scholarly journals Atorvastatin Extends the Therapeutic Window for tPA to 6 h after the Onset of Embolic Stroke in Rats

2009 ◽  
Vol 29 (11) ◽  
pp. 1816-1824 ◽  
Author(s):  
Li Zhang ◽  
Michael Chopp ◽  
Longfei Jia ◽  
Yisheng Cui ◽  
Mei Lu ◽  
...  
Keyword(s):  
Infarct Volume ◽  
Neuroprotective Effect ◽  
Hemorrhagic Transformation ◽  
Embolic Stroke ◽  
Intercellular Adhesion Molecule ◽  
Therapeutic Window ◽  
Control Group ◽  
Intercellular Adhesion Molecule 1 ◽  
Vascular Events ◽  
Protease Activated Receptor 1

We investigated the neuroprotective effect of atorvastatin in combination with delayed thrombolytic therapy in a rat model of embolic stroke. Rats subjected to embolic middle cerebral artery (MCA) occlusion were treated with atorvastatin at 4 h, followed by tissue plasminogen activator (tPA) at 6 or 8 h after stroke. The combination of atorvastatin at 4 h and tPA at 6 h significantly decreased the size of the embolus at the origin of the MCA, improved microvascular patency, and reduced infarct volume, but did not increase the incidence of hemorrhagic transformation compared with vehicle-treated control animals. However, monotherapy with tPA at 6 h increased the incidence of hemorrhagic transformation and failed to reduce infarct volume compared with the control group. In addition, adjuvant treatment with atorvastatin at 4 h and with tPA at 6 h reduced tPA-induced upregulation of protease-activated receptor-1, intercellular adhesion molecule-1, and matrix metalloproteinase-9, and concomitantly reduced cerebral microvascular platelet, neutrophil, and fibrin deposition compared with rats treated with tPA alone at 6 h. In conclusion, a combination of atorvastatin and tPA extended the therapeutic window for stroke to 6 h without increasing the incidence of hemorrhagic transformation. Atorvastatin blocked delayed tPA-potentiated adverse cerebral vascular events, which likely contributes to the neuroprotective effect of the combination therapy.

Treatment of embolic stroke in rats with bortezomib and recombinant human tissue plasminogen activator

2006 ◽  
Vol 95 (01) ◽  
pp. 166-173 ◽  
Author(s):  
Li Zhang ◽  
Zheng Zhang ◽  
Xianshuang Liu ◽  
Ann Hozeska ◽  
Nancy Stagliano ◽  
...  
Keyword(s):  
Plasminogen Activator ◽  
Tissue Plasminogen Activator ◽  
Vascular Function ◽  
Inflammatory Responses ◽  
Focal Cerebral Ischemia ◽  
Infarct Volume ◽  
Neuroprotective Effect ◽  
Therapeutic Window ◽  
Vascular Events ◽  
Tissue Plasminogen

SummaryStroke elicits a progressive vascular dysfunction, which contributes to the evolution of brain injury. Thrombolysis with tissue plasminogen activator (tPA) promotes adverse vascular events that limit the therapeutic window of stroke to three hours. Proteasome inhibitors reduce vascular thrombotic and inflammatory events, and consequently protect vascular function. The present study evaluated the neuroprotective effect of bortezomib,a potent and selective inhibitor of the proteasome, alone and in combination with delayed thrombolytic therapy on a rat model of embolic focal cerebral ischemia. Treatment with bortezomib reduces adverse cerebrovascular events including secondary thrombosis,inflammatory responses,and blood brain barrier (BBB) disruption, and hence reduces infarct volume and neurological functional deficit when administrated within 4 h after stroke onset. Combination of bortezomib and tPA extends the thrombolytic window for stroke to6 h, which is associated with the improvement of vascular patency and integrity. Real time RT-PCR of endothelial cells isolated by laser-capture microdissection from brain tissue and Western blot analysis showed that bortezomib upregulates endothelial nitric oxide synthase (eNOS) expression and blocks NF-κB activation. These results demonstrate that bortezomib promotes eNOS dependent vascular protection, and reduces NF-κB dependent vascular disruption, all of which may contribute to neuroprotection after stroke.

