Early Electroacupuncture Extends the rtPA Time Window to 6 h in a Male Rat Model of Embolic Stroke via the ERK1/2-MMP9 Pathway

Background. Recombinant tissue plasminogen activator (rtPA) is the only recommended pharmacological treatment for acute ischemic stroke, but it has a restricted therapeutic time window. When administered at time points greater than 4.5 h after stroke onset, rtPA disrupts the blood-brain barrier (BBB), which leads to serious brain edema and hemorrhagic transformation. Electroacupuncture (EA) exerts a neuroprotective effect on cerebral ischemia; however, researchers have not clearly determined whether EA increases the safety of thrombolysis and extends the therapeutic time window of rtPA administration following ischemic stroke. Objective. The present study was conducted to test the hypothesis that EA extends the therapeutic time window of rtPA for ischemic stroke in a male rat model of embolic stroke. Methods. SD rats were randomly divided into the sham operation group, model group, rtPA group, EA+rtPA group, and rtPA+MEK1/2 inhibitor group. An injection of rtPA was administered 6 h after ischemia. Rats were treated with EA at the Shuigou (GV26) and Neiguan (PC6) acupoints at 2 h after ischemia. Neurological function, infarct volume, BBB permeability, brain edema, and hemorrhagic transformation were assessed at 24 h after ischemia. Western blotting and immunofluorescence staining were performed to detect the levels of proteins involved in the ERK1/2 signaling pathway (MEK1/2 and ERK1/2), tight junction proteins (Claudin5 and ZO-1), and MMP9 in the ischemic penumbra at 24 h after stroke. Results. Delayed rtPA treatment aggravated hemorrhagic transformation and brain edema. However, treatment with EA plus rtPA significantly improved neurological function and reduced the infarct volume, hemorrhagic transformation, brain edema, and EB leakage in rats compared with rtPA alone. EA increased the levels of tight junction proteins, inhibited the activation of the ERK1/2 signaling pathway, and reduced MMP9 overexpression induced by delayed rtPA thrombolysis. Conclusions. EA potentially represents an effective adjunct method to increase the safety of thrombolytic therapy and extend the therapeutic time window of rtPA administration following ischemic stroke. This neuroprotective effect may be mediated by the inhibition of the ERK1/2-MMP9 pathway and alleviation of the destruction of the BBB.

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VEGF Protects Brain against Focal Ischemia without Increasing Blood–Brain Permeability When Administered Intracerebroventricularly

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/sj.jcbfm.9600109 ◽

2005 ◽

Vol 25 (9) ◽

pp. 1111-1118 ◽

Cited By ~ 118

Author(s):

Dilaver Kaya ◽

Yasemin Gürsoy-Özdemir ◽

Muge Yemisci ◽

Neşe Tuncer ◽

Sevinç Aktan ◽

...

Keyword(s):

Vascular Endothelial Growth Factor ◽

Growth Factor ◽

Time Window ◽

Focal Cerebral Ischemia ◽

Infarct Volume ◽

Neuroprotective Effect ◽

Hemorrhagic Transformation ◽

Vascular Endothelial ◽

Blood Brain ◽

Endothelial Growth Factor

Delayed administration of vascular endothelial growth factor (VEGF) promotes functional recovery after focal cerebral ischemia. However, early intravenous injection of VEGF increases blood–brain barrier (BBB) leakage, hemorrhagic transformation and infarct volume whereas its application to cortical surface is neuroprotective. We have investigated whether or not early intracerebroventricular administration of VEGF could replicate the neuroprotective effect observed with topical application and the mechanism of action of this protection. Mice were subjected to 90 mins middle cerebral artery (MCA) occlusion and 24 h of reperfusion. Vascular endothelial growth factor (8 ng, intracerebroventricular) was administered 1 or 3 h after reperfusion. Compared with the vehicle-treated (intracerebroventricular) group, VEGF decreased the infarct volume along with BBB leakage in both treatment groups. Neurologic disability scores improved in parallel to the changes in infarct volume. Independently of the decrease in infarct size, VEGF also reduced the number of TUNEL-positive apoptotic neurons. Phospo-Akt levels were significantly higher in ischemic hemispheres of the VEGF-treated mice. Contrary to intracerebroventricular route, intravenous administration of VEGF (15 μg/kg) enhanced the infarct volume as previously reported for the rat. In conclusion, single intracerebroventricular injection of VEGF protects brain against ischemia without adversely affecting BBB permeability, and has a relatively long therapeutic time window. This early neuroprotective action, observed well before recovery-promoting actions such as angiogenesis, possibly involves activation of the PI-3-Akt pathway.

