Abstract WMP44: Functional Recovery Following a Combination of Thrombin Inhibitor Argatroban and Tissue Plasminogen Activator (tPA) in Thromboembolic Stroke in Nonhuman Primates

Stroke ◽  
2017 ◽  
Vol 48 (suppl_1) ◽  
Author(s):  
Junko Suzuki ◽  
Yoshitaka Itani ◽  
Shinya Ogawa ◽  
Kazunori Yamanaka ◽  
Ikuo Hayashi ◽  
...  
Keyword(s):  
Acute Stroke ◽  
Plasminogen Activator ◽  
Functional Recovery ◽  
Nonhuman Primates ◽  
Infarct Volume ◽  
Thrombin Inhibitor ◽  
Thromboembolic Stroke ◽  
Brain Infarct ◽  
Occlusion Time ◽  
Tissue Plasminogen

Introduction: Early treatment following an acute stroke with the thrombolytic tissue plasminogen activator (tPA) increases functional recovery. Complications of tPA treatment include hemorrhaging and narrow therapeutic time window. Thus, better treatments for acute stroke are needed. While a number of novel treatments for acute ischemic stroke have been derived from preclinical rodent stroke models, to date, none have succeeded in clinical studies. Nonhuman primates are phylogenetically closer to humans than rodents, which could narrow the current translational shortfall between preclinical and clinical findings. The goal of the current study was to test the effect of a combination of argatroban, a thrombin inhibitor, and tPA on functional recovery and brain infarction size following thromboembolic ischemia in nonhuman primates. Methods: Autologous blood clots were injected into the internal carotid artery of cynomolgus macaques to induced a thromboembolic stroke. Either tPA (0.9 mg/kg; n = 8) or vehicle (n = 8) was intravenously infused for one hour an hour following the induction of ischemia. In a third group, after completion of tPA infusion, argatroban (0.6 mg/kg; n= 7) was intravenously infused for 22 hours. Doppler ultrasound recorded middle cerebral artery (MCA) blood flow for six hours following induction of stroke. In addition, brain infarct volume (TTC staining) and functional assessment (Neurologic Deficit Score; NDS) were determined 24 hours after ischemia. Results: Compared to vehicle treatment, tPA treatment significantly decreased MCA occlusion time, brain infarct volume and NDS. Treatment with the combination of argatroban and tPA decreased occlusion time, brain infarct volume and NDS similar to tPA treatment alone. Conclusion: The current study suggests that the addition of argatroban could enhance recanalization rates observed with tPA treatment alone. However, in contrast to previous findings in rats, the combination of argatroban and tPA does not appear to further enhance tissue or functional recovery from a thromboembolic stroke compared to tPA treatment alone.

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.

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.

scholarly journals Fatal ischaemic brain oedema after early thrombolysis with tissue plasminogen activator in acute stroke.

BMJ ◽  
1988 ◽  
Vol 297 (6663) ◽  
pp. 1571-1574 ◽  
Author(s):  
P. J. Koudstaal ◽  
J. Stibbe ◽  
M. Vermeulen
Keyword(s):  
Acute Stroke ◽  
Plasminogen Activator ◽  
Tissue Plasminogen Activator ◽  
Brain Oedema ◽  
Ischaemic Brain ◽  
Tissue Plasminogen

Activation of complement by tissue plasminogen activator, but not acute cerebral ischemia, in a rabbit model of thromboembolic stroke

1997 ◽  
Vol 86 (1) ◽  
pp. 139-142 ◽  
Author(s):  
Martin M. Bednar ◽  
Cordell E. Gross ◽  
Sheila R. Russell ◽  
David Short ◽  
Patricia C. Giclas
Keyword(s):  
Cerebral Ischemia ◽  
Plasminogen Activator ◽  
Complement Activation ◽  
Rabbit Model ◽  
Thromboembolic Stroke ◽  
Content Type ◽  
Acute Cerebral Ischemia ◽  
Tissue Plasminogen ◽  
Before And After ◽  
Fine Print