scholarly journals Effects of PS-519 combined with thrombolytic therapy in embolic stroke in rat

Stroke ◽  
2001 ◽  
Vol 32 (suppl_1) ◽  
pp. 351-351
Author(s):  
Li Zhang ◽  
Zheng G Zhang ◽  
Michael Chopp ◽  
Peter J Elliott ◽  
Julian Adams
Keyword(s):  
Combination Treatment ◽  
Cell Damage ◽  
Infarct Volume ◽  
Body Weight Loss ◽  
Embolic Stroke ◽  
Therapeutic Window ◽  
Control Group ◽  
Lesion Volume ◽  
Treatment Groups ◽  
Mca Occlusion

P67 We evaluated the effect of a proteasome inhibitor (PS-519) which blocks the activation of NF-kB, alone or combination with thrombolysis, on ischemic cell damage after embolic stroke in rat. Male Wistar rats (n=44) were subjected to embolic middle cerebral artery (MCA) occlusion. Animals were randomly assigned into seven groups: PS-519 treatment groups (n=6 each group) were infused intravenously with PS-519(1.0 mg/kg) at 2 h, 4 h, or 6 h after MCA occlusion, respectively. Combination treatment groups (n=6 each group) PS-519(1.0 mg/kg) followed by rtPA (10 mg/kg) were administered at 2 h, 4 h, or 6 h after MCA occlusion. A control group (n=8) was administered saline at 2 h after MCA occlusion. Rats were sacrificed 7 days after MCA occlusion, infarct volume and gross hemorrhage were measured. In PS-519 treatment groups: infarct volume was significantly (p<0.05) reduced by PS-519 treatment at 2 (19”3.5%) and 4 h (22“3.1%) after MCA occlusion when compared with the control group (34”3.5%). However, no significant reduction of lesion volume was found in the 6 hour treated group (34“2.5%). In the combination treatment groups: infarction volume was significantly (p<0.05) reduced in all three groups compared with control: 2 h (18”4.3%), 4 h (21“3.6%), 6 h (21”4.4%). None of treated rats and 25% of control rats had intracerebral gross hemorrhage. Significant reductions (p<0.05) in neurological deficit and body weight loss were found in all treated groups except the group that treated with PS-519 alone at 6 h. Our results demonstrate that administration of PS-519 alone, or combination with rtPA significantly reduces ischemic cell damage. Moreover, combination treatment with PS-519 and rtPA expands the therapeutic window to at least 6 h after embolic stroke. This suggests that combination therapy might lead to improved neurological outcome beyond that which would occur with neuroprotective treatment or thrombolytics alone.

scholarly journals Correlations Between Different Angiogenic and Inflammatory Factors in Vitreous Fluid of Eyes With Proliferative Diabetic Retinopathy

2021 ◽  
Vol 8 ◽  
Author(s):  
Guanrong Wu ◽  
Baoyi Liu ◽  
Qiaowei Wu ◽  
Changting Tang ◽  
Zijing Du ◽  
...  
Keyword(s):  
Diabetic Retinopathy ◽  
Growth Factor ◽  
Proliferative Diabetic Retinopathy ◽  
Fasting Blood Glucose ◽  
Intercellular Adhesion Molecule ◽  
Inflammatory Factors ◽  
Control Group ◽  
Intercellular Adhesion Molecule 1 ◽  
Vitreous Fluid ◽  
Inflammation Mediators

