scholarly journals The Plasminogen Activation System Promotes Neurorepair in the Ischemic Brain

2019 ◽  
Vol 20 (9) ◽  
pp. 953-959 ◽  
Author(s):  
Manuel Yepes
Keyword(s):  
Ischemic Stroke ◽  
Cerebral Ischemia ◽  
Plasminogen Activator ◽  
Basic Research ◽  
Recovery Phase ◽  
Tissue Type ◽  
Plasminogen Activation ◽  
Ischemic Brain ◽  
Plasminogen Activation System ◽  
Type Plasminogen Activator

The plasminogen activation (PA) system was originally thought to exclusively promote the degradation of fibrin by catalyzing the conversion of plasminogen into plasmin via two serine proteinases: tissue-type plasminogen activator (tPA) and urokinase-type plasminogen activator (uPA). However, experimental evidence accumulated over the last 30 years indicates that tPA and uPA are also found in the central nervous system (CNS), where they have a plethora of functions that not always require plasmin generation or fibrin degradation. For example, plasminogen-dependent and - independent effects of tPA and uPA play a central role in the pathophysiological events that underlie one of the leading causes of mortality and disability in the world: cerebral ischemia. Indeed, recent work indicates that while the rapid release of tPA from the presynaptic compartment following the onset of cerebral ischemia protects the synapse from the deleterious effects of the ischemic injury, the secretion of uPA and its binding to its receptor (uPAR) during the recovery phase promotes the repair of synapses that have been lost to the acute ischemic insult. This restorative role of uPA has high translational significance because to this date there is no effective approach to induce neurorepair in the ischemic brain. Here we will discuss recent evidence that bridges the gap between basic research in the field of the PA system and the bedside of ischemic stroke patients, indicating that uPA and uPAR are potential targets for the development of therapeutic strategies to promote neurological recovery among ischemic stroke survivors.

scholarly journals Update on therapies for acute ischemic stroke

2000 ◽  
Vol 8 (5) ◽  
pp. 1-5 ◽  
Author(s):  
Dean D. Kindler ◽  
George A. Lopez ◽  
Bradford B. Worrall ◽  
Karen C. Johnston
Keyword(s):  
Ischemic Stroke ◽  
Cerebral Ischemia ◽  
Acute Ischemic Stroke ◽  
Plasminogen Activator ◽  
Tissue Type ◽  
Tissue Type Plasminogen Activator ◽  
Emerging Therapies ◽  
Type Plasminogen Activator ◽  
Acute Cerebral Ischemia ◽  
Promising Treatment

Acute ischemic stroke is now considered a neurological emergency for which there are new therapies. Neurosurgeons and neurologists need to remain apprised of advances in this field. The authors discuss approved and emerging therapies for patients suffering from acute ischemic stroke, based on a review of recent publications. Currently, intravenous tissue-type plasminogen activator is the only Food and Drug Administration–approved therapy for acute ischemic stroke. Intraarterial delivery of thrombolytics is a promising treatment and may be effective in selected patients. Other therapies for acute cerebral ischemia are intriguing but still in the investigational stages.

scholarly journals The Role of the Plasminogen Activation System in Angioedema: Novel Insights on the Pathogenesis

2021 ◽  
Vol 10 (3) ◽  
pp. 518
Author(s):  
Filomena Napolitano ◽  
Nunzia Montuori
Keyword(s):  
Plasminogen Activator ◽  
Blood Clot ◽  
Active Form ◽  
Tissue Type ◽  
Plasminogen Activation ◽  
Scientific Debate ◽  
Plasminogen Activation System ◽  
Type Plasminogen Activator ◽  
Urokinase Type Plasminogen Activator ◽  
Normal Blood Flow

