke In Mice

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Yasuhiro Suzuki ◽  
Nobuo Nagai ◽  
Desire Collen ◽  
Roger Lijnen ◽  
Kazuo Umemura
Keyword(s):  
Ischemic Stroke ◽  
Plasminogen Activator ◽  
Placebo Treatment ◽  
Artery Occlusion ◽  
Intracranial Bleeding ◽  
Tissue Type ◽  
Tissue Type Plasminogen Activator ◽  
Mmp Inhibitor ◽  
Type Plasminogen Activator ◽  
Cerebral Artery Occlusion

Background: Tissue-type plasminogen activator (t-PA) is approved for treatment of ischemic stroke patients, but it may increase the risk of intracranial bleeding (ICB). Matrix metalloproteinases (MMPs), which can be activated through the plasminogen/plasmin system, may contribute to ICB after ischemic stroke. Objectives: To explore the contribution of plasminogen, MMP-3 and MMP-9 to ICB associated with t-PA treatment after ischemic stroke. Methods: Using a thrombotic middle cerebral artery occlusion (MCA-O) model, ICB was studied in mice with genetic deficiencies of plasminogen (Plg −/ − ), stromelysin-1 (MMP-3 −/ − ) or gelatinase B (MMP-9 −/ − ) and their corresponding wild-type (WT) littermates. t-PA (10 mg/kg) or its equivalent volume of solvent was administered intravenously 4 hours after MCA-O. The induction of MMP-3 and MMP-9 was also studied in C57BL/6 WT mice. Results: In MMP-3 +/+ WT mice given solvent, ICB was 4.3 ± 2.9 mm 3 (mean ± SD), which was significantly increased with tPA treatment to 9.7 ± 4.7 mm 3 (P<0.05), whereas ICB in MMP-3 −/ − mice was not altered by t-PA treatment (5.7 ± 2.7 mm 3 , as compared to 5.1 ± 1.8 mm 3 without tPA; n = 7–9 in each group). ICB induced by t-PA was significantly less in Plg −/ − (5.7 ± 3.9 mm 3 ) than in WT mice (8.8 ± 3.2 mm 3 , p<0.05) but ICB by t-PA in MMP-9 −/ − (8.3 ± 2.3 mm 3 ) was comparable with that in WT (8.3 ± 3.1 mm 3 ; n=8 –12 in each group). Administration of the broad-spectrum MMP inhibitor GM6001 after t-PA treatment reduced ICB significantly in MMP-3 +/+ (from 6.4 ± 1.9 mm 3 to 4.1 ± 1.9 mm 3 , p<0.05) but not in MMP-3 −/ − mice (2.2 ± 0.6 mm 3 without versus 2.9 ± 1.5 mm 3 with GM6001; n=6 – 8 in each group). MMP-3 expression was significantly enhanced at the ischemic hemisphere; with placebo treatment, it was expressed only in neurons, whereas it was upregulated in endothelial cells with t-PA treatment. Although MMP-9 expression was also significantly enhanced at the ischemic brain, the amount and the distribution were comparable in mice with and without t-PA treatment. Conclusions: Our data with gene deficient mice suggest that plasminogen and MMP-3 are relatively more important than MMP-9 for the increased ICB induced by t-PA treatment of ischemic stroke.

Abstract TMP19: Intravenous Recombinant Tissue-type Plasminogen Activator Use in Young Adults With Acute Ischemic Stroke

Stroke ◽  
2017 ◽  
Vol 48 (suppl_1) ◽  
Author(s):  
Jodi A Dodds ◽  
Ying Xian ◽  
Shubin Sheng ◽  
Gregg Fonarow ◽  
Ronald A Matsouaka ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Acute Ischemic Stroke ◽  
Plasminogen Activator ◽  
Older Patients ◽  
Young Patients ◽  
Tissue Type ◽  
Stroke Patients ◽  
Younger Patients ◽  
Tissue Type Plasminogen Activator ◽  
Type Plasminogen Activator

Background: Intravenous recombinant tissue-type plasminogen activator (rt-PA) administration improves outcomes in acute ischemic stroke. However, young patients (<40 years old) presenting with stroke symptoms may experience delays in treatment due to misdiagnosis or a reluctance to treat since they do not fit the profile of a typical stroke patient. Methods: We analyzed data from the large national Get With The Guidelines–Stroke registry for acute ischemic stroke patients hospitalized between January 2009 and September 2015. Multivariable models with generalized estimating equations (GEE) were used to test for differences between younger (age 18-40) and older (age > 40) acute ischemic stroke patients, controlling for patient and hospital characteristics including stroke severity. Results: Of 1,320,965 AIS patients admitted to participating hospitals, 2.3% (30,448) were aged 18-40. Among these patients, 12.5% received rt-PA versus 8.8% of those aged >40 (p<0.001). Of patients arriving within 3.5 hours of symptom onset without contraindications, 68.7% of younger patients received IV rt-PA versus 63.3% of older patients (adjusted OR [aOR] 1.30, 95% CI 1.21 to 1.40), without evidence that age-related differences varied by sex (interaction p-value 0.25). Odds ratios of achieving target door-to-CT times and door-to-needle (DTN) times, and outcomes of rtPA-treated patients, are shown in the Table. Conclusions: Young acute ischemic stroke patients did not receive rt-PA treatment at lower rates than older patients. Outcomes were better and the rate of symptomatic intracranial hemorrhage was lower in the young patients. However, younger patients had significantly longer door-to-CT and DTN times, providing an opportunity to improve the care of these patients.

scholarly journals Strategies Used by Hospitals to Improve Speed of Tissue-Type Plasminogen Activator Treatment in Acute Ischemic Stroke

Stroke ◽  
2014 ◽  
Vol 45 (5) ◽  
pp. 1387-1395 ◽  
Author(s):  
Ying Xian ◽  
Eric E. Smith ◽  
Xin Zhao ◽  
Eric D. Peterson ◽  
DaiWai M. Olson ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Acute Ischemic Stroke ◽  
Plasminogen Activator ◽  
Tissue Type ◽  
Tissue Type Plasminogen Activator ◽  
Type Plasminogen Activator

scholarly journals Intravenous Tissue-Type Plasminogen Activator in Acute Ischemic Stroke Patients With History of Stroke Plus Diabetes Mellitus

Stroke ◽  
2019 ◽  
Vol 50 (6) ◽  
pp. 1497-1503 ◽  
Author(s):  
Matthew E. Ehrlich ◽  
Li Liang ◽  
Haolin Xu ◽  
Andrzej S. Kosinski ◽  
Adrian F. Hernandez ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Ischemic Stroke ◽  
Acute Ischemic Stroke ◽  
Plasminogen Activator ◽  
Tissue Type ◽  
Stroke Patients ◽  
Tissue Type Plasminogen Activator ◽  
Type Plasminogen Activator ◽  
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