Purpose: To investigate the expression of various angiogenesis and inflammation mediators in the vitreous fluid of eyes with proliferative diabetic retinopathy (PDR).Methods: A total of 38 eyes with PDR and 37 control eyes were included. Vitreous fluid was collected during vitrectomy. Vitreous levels of colony stimulating factor-1 receptor (CSF-1R), syndecan-1, placental growth factor (PIGF), and angiopoietin-like protein 4 (ANGPTL-4) were measured by multiplex immunoassay. Vitreous levels of vascular endothelial growth factor (VEGF), interleukin-6 (IL-6), interleukin-8 (IL-8), monocyte chemotactic protein-1 (MCP-1), tumor necrosis factor-α (TNF-α), and intercellular adhesion molecule-1 (ICAM-1) were measured by cytometric beads array. Levels of these mediators were compared between the PDR and control eyes. Correlations between levels of different mediators and between these mediators and kidney function metrics in the PDR group were also analyzed.Results: Vitreous levels of syndecan-1, PIGF, ANGPTL-4, VEGF, and IL-8 were significantly higher in the PDR group compared to the control group (all p &lt; 0.05). Levels of VEGF were significantly correlated with levels of syndecan-1, PIGF, and ANGPTL-4 (r = 0.370 to 0.497, all p &lt; 0.05). Significant positive correlations were detected between levels of any two of the following mediators including syndecan-1, PIGF, ANGPTL-4, and IL-8 (r = 0.370 to 0.906, all p &lt; 0.05). Apart from VEGF, levels of these mediators were positively correlated with serum creatinine and blood urea nitrogen (r = 0.328 to 0.638, all p &lt; 0.05), and negatively correlated with fasting blood glucose and estimated glomerular filtration rate (r = −0.325 to −0.603, all p &lt; 0.05).Conclusions: Correlations between different angiogenesis and inflammation mediators were observed in eyes with PDR, suggesting cross-talks of different angiogenesis and inflammation pathways in the pathogenesis of PDR. The levels of angiogenesis and inflammation in PDR are correlated with kidney damage, indicating possible common pathways in diabetic retinopathy and nephropathy.

scholarly journals Analysis of Combined Treatment of Embolic Stroke in Rat with r-tPA and a GPIIb/IIIa Inhibitor

2005 ◽  
Vol 25 (1) ◽  
pp. 87-97 ◽  
Author(s):  
Guangliang Ding ◽  
Quan Jiang ◽  
Li Zhang ◽  
Zheng Gang Zhang ◽  
Lian Li ◽  
...  
Keyword(s):  
Magnetic Resonance Imaging ◽  
Magnetic Resonance ◽  
Thrombolytic Therapy ◽  
Combination Treatment ◽  
Infarct Volume ◽  
Embolic Stroke ◽  
Control Group ◽  
Resonance Imaging ◽  
Cerebral Microvessels ◽  
Magnetic Resonance Imaging Mri

Suppression of platelet activation improves the efficacy of thrombolytic therapy for stroke. Thus, combination treatment with recombinant tissue plasminogen activator (r-tPA) and 7E3 F(ab′)2, a GPIIb/IIIa inhibitor that binds the platelet to fibrin, may improve the efficacy of thrombolytic therapy in embolic stroke. Magnetic resonance imaging (MRI) was used to monitor treatment response in rats subjected to embolic middle cerebral artery (MCA) occlusion (MCAo). Animals were randomized into treated ( n = 12) and control ( n = 10) groups and received intravenous combination therapy or saline, respectively, 4 hours after MCAo. Magnetic resonance imaging (MRI) measurements performed 1 hour after MCAo showed no difference between groups. However, an increased incidence (50%) of MCA recanalization was found in the treated group at 24 hours compared with 20% in the control group. The area of low cerebral blood flow at 24 and 48 hours was significantly smaller in the combination treatment group, and the lesion size, as indicated from the T2 and T1 maps, differed significantly between groups. Fluorescence microscopy measurements of cerebral microvessels perfused with fluorescein isothiocyanate-dextran and measurements of infarct volume revealed that the combination treatment significantly increased microvascular patency and reduced infarct volume, respectively, compared with the control rats. The efficacy of combination treatment 4 hours after ischemia is reflected by MRI indices of tissue perfusion, MCA recanalization, and reduction of lesion volume. The treatment also reduced secondary microvascular perfusion deficits.