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Normobaric Hyperoxia Slows Blood–Brain Barrier Damage and Expands the Therapeutic Time Window for Tissue-Type Plasminogen Activator Treatment in Cerebral Ischemia

Stroke ◽

10.1161/strokeaha.114.008599 ◽

2015 ◽

Vol 46 (5) ◽

pp. 1344-1351 ◽

Cited By ~ 47

Author(s):

Jia Liang ◽

Zhifeng Qi ◽

Wenlan Liu ◽

Peng Wang ◽

Wenjuan Shi ◽

...

Keyword(s):

Time Window ◽

Tissue Type ◽

Tight Junction Proteins ◽

Normobaric Hyperoxia ◽

Cerebral Microvessels ◽

Tissue Type Plasminogen Activator ◽

Type Plasminogen Activator ◽

Metalloproteinase 9 ◽

Therapeutic Time Window ◽

Junction Proteins

Background and Purpose— Prolonged ischemia causes blood–brain barrier (BBB) damage and increases the incidence of neurovasculature complications secondary to reperfusion. Therefore, targeting ischemic BBB damage pathogenesis is critical to reducing neurovasculature complications and expanding the therapeutic time window of tissue-type plasminogen activator (tPA) thrombolysis. This study investigates whether increasing cerebral tissue P O 2 through normobaric hyperoxia (NBO) treatment will slow the progression of BBB damage and, thus, improve the outcome of delayed tPA treatment after cerebral ischemia. Methods— Rats were exposed to NBO (100% O 2 ) or normoxia (21% O 2 ) during 3-, 5-, or, 7-hour middle cerebral artery occlusion. Fifteen minutes before reperfusion, tPA was continuously infused to rats for 30 minutes. Neurological score, mortality rate, and BBB permeability were determined. Matrix metalloproteinase-9 was measured by gelatin zymography and tight junction proteins (occludin and cluadin-5) by Western blot in the isolated cerebral microvessels. Results— NBO slowed the progression of ischemic BBB damage pathogenesis, evidenced by reduced Evan blue leakage, smaller edema, and hemorrhagic volume in NBO-treated rats. NBO treatment reduced matrix metalloproteinase-9 induction and the loss of tight junction proteins in ischemic cerebral microvessels. NBO-afforded BBB protection was maintained during tPA reperfusion, resulting in improved neurological functions, significant reductions in brain edema, hemorrhagic volume, and mortality rate, even when tPA was given after prolonged ischemia (7 hours). Conclusions— Early NBO treatment slows ischemic BBB damage pathogenesis and significantly improves the outcome of delayed tPA treatment, providing new evidence supporting NBO as an effective adjunctive therapy to extend the time window of tPA thrombolysis for ischemic stroke.

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Serum tight-junction proteins predict hemorrhagic transformation in ischemic stroke patients

Neurology ◽

10.1212/wnl.0b013e31826e9a83 ◽

2012 ◽

Vol 79 (16) ◽

pp. 1677-1685 ◽

Cited By ~ 51

Author(s):

R. Kazmierski ◽

S. Michalak ◽

A. Wencel-Warot ◽

W. L. Nowinski

Keyword(s):

Ischemic Stroke ◽

Tight Junction ◽

Hemorrhagic Transformation ◽

Tight Junction Proteins ◽

Stroke Patients ◽

Junction Proteins

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Current Perspectives Regarding Stem Cell-based Therapy for Ischemic Stroke

Current Pharmaceutical Design ◽

10.2174/1381612824666180604111806 ◽

2018 ◽

Vol 24 (28) ◽

pp. 3332-3340 ◽

Cited By ~ 4

Author(s):

Kyeong-Ah Kwak ◽

Ho-Beom Kwon ◽

Joo Won Lee ◽

Young-Seok Park

Keyword(s):

Clinical Trials ◽

Stem Cell ◽

Ischemic Stroke ◽

Time Window ◽

Experimental Studies ◽

Cell Type ◽

Stroke Treatment ◽

Cell Based Therapy ◽

Regenerative Approach ◽

Therapeutic Time Window

Stroke is a leading cause of death and disability worldwide. Conventional treatment has a limitation of very narrow therapeutic time window and its devastating nature necessitate a novel regenerative approach. Transplanted stem cells resulted in functional recovery through multiple mechanisms including neuroprotection, neurogenesis, angiogenesis, immunomodulation, and anti-inflammatory effects. Despite the promising features shown in experimental studies, results from clinical trials are inconclusive from the perspective of efficacy. The present review presents a synopsis of stem cell research on ischemic stroke treatment according to cell type. Clinical trials to the present are briefly summarized. Finally, the hurdles and issues to be solved are discussed for clinical application.