The main physiological functions of plasmin, the active form of its proenzyme plasminogen, are blood clot fibrinolysis and restoration of normal blood flow. The plasminogen activation (PA) system includes urokinase-type plasminogen activator (uPA), tissue-type PA (tPA), and two types of plasminogen activator inhibitors (PAI-1 and PAI-2). In addition to the regulation of fibrinolysis, the PA system plays an important role in other biological processes, which include degradation of extracellular matrix such as embryogenesis, cell migration, tissue remodeling, wound healing, angiogenesis, inflammation, and immune response. Recently, the link between PA system and angioedema has been a subject of scientific debate. Angioedema is defined as localized and self-limiting edema of subcutaneous and submucosal tissues, mediated by bradykinin and mast cell mediators. Different forms of angioedema are linked to uncontrolled activation of coagulation and fibrinolysis systems. Moreover, plasmin itself can induce a potentiation of bradykinin production with consequent swelling episodes. The number of studies investigating the PA system involvement in angioedema has grown in recent years, highlighting its relevance in etiopathogenesis. In this review, we present the components and diverse functions of the PA system in physiology and its importance in angioedema pathogenesis.

scholarly journals Changes in the content of some components of the plasminogen activation system in the plasma of bladder cancer patients

2020 ◽  
Vol 80 (1) ◽  
pp. 15-19
Author(s):  
V. Dmytryk ◽  
O. Savchuk ◽  
P. Yakovlev
Keyword(s):  
Bladder Cancer ◽  
Blood Plasma ◽  
Plasminogen Activator ◽  
Tissue Type ◽  
Plasminogen Activation ◽  
Invasion And Metastasis ◽  
Plasminogen Activation System ◽  
Type Plasminogen Activator ◽  
Activation System ◽  
Pai 1

Bladder cancer (BC) continues to be a disease with a high mortality rate. Bladder cancer is the sixth for men and seventeenth for women in the incidence of malignancy worldwide. The invasion and metastasis of malignant tumors are caused by a sequence of processes, including loss of cell-cell and / or cell-matrix adhesion, proteolysis, and induction of angiogenesis. Different protease systems are involved in these processes, especially during the invasion and development of metastases. One such protease system is a plasminogen activation system or fibrinolysis system. Changes in the balance of plasminogen activation systems have been investigated in many types of malignancies, and these changes may not only indicate the functioning of this system but may also have prognostic significance. In malignancies, the components of this system are involved in the growth, invasion, and metastasis of tumors, affecting cell migration and angiogenesis. The main, but a well-studied component of the plasminogen activation system is serine proteinase – urokinase-type plasminogen activator (uPA). In contrast to uPA, tissue-type plasminogen activator (tPA) is characterized by a high affinity for fibrin and is involved in thrombolysis. Both types of plasminogen activators are synthesized in tumor tissues: tPA and uPA. The largest player among the inhibitors of fibrinolysis is the plasminogen activator inhibitor type 1 (PAI-1), involved in the pathogenesis of many cardiovascular diseases, as well as in cancer. The purpose of this study was to detect changes in the content of plasminogen activator tissue type tPA and PAI-1 in the blood plasma of patients with BC at different stages of the disease. The study involved 40 men who were verified with a diagnosis of BC. The content of tPA and PAI-1 in preoperative blood plasma was determined by enzyme immunoassay in ELISA modification. In our study, changes in the tPA and PAI-1 content of the blood plasma at different stages were identified, which can characterize tumor growth and invasion and can supplement existing disease information.

scholarly journals Tissue-type plasminogen activator protects the postsynaptic density in the ischemic brain

2018 ◽  
Vol 38 (11) ◽  
pp. 1896-1910 ◽  
Author(s):  
Valerie Jeanneret ◽  
Juan P Ospina ◽  
Ariel Diaz ◽  
Luis G Manrique ◽  
Paola Merino ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Plasminogen Activator ◽  
Ampa Receptors ◽  
Postsynaptic Density ◽  
Scaffolding Protein ◽  
Tissue Type ◽  
Ischemic Brain ◽  
Tissue Type Plasminogen Activator ◽  
Type Plasminogen Activator ◽  
Presynaptic Release