✓ Although complement activation is associated with tissue injury during inflammatory and ischemic states, complement activation in states of acute cerebral ischemia before and after administration of tissue plasminogen activator (TPA) has not yet been examined and is the focus of this investigation. Twenty-four New Zealand White rabbits weighing 3 to 3.5 kg were used for this study. Of these, 20 were subjected to intracranial autologous clot embolization via the internal carotid artery. Three hours postembolization, rabbits received an intravenous infusion of TPA (6.3 mg/kg, 20% bolus with the remainder infused over a 2-hour interval; 12 animals) or vehicle (eight animals). All animals were observed for a total of 7 or 8 hours postembolization. These two groups were compared to a cohort undergoing sham operation with subsequent TPA infusion (four animals). Plasma samples to quantify complement component C5 hemolytic activity (C5H5O) were obtained at the following time points: 30 minutes before and after clot embolization; 1 hour before and 1 hour after the initiation of therapy with TPA or vehicle and at the completion of the protocol; 7 to 8 hours after clot embolization. The C5 activation was not detected as the result of acute cerebral ischemia. However, animals receiving TPA with or without concomitant clot embolization exhibited C5 activation as assessed by a reduction in C5 hemolytic function, both 1 hour after initiation of TPA infusion (78.7 ± 10.3% and 77.5 ± 9.9% of baseline value, respectively; mean ± standard error of the mean [SEM]) and at the end of the protocol, 2 hours after the completion of the TPA infusion (72.5 ± 8.8% and 53.3 ± 8.1%, respectively; mean ± SEM, p < 0.05, each group). This study supports the conclusion that TPA, but not acute cerebral ischemia, may activate the complement cascade in this rabbit model of thromboembolic stroke.

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.

Abstract WP105: Tissue Plasminogen Activator (tPA) is Essential for Functional Recovery After Stroke by Promoting Axonal Outgrowth

Stroke ◽  
2017 ◽  
Vol 48 (suppl_1) ◽  
Author(s):  
Shubei Ma
Keyword(s):  
Ischemic Stroke ◽  
White Matter ◽  
Plasminogen Activator ◽  
Tissue Plasminogen Activator ◽  
Functional Recovery ◽  
Stroke Recovery ◽  
White Matter Integrity ◽  
Blue Staining ◽  
Tissue Plasminogen

Objectives: Stroke is the leading cause of long term neurological disability with limited therapeutic options. Human recombinant tissue plasminogen activator (tPA) is currently the only FDA approved drug for the thrombolytic treatment of ischemic stroke. Emerging evidence suggests that the effects of tPA in ischemic brain may extend beyond its thrombolytic activity. In this study, we investigated the role of tPA in long term stroke recovery. Methods: Cortical infarct was induced by distal middle cerebral artery occlusion (dMCAO) in tPA knockout (KO) and wild type (WT) mice. Sensorimotor functions were evaluated at 3-35 days after dMCAO. White matter integrity was assessed by luxol fast blue staining, immunohistochemistry for SMI-32, and diffusion tensor imaging (DTI). The neuronal tracer biotinylated dextran amine (BDA) was used to label the corticorubral tract and the corticospinal tract. For rescue experiment, tPA (2mg/kg) was delivered intranasally to tPA KO mice once a day for 14 days starting 6h after dMCAO. Results: Infarct volume was comparable between tPA KO and WT mice after dMCAO. Sensorimotor deficits after dMCAO were exacerbated in tPA KO mice than WT mice. tPA KO mice also showed more severe demyelination in post-stroke white matter and reduced axonal sprouting at 35 days after dMCAO compared to WT mice. DTI studies revealed deteriorated white matter integrity in tPA KO mice, as manifested by decreased fractional anisotropy. Intranasal delivery of tPA after dMCAO rescued the neurological phenotype shown by tPA KO mice. Conclusion: Endogenous tPA promotes white matter integrity and is essential for functional recovery after ischemic stroke. tPA may be a novel neurorestorative therapy for stroke recovery.

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