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Abstract WP47: Reperfusion Following Ischemic Stroke is Associated with Reduced Brain Edema

Stroke ◽

10.1161/str.48.suppl_1.wp47 ◽

2017 ◽

Vol 48 (suppl_1) ◽

Author(s):

Hannah J Irvine ◽

Thomas W Battey ◽

Ann-Christin Ostwaldt ◽

Bruce C Campbell ◽

Stephen M Davis ◽

...

Keyword(s):

Ischemic Stroke ◽

Brain Edema ◽

Infarct Volume ◽

Brain Magnetic Resonance Imaging ◽

Lesion Volume ◽

Stroke Patients ◽

Early Reperfusion ◽

Echoplanar Imaging ◽

Swelling Volume

Introduction: Revascularization is a robust therapy for acute ischemic stroke, but animal studies suggest that reperfusion edema may attenuate its beneficial effects. In stroke patients, early reperfusion consistently reduces infarct volume and improves long-term functional outcome, but there is little clinical data available regarding reperfusion edema. We sought to elucidate the relationship between reperfusion and brain edema in a patient cohort of moderate to severe stroke. Methods: Seventy-one patients enrolled in the Echoplanar Imaging Thrombolysis Evaluation Trial (EPITHET) with serial brain magnetic resonance imaging and perfusion-weighted imaging (PWI) were analyzed. Reperfusion percentage was calculated based on the difference in PWI lesion volume at baseline and follow-up (day 3-5). Midline shift (MLS) was measured on the day 3-5 fluid attenuated inversion recovery (FLAIR) sequence. Swelling volume and infarct growth volume were assessed using region-of-interest analysis on the baseline and follow-up DWI scans based on our prior methods. Results: Greater percentage of reperfusion was associated with less MLS (Spearman ρ = -0.46; P <0.0001) and reduced swelling volume (Spearman ρ = -0.56; P <0.0001). In multivariate analysis, reperfusion was an independent predictor of less MLS ( P <0.006) and decreased swelling volume ( P <0.0054), after adjusting for age, baseline NIHSS, admission blood glucose, baseline DWI volume, and IV tPA treatment. Conclusions: Reperfusion is associated with reduced brain edema as measured by MLS and swelling volume. While our data do not exclude the possibility of reperfusion edema in certain circumstances, in stroke patients, reperfusion following acute stroke is predominantly linked to less brain swelling.

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Abstract T P10: Therapeutic Time Window for Endovascular Therapy of Acute Ischemic Stroke Depends on THRIVE Score: A Retrospective Single-center Study

Stroke ◽

10.1161/str.46.suppl_1.tp10 ◽

2015 ◽

Vol 46 (suppl_1) ◽

Author(s):

Kenichi Todo ◽

Nobuyuki Sakai ◽

Tomoyuki Kono ◽

Taku Hoshi ◽

Hirotoshi Imamura ◽

...

Keyword(s):

