Hemorrhagic Transformation after Tissue Plasminogen Activator Reperfusion Therapy for Ischemic Stroke: Mechanisms, Models, and Biomarkers

Wang, Wei; Li, Mingchang; Chen, Qianxue; Wang, Jian

doi:10.1007/s12035-014-8952-x

Cited by 117 publications

(90 citation statements)

References 100 publications

(113 reference statements)

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“…Excessive free radicals, including hydroxyl radical, superoxide anion, and H 2 O 2 , are generated early and consume intrinsic antioxidant systems such as SOD, GSH, and GSH-px. These free radicals lead to neuronal damage by promoting lipid peroxidation, protein breakdown, and DNA damage that in turn induces cellular apoptosis, endothelial damage, and blood-brain barrier disruption [53–56]. Importantly, brain is an organ with a high content of polyunsaturated fatty acids, which makes it vulnerable to free radical attacks and lipid peroxidation.…”

Section: Discussionmentioning

confidence: 99%

Cerebroprotection by salvianolic acid B after experimental subarachnoid hemorrhage occurs via Nrf2- and SIRT1-dependent pathways

Zhang

et al. 2018

Free Radical Biology and Medicine

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Salvianolic acid B (SalB), a natural polyphenolic compound extracted from the herb of Salvia miltiorrhiza, possesses antioxidant and neuroprotective properties and has been shown to be beneficial for diseases that affect vasculature and cognitive function. Here we investigated the protective effects of SalB against subarachnoid hemorrhage (SAH)-induced oxidative damage, and the involvement of underlying molecular mechanisms. In a rat model of SAH, SalB inhibited SAH-induced oxidative damage. The reduction in oxidative damage was associated with suppressed reactive oxygen species generation; decreased lipid peroxidation; and increased glutathione peroxidase, glutathione, and superoxide dismutase activities. Concomitant with the suppressed oxidative stress, SalB significantly reduced neurologic impairment, brain edema, and neural cell apoptosis after SAH. Moreover, SalB dramatically induced nuclear factor-erythroid 2-related factor 2 (Nrf2) nuclear translocation and increased expression of heme oxygenase-1 and NADPH: quinine oxidoreductase-1. In a mouse model of SAH, Nrf2 knockout significantly reversed the antioxidant effects of SalB against SAH. Additionally, SalB activated sirtuin 1 (SIRT1) expression, whereas SIRT1-specific inhibitor sirtinol pretreatment significantly suppressed SalB-induced SIRT1 activation and Nrf2 expression. Sirtinol pretreatment also reversed the antioxidant and neuroprotective effects of SalB. In primary cultured cortical neurons, SalB suppressed oxidative damage, alleviated neuronal degeneration, and improved cell viability. These beneficial effects were associated with activation of the SIRT1 and Nrf2 signaling pathway and were reversed by sirtinol treatment. Taken together, these in vivo and in vitro findings suggest that SalB provides protection against SAH-triggered oxidative damage by upregulating the Nrf2 antioxidant signaling pathway, which may be modulated by SIRT1 activation.

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Section: Discussionmentioning

confidence: 99%

Cerebroprotection by salvianolic acid B after experimental subarachnoid hemorrhage occurs via Nrf2- and SIRT1-dependent pathways

Zhang

et al. 2018

Free Radical Biology and Medicine

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“…Activation of MMPs (Jin et al, 2010b; Vivien et al, 2011) and PARP activity (Crome et al, 2007) have been implicated in rt-PA-mediated vascular toxicity (damaging BBB, damage to microvessels, etc.) (Jickling et al, 2014; Wang et al, 2015a; Wang et al, 2004). Further study showed that rt-PA through plasmin enhances endothelial microparticle release, which has an impact on growth and morphology of cerebral endothelial cells (Garraud et al, 2016).…”

Section: Recently Identified Therapeutic Aims and Therapiesmentioning

confidence: 99%

Targeting vascular inflammation in ischemic stroke: Recent developments on novel immunomodulatory approaches

