Abstract WMP99: Alpha2-Antiplasmin Inactivation Reduces Hemorrhagic Transformation and Ischemic Brain Injury After Tissue Plasminogen Activator Therapy and Mechanical Reperfusion

Stroke ◽  
2020 ◽  
Vol 51 (Suppl_1) ◽  
Author(s):  
Sofiyan Saleem ◽  
Guy L Reed
Keyword(s):  
Brain Injury ◽  
Plasminogen Activator ◽  
Tissue Plasminogen Activator ◽  
Infarct Volume ◽  
Ischemic Brain Injury ◽  
Brain Hemorrhage ◽  
Brain Swelling ◽  
Brain Infarct ◽  
Ischemic Brain ◽  
Tissue Plasminogen

Tissue plasminogen activator (r-tPA) therapy followed by thrombectomy-mediated, mechanical reperfusion profoundly reduces neurologic disability in appropriately selected patients. Nevertheless, a high proportion of these patients (20-37%) develop brain hemorrhage. We examined the contribution of α2-antiplasmin, a fast-acting plasmin inhibitor, to brain hemorrhage and ischemic injury following r-tPA treatment and mechanical reperfusion. Methods: Mice (C57Bl6) underwent 1 to 4 h of middle cerebral artery occlusion followed by treatment with r-tPA alone (10 mg/kg), r-tPA (10 mg/kg) plus an α2AP inhibitor (α2AP-I, 10 mg/kg) antibody or saline, followed by reperfusion. Mice were assessed by neurobehavioral measures (Bederson score and corner test) and histology 24 h post-ischemic stroke. Analyses were performed in a blinded fashion. Time course studies in r-tPA-treated mice showed that intracerebral hemorrhage (p<0.05), brain infarct volume (p<0.001) and brain swelling (p<0.01) increased progressively with ischemic time, with a plateau at 3 h of ischemia, as compared to saline treated controls. Mice treated at 3 h with r r-tPA + α2AP-I showed significantly (p<0.05) reduced brain hemorrhage, brain infarct volume (p<0.01) and brain swelling (p<0.05). Treatment with r-tPA + α2AP-I also significantly improved neurobehavioral deficits (p<0.01) and sensory motor dysfunction (p<0.01) at 24h of reperfusion. Conclusion: α2AP contributes to the increased brain hemorrhage and ischemic brain injury associated with r-tPA treatment followed by mechanical reperfusion. Targeting a2AP appears beneficial, because specific, monoclonal antibody-mediated inhibition of α2AP markedly reduced brain hemorrhage, infarction, swelling and neurobehavioral disability.

Tissue-plasminogen activator-induced ischemic brain injury is reversed by melatonin: role of iNOS and Akt

2005 ◽  
Vol 39 (2) ◽  
pp. 151-155 ◽  
Author(s):  
Ertugrul Kilic ◽  
Ülkan Kilic ◽  
Russel J. Reiter ◽  
Claudio L. Bassetti ◽  
Dirk M. Hermann
Keyword(s):  
Brain Injury ◽  
Plasminogen Activator ◽  
Tissue Plasminogen Activator ◽  
Ischemic Brain Injury ◽  
Ischemic Brain ◽  
Tissue Plasminogen

scholarly journals Rosiglitazone Alone Or in Combination with Tissue Plasminogen Activator Improves Ischemic Brain Injury in an Embolic Model in Rats

2009 ◽  
Vol 29 (10) ◽  
pp. 1683-1694 ◽  
Author(s):  
Chen Xu Wang ◽  
Xiuqing Ding ◽  
Raza Noor ◽  
Christina Pegg ◽  
Chunyan He ◽  
...  
Keyword(s):  
Brain Injury ◽  
Plasminogen Activator ◽  
Collagen Type ◽  
Collagen Type Iv ◽  
Ischemic Brain Injury ◽  
Ischemic Brain ◽  
Type Iv ◽  
Injured Brain ◽  
Tissue Plasminogen ◽  
Rosiglitazone Treatment

In this study, we examined whether rosiglitazone, a peroxisome proliferator-activated receptor gamma (PPAR γ) agonist, is neuroprotective in focal ischemic brain injury, and whether rosiglitazone can enhance the protective action of tissue plasminogen activator (tPA), an agent used clinically for thrombolytic therapy. Rats were subjected to ischemic brain injury by embolizing preformed clots into the middle cerebral artery (MCA). Treatment with rosiglitazone reduced infarction and improved functional recovery; it also enhanced the neuroprotective action of tPA and lengthened the time window for initiating tPA treatment. Occlusion of MCA resulted in a loss of collagen type IV, a major structural protein of the microvascular basal lamina, and tPA treatment worsened this loss. Rosiglitazone treatment prevented the reduction of collagen type IV in the ischemic injured brain by inhibiting the activation of matrix metallopeptidase-9 (MMP-9). In addition, rosiglitazone treatment reduced inflammatory reactions in the ischemic injured brain. Rosiglitazone either alone or in combination with tPA is an effective agent in the reduction of ischemic brain injury. The reduction of microvascular damage and inflammation contributes to the beneficial actions of rosiglitazone.