Ischemic Stroke ◽

Acute Ischemic Stroke ◽

Endovascular Therapy ◽

Time Window ◽

Medical Center ◽

Multivariate Logistic Regression Analysis ◽

Symptom Duration ◽

Vascular Events ◽

Good Outcome ◽

Therapeutic Time Window

Background and purpose: The outcome after endovascular therapy in acute ischemic stroke is associated with onset-to-reperfusion time (ORT). The Totaled Health Risks in Vascular Events (THRIVE) score is also an important pre-thrapeutic predictor of outcome. We hypothesized that the therapeutic time window is narrower in patients with the higher THRIVE score. Methods: We retrospectively studied consecutive 109 ischemic stroke patients with successful reperfusion after endovascular therapy between October 2005 and March 2014 at a single institute (Kobe City Medical Center General Hospital). Inclusion criteria was as follows: National Institutes of Health Stroke Scale (NIHSS) score ≥8, stroke symptom duration ≤8 h, premorbid modified Rankin Scale (mRS) score ≤2, and thrombolysis myocardial infarction score 2-3. We analyzed the relationships of ORT, THRIVE score, and THRIVE+ORT score with good outcome (mRS ≤2 at 3 months). The THRIVE+ORT score was defined as the sum of the THRIVE score and ORT (h). Results: Median ORT was 5.5 h (IQR; 4.4-7.1 h), median THRIVE score was 5 (IQR; 4-6), and median THRIVE+ORT score was 10.8 (IQR; 9.2-12.5). Good outcome rates for patients with ORT ≤4 h, >4 and ≤6 h, >6 and ≤8 h, and >8h were 50.0%, 45.8%, 37.0%, and 21.4%, respectively (p=0.3), those with THRIVE score ≤3, >3 and ≤5, >5 and ≤7, and >7 were 57.1%, 51.4%, 28.3%, and 20.0%, respectively (p9 and ≤11, >11 and ≤13, and >13 were 64.0%, 44.1%, 34.4%, and 16.7%, respectively (p<0.05). Multivariate logistic regression analysis revealed that THRIVE+ORT score was an independent predictor of good outcome after adjusted for THRIVE score (odds ratio [OR], 1.367; 95% confidence interval [CI], 1.082-1.728) or after adjusted for ORT (OR, 1.517: 95% CI, 1.160-1.983). Conclusion: Our study showed that THRIVE+ORT score was associated with outcome that was independent from THRIVE score or ORT. This is the first report to suggest that patients with the higher THRIVE score require the shorter ORT for good outcome.

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Abstract 3681: Early Anticoagulation Is Not Associated With Hemorrhagic Transformation Of Ischemic Stroke In Patients With Atrial Fibrillation

Stroke ◽

10.1161/str.43.suppl_1.a3681 ◽

2012 ◽

Vol 43 (suppl_1) ◽

Author(s):

H. B Brouwers ◽

Svetlana Lorenzano ◽

Lyndsey H Starks ◽

David M Greer ◽

Steven K Feske ◽

...

Keyword(s):

Atrial Fibrillation ◽

Ischemic Stroke ◽

Acute Ischemic Stroke ◽

Clinical Data ◽

Infarct Volume ◽

Hemorrhagic Transformation ◽

P Value ◽

Long Term Outcome ◽

Nihss Score

Purpose: Hemorrhagic transformation (HT) is a common and potentially devastating complication of ischemic stroke, however its prevalence, predictors, and outcome remain unclear. Early anticoagulation is thought to be a risk factor for HT which raises the clinical question when to (re)start anticoagulation in ischemic stroke patients who have a compelling indication, such as atrial fibrillation. We conducted a prospective cohort study to address this question and to identify association of hemorrhagic transformation with outcome measures in patients with atrial fibrillation in the setting of acute ischemic stroke. Materials and Methods: We performed a prospective study which enrolled consecutive patients admitted with acute ischemic stroke presenting to a single center over a three-year period. As part of the observational study, baseline clinical data and stroke characteristics as well as 3 month functional outcome were collected. For this sub-study, we restricted the analysis to subjects diagnosed with atrial fibrillation. CT and MRI scans were reviewed by experienced readers, blinded to clinical data, to assess for hemorrhagic transformation (using ECASS 2 criteria), microbleeds and infarct volumes in both admission and follow-up scans. Clinical and outcome data were analyzed for association with hemorrhagic transformation. Results: Of 94 patients, 63 had a history of atrial fibrillation (67.0%) and 31 had newly discovered atrial fibrillation (33.0%). We identified HT in 3 of 94 baseline scans (3.2%) and 22 of 48 follow-up scans (45.8%) obtained a median of 3 days post-stroke. In-hospital initiation of either anti-platelet (n = 36; OR 0.34 [95% CI 0.10-1.16], p-value = 0.09) or anticoagulation with unfractionated intravenous heparin or low molecular weight heparin (n = 72; OR 0.25 [95% CI 0.06-1.15], p-value = 0.08) was not associated with HT. Initial NIH Stroke Scale (NIHSS) score (median 13.0 [IQR 15.0] vs. 7.0 [IQR 10.0], p-value = 0.029) and baseline infarct volume (median 17 [IQR 42.03] vs. 5 [IQR 10.95], p-value = 0.011) were significantly higher in patients with HT compared to those without. Hemorrhagic transformation was associated with a significantly higher 48-hour median NIHSS score (20 [IQR 3.0] vs. 2 [IQR 3.25], p-value = 0.007) and larger final infarct volume (81.40 [IQR 82.75] vs. 9.95 [IQR 19.73], p-value < 0.001). Finally, we found a trend towards poorer 3-month modified Rankin Scale scores in subjects with HT (OR 11.25 [95% CI 0.97-130.22], p-value = 0.05). Conclusion: In patients with atrial fibrillation, initial NIHSS score and baseline infarct volume are associated with hemorrhagic transformation in acute ischemic stroke. Early initiation of antithrombotic therapy was not associated with hemorrhagic transformation. Patients with hemorrhagic transformation were found to have a poorer short and long term outcome and larger final infarct volumes.