Cerebral ischemia causes the presynaptic release of tissue-type plasminogen activator (tPA). The postsynaptic density (PSD) is a postsynaptic structure that provides a matrix where signaling transduction of excitatory synapses takes place. The postsynaptic density protein-95 (PSD-95) is the most abundant scaffolding protein in the postsynaptic density (PSD), where it modulates the postsynaptic response to the presynaptic release of glutamate by regulating the anchoring of glutamate receptors to the PSD. We found that tPA induces the local translation of PSD-95 mRNA and the subsequent recruitment of PSD-95 protein to the PSD, via plasminogen-independent activation of TrkB receptors. Our data show that PSD-95 is removed from the PSD during the early stages of cerebral ischemia, and that this effect is abrogated by either the release of neuronal tPA, or intravenous administration of recombinant tPA (rtPA). We report that the effect of tPA on PSD-95 is associated with inhibition of the phosphorylation and recruitment of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors to the PSD, known to amplify the effect of the excitotoxic injury, and that this is followed by TrkB-mediated protection of dendritic spines from the harmful effects of the hypoxic insult. These data reveal that tPA is a synaptic protector in the ischemic brain.

scholarly journals Urokinase-type plasminogen activator (uPA) protects the tripartite synapse in the ischemic brain via ezrin-mediated formation of peripheral astrocytic processes

2018 ◽  
Vol 39 (11) ◽  
pp. 2157-2171 ◽  
Author(s):  
Ariel Diaz ◽  
Paola Merino ◽  
Luis G Manrique ◽  
Lihong Cheng ◽  
Manuel Yepes
Keyword(s):  
Ischemic Stroke ◽  
Plasminogen Activator ◽  
Harmful Effect ◽  
Ischemic Injury ◽  
Adult Brain ◽  
Subsequent Formation ◽  
Ischemic Brain ◽  
Tripartite Synapse ◽  
Type Plasminogen Activator ◽  
Urokinase Type Plasminogen Activator

Cerebral ischemia has a harmful effect on the synapse associated with neurological impairment. The “tripartite synapse” is assembled by the pre- and postsynaptic terminals, embraced by astrocytic elongations known as peripheral astrocytic processes (PAPs). Ischemic stroke induces the detachment of PAPs from the synapse, leading to synaptic dysfunction and neuronal death. Ezrin is a membrane-associated protein, required for the formation of PAPs, that links the cell surface to the actin cytoskeleton. Urokinase-type plasminogen activator (uPA) is a serine proteinase that upon binding to its receptor (uPAR) promotes neurite growth during development. In the adult brain, neurons release uPA and astrocytes recruit uPAR to the plasma membrane during the recovery phase from an ischemic stroke, and uPA/uPAR binding promotes functional improvement following an ischemic injury. We found that uPA induces the synthesis of ezrin in astrocytes, with the subsequent formation of PAPs that enter in direct contact with the synapse. Furthermore, either the release of neuronal uPA or intravenous treatment with recombinant uPA (ruPA) induces the formation of PAPs in the ischemic brain, and the interaction of these PAPs with the pre- and postsynaptic terminals protects the integrity of the “tripartite synapse” from the harmful effects of the ischemic injury.

Abstract 1029: Stromelysin-1 is Critical For Intracranial Bleeding After Tissue-type plasminogen activator Treatment Of Stroke In Mice

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Yasuhiro Suzuki ◽  
Nobuo Nagai ◽  
Desire Collen ◽  
Roger Lijnen ◽  
Kazuo Umemura
Keyword(s):  
Ischemic Stroke ◽  
Plasminogen Activator ◽  
Placebo Treatment ◽  
Artery Occlusion ◽  
Intracranial Bleeding ◽  
Tissue Type ◽  
Tissue Type Plasminogen Activator ◽  
Mmp Inhibitor ◽  
Type Plasminogen Activator ◽  
Cerebral Artery Occlusion