scholarly journals Human Recombinant Tissue-Plasminogen Activator (Alteplase): Why Not Use the ‘Human’ Dose for Stroke Studies in Rats?

2010 ◽  
Vol 30 (5) ◽  
pp. 900-903 ◽  
Author(s):  
Benoît Haelewyn ◽  
Jean-Jacques Risso ◽  
Jacques H Abraini
Keyword(s):  
Plasminogen Activator ◽  
Tissue Plasminogen Activator ◽  
Infarct Volume ◽  
Recombinant Tissue Plasminogen Activator ◽  
Brain Infarct ◽  
Clinical Dose ◽  
Human Dose ◽  
Tissue Plasminogen ◽  
Mean Time

Since a pioneer work that has shown in vitro that the rat's fibrinolytic system is 10-fold less sensitive to recombinant tissue-plasminogen activator (rtPA) than the human system, most preclinical studies are performed with 10 instead of 0.9 mg/kg rtPA (the clinical dose in stroke patients). In this study, we compared the effects of these doses on mean time to reperfusion, reperfusion slope, brain infarct volume and edema in a rat model of thrombo-embolic stroke. Our data provide evidence that the dose of 0.9 mg/kg rtPA is as appropriate as that of 10 mg/kg for preclinical stroke studies in rodents.

Abstract TMP69: Endoglin Deficiency Exacerbates Ischemic Brain Injury

Stroke ◽  
2013 ◽  
Vol 44 (suppl_1) ◽  
Author(s):  
Fanxia Shen ◽  
Vincent Degos ◽  
Zhenying Han ◽  
Eun-Jung Choi ◽  
William L. Young ◽  
...  
Keyword(s):  
Brain Injury ◽  
Infarct Volume ◽  
Paradoxical Embolism ◽  
Artery Occlusion ◽  
Vascular Density ◽  
Ischemic Brain Injury ◽  
Myocardial Repair ◽  
Ischemic Brain ◽  
Removal Time ◽  
Adhesive Removal

Background and Objective: Endoglin (Eng) deficiency causes hereditary hemorrhagic telangiectasia (HHT) and impairs myocardial repair. Pulmonary arteriovenous malformations in HHT patients are associated with a high incidence of paradoxical embolism in the cerebral circulation and ischemic brain injury. We hypothesized that Eng deficiency exacerbates ischemic brain injury. Methods: Eng heterozygous ( Eng +/- ) mice and wild type (WT) mice underwent permanent distal middle cerebral artery occlusion (pMCAO). Infarct volume and CD68 + cells were quantified 3 days and vascular density was determined 60 days after pMCAO. Behavior was assessed by corner test and adhesive removal test at 3, 15, 30 and 60 days after pMCAO. Matrix metalloproteinase 9 (Mmp9) and Notch1 expression in bone marrow (BM)-derived macrophages from Eng +/- and WT were analyzed using real-time RT-PCR. Results: Eng +/- mice had a larger Infarct volume than WT mice (22±6% of the affected hemisphere vs. 16±6%, p=0.04). Eng +/- mice had longer adhesive-removal time (p<0.05) and more frequent turning to the lesion side than WT mice at 15, 30 and 60 days (p<0.05) after pMCAO. Both groups had similar numbers of CD68 + cells in the peri-infarct area at 3 days after pMCAO (370±80 vs 338±44 cells/mm 2 , p=0.37), but Eng +/- mice had lower peri-infarct vessel density (417±69 vs 490±52 vessels/mm 2 , p=0.05) at 60 days after pMCAO. Up-regulation of Mmp9 and Notch1 expression in response to VEGF was attenuated in Eng +/- BM-derived macrophages. Conclusions: Endoglin deficiency exacerbated brain injury and behavior dysfunction in mice after pMCAO and was associated with reduced angiogenesis. Although macrophage homing was not affected, reduced expression of two angiogenic-related genes, Mmp9 and Notch1 , by Eng +/- BM-derived macrophages suggests a potential role of these cells in recovery from an ischemic injury.

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.

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