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Abstract P12: Alteplase Reduces Mortality in Patients With Ischemic Stroke and Atrial Fibrillation: Analysis of the IAC Study

Stroke ◽

10.1161/str.52.suppl_1.p12 ◽

2021 ◽

Vol 52 (Suppl_1) ◽

Author(s):

Shadi Yaghi ◽

Eva Mistry ◽

Adam H De Havenon ◽

Christopher Leon Guerrero ◽

Amre Nouh ◽

...

Keyword(s):

Atrial Fibrillation ◽

Ischemic Stroke ◽

Acute Ischemic Stroke ◽

Infarct Volume ◽

Intravenous Thrombolysis ◽

The United States ◽

Hemorrhagic Transformation ◽

Stroke Patients ◽

Increased Risk ◽

Significant Difference

Background and Purpose: Multiple studies have established that intravenous thrombolysis with alteplase improves outcome after acute ischemic stroke. However, assessment of thrombolysis’ efficacy in stroke patients with atrial fibrillation (AF) has yielded mixed results. We sought to determine the association of alteplase with mortality, hemorrhagic transformation (HT), infarct volume, and mortality in patients with AF and acute ischemic stroke. Methods: We retrospectively analyzed consecutive acute ischemic stroke patients with AF included in the Initiation of Anticoagulation after Cardioembolic stroke (IAC) study, which pooled data from 8 comprehensive stroke centers in the United States. 1889 (90.6%) had available 90-day follow up data and were included. For our primary analysis we used a cohort of 1367/1889 (72.4%) patients who did not undergo mechanical thrombectomy (MT). Secondary analyses were repeated in the patients that underwent MT (n=522). Binary logistic regression was used to determine whether alteplase use was independently associated with risk of HT, final infarct volume, and 90-day mortality, respectively, adjusting for potential confounders. Results: In our primary analyses we found that alteplase use was independently associated with an increased risk for HT (adjusted OR 2.14, 95% CI 1.49 - 3.07, p <0.001) but overall reduced risk of 90-day mortality (adjusted OR 0.58, 95% CI 0.39 - 0.87, p = 0.009). Among patients undergoing MT, alteplase use was associated with a trend towards a reduction in 90-day mortality (adjusted OR 0.68 95% CI 0.45 - 1.04, p = 0.077). In the subgroup of patients prescribed DOAC treatment (n = 327; 24 received alteplase), alteplase treatment was associated with a trend towards smaller infarct size (< 10 mL), (adjusted OR 0.40, 95% CI 0.15 - 1.12, p = 0.082) without a significant difference in the odds of 90-day mortality (adjusted OR 0.51, 95% CI 0.12 - 2.13, p = 0.357) or hemorrhagic transformation (adjusted OR 0.27, 95% CI 0.03 - 2.07, p = 0.206). Conclusion: Thrombolysis with intravenous alteplase was associated with reduced 90-day mortality in AF patients with acute ischemic stroke not undergoing MT. Further study is required to assess the safety and efficacy of alteplase in AF patients undergoing MT and those on DOACs.

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Abstract TP315: D-dimer is Associated With 30-day Mortality in Acute Ischemic Stroke With Active Cancer

Stroke ◽

10.1161/str.48.suppl_1.tp315 ◽

2017 ◽

Vol 48 (suppl_1) ◽

Author(s):

Ki Woong Nam ◽

Chi Kyung Kim ◽

Tae Jung Kim ◽

Sang Joon An ◽

Kyungmi Oh ◽

...