Background: Tissue-type plasminogen activator (t-PA) is approved for treatment of ischemic stroke patients, but it may increase the risk of intracranial bleeding (ICB). Matrix metalloproteinases (MMPs), which can be activated through the plasminogen/plasmin system, may contribute to ICB after ischemic stroke. Objectives: To explore the contribution of plasminogen, MMP-3 and MMP-9 to ICB associated with t-PA treatment after ischemic stroke. Methods: Using a thrombotic middle cerebral artery occlusion (MCA-O) model, ICB was studied in mice with genetic deficiencies of plasminogen (Plg −/ − ), stromelysin-1 (MMP-3 −/ − ) or gelatinase B (MMP-9 −/ − ) and their corresponding wild-type (WT) littermates. t-PA (10 mg/kg) or its equivalent volume of solvent was administered intravenously 4 hours after MCA-O. The induction of MMP-3 and MMP-9 was also studied in C57BL/6 WT mice. Results: In MMP-3 +/+ WT mice given solvent, ICB was 4.3 ± 2.9 mm 3 (mean ± SD), which was significantly increased with tPA treatment to 9.7 ± 4.7 mm 3 (P<0.05), whereas ICB in MMP-3 −/ − mice was not altered by t-PA treatment (5.7 ± 2.7 mm 3 , as compared to 5.1 ± 1.8 mm 3 without tPA; n = 7–9 in each group). ICB induced by t-PA was significantly less in Plg −/ − (5.7 ± 3.9 mm 3 ) than in WT mice (8.8 ± 3.2 mm 3 , p<0.05) but ICB by t-PA in MMP-9 −/ − (8.3 ± 2.3 mm 3 ) was comparable with that in WT (8.3 ± 3.1 mm 3 ; n=8 –12 in each group). Administration of the broad-spectrum MMP inhibitor GM6001 after t-PA treatment reduced ICB significantly in MMP-3 +/+ (from 6.4 ± 1.9 mm 3 to 4.1 ± 1.9 mm 3 , p<0.05) but not in MMP-3 −/ − mice (2.2 ± 0.6 mm 3 without versus 2.9 ± 1.5 mm 3 with GM6001; n=6 – 8 in each group). MMP-3 expression was significantly enhanced at the ischemic hemisphere; with placebo treatment, it was expressed only in neurons, whereas it was upregulated in endothelial cells with t-PA treatment. Although MMP-9 expression was also significantly enhanced at the ischemic brain, the amount and the distribution were comparable in mice with and without t-PA treatment. Conclusions: Our data with gene deficient mice suggest that plasminogen and MMP-3 are relatively more important than MMP-9 for the increased ICB induced by t-PA treatment of ischemic stroke.

Abstract TMP19: Intravenous Recombinant Tissue-type Plasminogen Activator Use in Young Adults With Acute Ischemic Stroke

Stroke ◽  
2017 ◽  
Vol 48 (suppl_1) ◽  
Author(s):  
Jodi A Dodds ◽  
Ying Xian ◽  
Shubin Sheng ◽  
Gregg Fonarow ◽  
Ronald A Matsouaka ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Acute Ischemic Stroke ◽  
Plasminogen Activator ◽  
Older Patients ◽  
Young Patients ◽  
Tissue Type ◽  
Stroke Patients ◽  
Younger Patients ◽  
Tissue Type Plasminogen Activator ◽  
Type Plasminogen Activator

Background: Intravenous recombinant tissue-type plasminogen activator (rt-PA) administration improves outcomes in acute ischemic stroke. However, young patients (<40 years old) presenting with stroke symptoms may experience delays in treatment due to misdiagnosis or a reluctance to treat since they do not fit the profile of a typical stroke patient. Methods: We analyzed data from the large national Get With The Guidelines–Stroke registry for acute ischemic stroke patients hospitalized between January 2009 and September 2015. Multivariable models with generalized estimating equations (GEE) were used to test for differences between younger (age 18-40) and older (age > 40) acute ischemic stroke patients, controlling for patient and hospital characteristics including stroke severity. Results: Of 1,320,965 AIS patients admitted to participating hospitals, 2.3% (30,448) were aged 18-40. Among these patients, 12.5% received rt-PA versus 8.8% of those aged >40 (p<0.001). Of patients arriving within 3.5 hours of symptom onset without contraindications, 68.7% of younger patients received IV rt-PA versus 63.3% of older patients (adjusted OR [aOR] 1.30, 95% CI 1.21 to 1.40), without evidence that age-related differences varied by sex (interaction p-value 0.25). Odds ratios of achieving target door-to-CT times and door-to-needle (DTN) times, and outcomes of rtPA-treated patients, are shown in the Table. Conclusions: Young acute ischemic stroke patients did not receive rt-PA treatment at lower rates than older patients. Outcomes were better and the rate of symptomatic intracranial hemorrhage was lower in the young patients. However, younger patients had significantly longer door-to-CT and DTN times, providing an opportunity to improve the care of these patients.

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