Abstract T P26: Combining Clinical and Imaging Data to Develop a Highly Predictive Model of Outcomes in the MR RESCUE Trial

Stroke ◽  
2015 ◽  
Vol 46 (suppl_1) ◽  
Author(s):  
Chelsea S Kidwell ◽  
Reza Jahan ◽  
Jeffrey Gornbein ◽  
Jeffry R Alger ◽  
Val Nenov ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Acute Ischemic Stroke ◽  
Infarct Volume ◽  
Patient Characteristics ◽  
Hemorrhagic Transformation ◽  
Imaging Data ◽  
Vascular Events ◽  
Vessel Occlusion ◽  
Intermediate Variables ◽  
Core Volume

Background: Identifying patient characteristics that predict outcomes in acute ischemic stroke may assist in triaging those who are candidates for endovascular therapies. We sought to identify predictors of outcome in the overall Mechanical Retrieval and Recanalization of Stroke Clots Using Embolectomy (MR RESCUE) cohort and compare results to the previously validated Totaled Health Risks in Vascular Events (THRIVE) score. Methods: MR RESCUE randomized 118 acute ischemic stroke patients with multimodal imaging to embolectomy or standard care within 8 hours of onset. For this analysis, we investigated 17 baseline variables (e.g. age, predicted core volume, time to enrollment) and 8 intermediate variables (e.g. hemorrhagic transformation, day 7 recanalization, final infarct volume) with the potential to impact outcomes (day 90 mRS). The baseline variables were analyzed employing bivariate and multivariate methods (random forest and logistic regression). Two models were developed, one including only significant baseline variables, and the second also incorporating significant intermediate variables. Results: A multivariate model (Table) employing only baseline covariates achieved an overall accuracy (C statistic) of 85% in predicting poor outcome (day 90 mRS 3-6) compared to 80.5% for the THRIVE score. A second model (Table) adding significant intermediate variables achieved 89% accuracy in predicting day 90 mRS. Conclusions: In the MR RESCUE trial, advanced imaging variables, including predicted core volume and site of vessel occlusion, contributed to a highly accurate multivariable model of outcome. In the development phase, this model achieved higher accuracy than the THRIVE score. Future studies are needed to validate this model in an independent cohort.

Exercise suppresses macrophage antigen presentation

1999 ◽  
Vol 87 (6) ◽  
pp. 2253-2258 ◽  
Author(s):  
M. A. Ceddia ◽  
J. A. Woods
Keyword(s):  
T Cells ◽  
Antigen Presentation ◽  
Home Cage ◽  
Interleukin 2 ◽  
Exhaustive Exercise ◽  
Intercellular Adhesion Molecule ◽  
Control Group ◽  
Intercellular Adhesion Molecule 1 ◽  
Cage Control ◽  
Wide Range

This study determined the effects of exercise on the ability of macrophages (Mφ) to present antigen to T cells. Pathogen-free male Balb/c mice (8 ± 2 wk of age) were randomly assigned to either home cage control, moderate exercise (Mod; 18 m/min, 5% grade, 0.5 h/day), exhaustive exercise (Exh, 18–30 m/min, 3 h/day), or treadmill control groups. The mice underwent treatments for 4 days during peritoneal thioglycolate inflammation. Peritoneal Mφ were harvested, purified, and incubated with chicken ovalbumin (C-OVA; 0–10 mg/ml) for 18 h. Mφ were then cocultured with C-OVA-specific T cells for 48 h, and the supernatants were analyzed via ELISA for interleukin-2 as an indication of Mφ antigen presentation (AP). Exh exhibited suppressed (∼25–34%) Mφ AP across a wide range of C-OVA doses when measured immediately, 3, and 24 h postexercise. In contrast, Mod had reduced Mφ AP only at 3 h postexercise. Mφ AP was also lower in the treadmill control (4–27%) compared with the home cage control group, but was significantly higher than Exh. The reduction in Mφ AP was not due to exercise-induced differences in Mφ number, percentage, or expression of intercellular adhesion molecule-1, B7–2, or major histocompatability complex II, molecules important in AP. In conclusion, our data lend evidence that may help explain the increased incidence of infection observed after prolonged exhaustive exercise or overtraining.