Keyword(s):

Ischemic Stroke ◽

Acute Ischemic Stroke ◽

Infarct Volume ◽

Hemorrhagic Transformation ◽

Stroke Patients ◽

Nihss Score ◽

Patients With Cancer ◽

Advanced Stages ◽

D Dimer ◽

Active Cancer

Background: Stroke in cancer patients is not rare, but is a devastating event with high mortality. However, the predictors of mortality in stroke patients with cancer have not been well addressed. D-dimer could be a useful predictor because it can reflect both thromboembolic events and advanced stages of cancer. In this study, we evaluate the possibility of D-dimer as a predictor of 30-day mortality in stroke patients with active cancer. Methods: We included 210 ischemic stroke patients with active cancer. The data of 30-day mortality were collected by reviewing medical records. We also collected follow-up D-dimer levels in 106 (50%) participants to evaluate the effects of treatment response on D-dimer levels. Results: Of the 210 participants, 30-day mortality occurred in 28 (13%) patients. Higher initial NIHSS score, D-dimer levels, CRP levels, frequent cryptogenic mechanism, systemic metastasis, multiple vascular territory lesion, hemorrhagic transformation, and larger infarct volume were related to 30-day mortality. In the multivariate analysis, D-dimer [adjusted OR (aOR) = 2.19; 95% CI, 1.46-3.28, P < 0.001] predicted 30-day mortality after adjusting for confounders. Initial NIHSS score (aOR = 1.07; 95% CI, 1.00-1.14, P = 0.043) and hemorrhagic transformation (aOR = 3.02; 95% CI, 1.10-8.29, P = 0.032) were also significant independently from D-dimer levels. In the analysis of D-dimer changes after treatment, the mortality group showed no significant decrease of D-dimer levels, despite treatment, while the survivor group showed opposite responses. Conclusions: D-dimer levels may predict 30-day mortality in acute ischemic stroke patients with active cancer.

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Peptide5 attenuates rtPA related brain microvascular endothelial cells reperfusion injury via the Wnt/β-catenin signalling pathway

Current Neurovascular Research ◽

10.2174/1567202618666210809115305 ◽

2021 ◽

Vol 18 ◽

Author(s):

Weimin Ren ◽

Chuyi Huang ◽

Heling Chu ◽

Yuping Tang ◽

Xiaobo Yang

Keyword(s):

Endothelial Cells ◽

Ischemic Stroke ◽

Endothelial Cell ◽

Cell Injury ◽

Time Window ◽

Microvascular Endothelial Cells ◽

Brain Microvascular Endothelial Cells ◽

Endothelial Cell Injury ◽

Endothelial Cell Death ◽

Therapeutic Time Window

Aims: Brain vascular endothelial cell dysfunction after rtPA treatment is a significant factor associated with poor prognosis, suggesting that alleviation of rtPA-related endothelial cell injury may represent a potential beneficial strategy along with rtPA thrombolysis. Background: Thrombolysis with recombinant tissue plasminogen activator (rtPA) is beneficial for acute ischemic stroke but may increase the risk of hemorrhagic transformation (HT), which is considered ischemia-reperfusion injury. The underlying reason may contribute to brain endothelial injury and dysfunction related to rtPA against ischemic stroke. As previous studies have demonstrated that transiently blocked Cx43 using peptide5 (Cx43 mimetic peptide) during retinal ischemia reduced vascular leakage, it is necessary to know whether this might help decrease side effect of rtPA within the therapeutic time window. Objective: This study aims to investigate the effects of peptide5 on rtPA-related cell injury during hypoxia/reoxygenation (H/R) within the therapeutic time window. Methods: In this study, we established a cell hypoxia/reoxygenation H/R model in cultured primary rat brain microvascular endothelial cells (RBMECs) and evaluated endothelial cell death and permeability after rtPA treatment with or without transient peptide5. In addition, we also investigated the potential signaling pathway to explore the underlying mechanisms preliminarily. Results: The results showed that peptide5 inhibited rtPA-related endothelial cell death and permeability. It also slightly increased tight junction (ZO-1, occluding, claudin-5) and β-catenin mRNA expression, demonstrating that peptide5 might attenuate endothelial cell injury by regulating the Wnt/β-catenin pathway. The following bioinformatic exploration from the GEO dataset GSE37239 was also consistent with our findings. Conclusion: This study showed that the application of peptide5 maintained cell viability and permeability associated with rtPA treatment, revealing a possible pathway that could be exploited to limit rtPA-related endothelial cell injury during ischemic stroke. Furthermore, the altered Wnt/β-catenin signaling pathway demonstrated that signaling pathways associated with Cx43 might have potential applications in the future. This study may provide a new way to attenuate HT and assist the application of rtPA in ischemic stroke.

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