Shekhar

Cunningham

Pabbidi

et al. 2018

European Journal of Pharmacology

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Ischemic stroke is a devastating and debilitating medical condition with limited therapeutic options. However, accumulating evidence indicates a central role of inflammation in all aspects of stroke including its initiation, the progression of injury, and recovery or wound healing. A central target of inflammation is disruption of the blood brain barrier or neurovascular unit. Here we discuss recent developments in identifying potential molecular targets and immunomodulatory approaches to preserve or protect barrier function and limit infarct damage and functional impairment. These include blocking harmful inflammatory signaling in endothelial cells, microglia/macrophages, or Th17/γδ T cells with biologics, third generation epoxyeicosatrienoic acid (EET) analogs with extended half-life, and miRNA antagomirs. Complementary beneficial pathways may be enhanced by miRNA mimetics or hyperbaric oxygenation. These immunomodulatory approaches could be used to greatly expand the therapeutic window for thrombolytic treatment with tissue plasminogen activator (t-PA). Moreover, nanoparticle technology allows for the selective targeting of endothelial cells for delivery of DNA/RNA oligonucleotides and neuroprotective drugs. In addition, although likely detrimental to the progression of ischemic stroke by inducing inflammation, oxidative stress, and neuronal cell death, 20-HETE may also reduce susceptibility of onset of ischemic stroke by maintaining autoregulation of cerebral blood flow. Although the interaction between inflammation and stroke is multifaceted, a better understanding of the mechanisms behind the pro-inflammatory state at all stages will hopefully help in developing novel immunomodulatory approaches to improve mortality and functional outcome of those inflicted with ischemic stroke.

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“…To investigate the effect of thrombin in the brain tissue, experimentally thrombin was injected into the ventricle of rats, causing vascular leakage and brain edema at 24 hours [2]. Thrombin acts on protease activated receptors, like SRC kinase, causing phosphorylation cascade on NMDA receptors [154]. and causing neuronal death via calcium dysregulation, ending up in MMP and VEGF release and a consequent BBB opening.…”

Section: Src Kinasementioning

confidence: 99%

Hemorrhagic transformation of ischemic stroke

J¹,

Hortobágyi²

2017

Vascul Dis Ther

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The better understanding of the diverse mechanisms leading to the hemorrhagic transformation of an ischemic stroke is the crucial point in the prevention of this altogether common phenomenon. The different individual risk factors include the anatomical variability of collateral blood supply, age, genetics, body weight, etiology of the occlusion, side of the occluded vessel, renal status, stroke severity, history of high serum glucose or hypertension and hypertension or hyperglycemia at the onset of the stroke, ferritin level, INR, antiplatelet usage or the platelet count etc. All these might contribute to the process of hemorrhagic transformation. These risk factors have been identified by retrospective epidemiological studies and are useful to identify patients who are at high risk for hemorrhagic conversion and help the decision between conservative, thrombolytic or more advanced treatments such as thrombectomy. The modulations of potential molecular targets participating in the process seem to be promising in animal models, but human trials are lacking the breakthrough success so far, both in extending the time frame of the thrombolysis and in replacing the recombinant tissue plasminogen activator (rtPA) as thrombolytic agent.So far, the careful preselection of patients eligible for thrombolytic therapy is the best way to prevent hemorrhagic transformation. The intensive research in the field revealing small but important molecular details are continuously contributing to the better understanding of hemorrhagic transformation with the intention of finding new agents that co-administrated to the rtPA or completely replacing that could decrease the risk of secondary bleeding.The aim of this review is to give comprehensive insight into the process of hemorrhagic transformation of ischemic stroke, starting with basic overview of the penumbra concept and the collateral supply followed by discussion of the recanalisation-reperfusion-hemorrhagic transformation process after vessel occlusion also highlighting the importance of timing and ratio of recanalisation spontaneously and in case of thrombolytic agent administration. We overview the risk factors of hemorrhagic transformation, which may be helpful to physicians to identify high risk patients before rtPA administration. The last part of the work is dealing with future therapeutic possibilities based on the so far revealed molecular mechanisms of hemorrhagic transformation. With the aim to assess the rate and influencing factors on the recanalisation and reperfusion rate 381 patients with large-vessel occlusion was investigated. The patient group involved ones treated with rtPA or treated conservatively. Partial or complete recanalisation was achieved in 121 out of 210 (58%) patients after intravenous rtPA administration. The recanalisation success was more likely if the patient had atrial fibrillation [4] -maybe because cardioembolic clots consists more fibrin and are more likely to reopen by plasmin proteolysis than thrombosis of an atherosclerotic plaq...

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Hemorrhagic Transformation after Tissue Plasminogen Activator Reperfusion Therapy for Ischemic Stroke: Mechanisms, Models, and Biomarkers

Cited by 117 publications

References 100 publications

Cerebroprotection by salvianolic acid B after experimental subarachnoid hemorrhage occurs via Nrf2- and SIRT1-dependent pathways

Cerebroprotection by salvianolic acid B after experimental subarachnoid hemorrhage occurs via Nrf2- and SIRT1-dependent pathways

Targeting vascular inflammation in ischemic stroke: Recent developments on novel immunomodulatory approaches

Hemorrhagic transformation of ischemic stroke

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