Endothelial Function in Patients with Severe and Moderate Haemophilia A and B

2018 ◽  
Vol 39 (02) ◽  
pp. 195-202
Author(s):  
Stephanie Böhmert ◽  
Ralf Schubert ◽  
Stephan Fichtlscherer ◽  
Sonja Alesci ◽  
Wolfgang Miesbach
Keyword(s):  
Endothelial Function ◽  
Adhesion Molecule ◽  
Reactive Hyperemia ◽  
Intercellular Adhesion Molecule ◽  
Control Group ◽  
Low Grade ◽  
Haemophilia A ◽  
Intercellular Adhesion Molecule 1 ◽  
Age Related ◽  
Artery Disease

AbstractThe life expectancy of patients with haemophilia has increased and therefore the interest in age-related comorbidities has grown. The aim of this study was to determine whether haemophilia patients have a different endothelial function compared with the general population. A total of 26 patients with severe or moderate haemophilia A or B, 14 controls and 36 patients with coronary artery disease (CAD) were included in this study. Five markers of endothelial dysfunction (MOEDs) were determined. Moreover, the endothelial function was examined using the Itamar Endo-PAT, and the reactive hyperemia index (RHI) was calculated from the results. The MOEDs soluble intercellular adhesion molecule-1 (p = 0.0095) and interleukin-6 (p = 0.010) were significantly higher for patients with haemophilia compared with the control group. The presence of increased adhesion molecule levels and low-grade inflammation is suggestive of a decreased endothelial function. RHI is impaired in CAD patients (1.862), whereas haemophilia patients have an RHI of 1.958 in comparison with 2.112 in controls (p = 0.127). Therefore, laboratory and functional measurements imply a possible higher risk for CAD in haemophilia patients.

Demonstration of therapeutic window of Cerebrolysin in embolic stroke: A prospective, randomized, blinded, and placebo-controlled study

2017 ◽  
Vol 12 (6) ◽  
pp. 628-635 ◽  
Author(s):  
Li Zhang ◽  
Michael Chopp ◽  
Mei Lu ◽  
Talan Zhang ◽  
Chao Li ◽  
...  
Keyword(s):  
Confidence Interval ◽  
Middle Cerebral Artery ◽  
Middle Cerebral Artery Occlusion ◽  
Cerebral Artery ◽  
Infarct Volume ◽  
Artery Occlusion ◽  
Mean Difference ◽  
Embolic Stroke ◽  
Therapeutic Window ◽  
Cerebral Artery Occlusion

Background and aims In an effort to characterize the effects of Cerebrolysin for treatment of stroke that are essential for successful clinical translation, we have demonstrated that Cerebrolysin dose dependently enhanced neurological functional recovery in experimental stroke. Here, we conduct a prospective, randomized, placebo-controlled, blinded study to examine the therapeutic window of Cerebrolysin treatment of rats subjected to embolic stroke. Methods Male Wistar rats age 3–4 months (n = 100) were subjected to embolic middle cerebral artery occlusion. Animals were randomized to receive saline or Cerebrolysin daily for 10 consecutive days starting 4, 24, 48, and 72 h after middle cerebral artery occlusion. Neurological outcome was measured weekly with a battery of behavioral tests (adhesive removal test, modified neurological severity score (mNSS), and foot-fault test). Global test was employed to assess Cerebrolysin effect on neurological recovery with estimation of mean difference between Cerebrolysin and control-treated groups and its 95% confidence interval in the intent-to-treat population, where a negative value of the mean difference and 95% confidence interval < 0 indicated a significant treatment effect. All rats were sacrificed 28 days after middle cerebral artery occlusion and infarct volume was measured. Results Cerebrolysin treatment initiated within 48 h after middle cerebral artery occlusion onset significantly improved functional outcome; mean differences and 95% confidence interval were −11.6 (−17.7, −5.4) at 4 h, −7.1 (−13.5, −0.8) at 24 h, −8.4 (−14.2, −8.6) at 48 h, and −4.9 (−11.4, 1.5) at 72 h. There were no differences on infarct volume and mortality rate among groups. Conclusions With a clinically relevant rigorous experimental design, our data demonstrate that Cerebrolysin treatment effectively improves stroke recovery when administered up to 48 h after middle cerebral artery occlusion.

Relationship between intercellular adhesion molecule-1 and morbidly adherent placenta

2018 ◽  
Vol 47 (1) ◽  
pp. 45-49
Author(s):  
Engin Korkmazer ◽  
Rampia Nizam ◽  
Emine Arslan ◽  
Özgür Akkurt
Keyword(s):  
Adhesion Molecule ◽  
Histochemical Staining ◽  
Uterine Wall ◽  
Intercellular Adhesion ◽  
Intercellular Adhesion Molecule ◽  
Control Group ◽  
Positive Staining ◽  
Intercellular Adhesion Molecule 1 ◽  
Morbidly Adherent Placenta ◽  
Adherent Placenta

Abstract Objective Morbidly adherent placenta (MAP) is a clinical condition the prevalance of which is steadily increasing. It is described as the invasion of the placenta into the uterine wall through the myometrium and beyond. Several studies have shown that intercellular adhesion molecule-1 (ICAM-1) increases the invasion capability of tumor cells and placental cells. In our study, we investigated the expression of ICAM-1 in MAP cases. Methods This is a prospective case-control study. Eighty-nine patients who were diagnosed with MAP and 96 patients, without adherent placenta, as a control group were included in the study. ICAM-1 staining was examined by immuno-histochemical staining in placental samples. Results Of the 89 patients in the MAP group, 72 (80.8%) showed positive staining, while 26 (27%) did so in the control group. ICAM-1 positive staining in the MAP group was statistically significantly higher (P=0.03). Conclusion This is the first study investigating the relationship between MAP and ICAM-1 in the literature. In our study, we showed that ICAM-1 expression increased in the MAP group.

scholarly journals Nitrite Does Not Provide Additional Protection to Thrombolysis in a Rat Model of Stroke with Delayed Reperfusion

2007 ◽  
Vol 28 (3) ◽  
pp. 482-489 ◽  
Author(s):  
Bawarjan Schatlo ◽  
Erica C Henning ◽  
Ryszard M Pluta ◽  
Lawrence L Latour ◽  
Nahal Golpayegani ◽  
...  
Keyword(s):  
Adjuvant Therapy ◽  
Infarct Volume ◽  
Recombinant Tissue Plasminogen Activator ◽  
Hemorrhagic Transformation ◽  
Artery Occlusion ◽  
Therapeutic Window ◽  
Controlled Study ◽  
Sprague Dawley ◽  
Vessel Morphology ◽  
Before And After

An adjuvant therapy to prolong the therapeutic window for stroke patients is urgently needed. This randomized, blinded, placebo-controlled study investigated adjuvant intravenous sodium nitrite with recombinant tissue plasminogen activator (rtPA) in middle cerebral artery occlusion (MCAO) with 6 and 2 h of ischemia followed by reperfusion in Sprague—Dawley rats ( n = 59). Quantitative diffusion, T1-, T2-weighted, and semiquantitative perfusion imaging were performed before and after reperfusion and at 48 h after ischemia to determine the spatiotemporal evolution of stroke. After 48 h animals were killed and examined to evaluate infarct size and evidence of hemorrhagic transformation. Factor VIII immunostaining was performed to assess vessel morphology. Nitrite treatment (6 h group: 37.5 μmol for more than 90 mins; 2 h group: 26.25 and 1.75 μmol for more than 60 mins) did not reduce infarct volume 48 h after MCAO compared with saline-treated placebo groups after 6 or 2 h of MCAO. Stroke progression from baseline to 48 h, based on the apparent diffusion coefficient and relative cerebral blood flow deficits before and after reperfusion and T2-weighted hyperintensity at 48 h, did not differ between treated and control animals. These results suggest that nitrite is not a protective adjuvant therapy to delayed rtPA administration after ischemic stroke in rats.

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