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Neurosurgical Review Jan 2024The discovery of the glymphatic system has revolutionized our understanding of cerebrospinal fluid (CSF) circulation and interstitial waste clearance in the brain. This... (Review)
Review
The discovery of the glymphatic system has revolutionized our understanding of cerebrospinal fluid (CSF) circulation and interstitial waste clearance in the brain. This scoping review aims to synthesize the current literature on the glymphatic system's role in neurosurgical conditions and its potential as a therapeutic target. We conducted a comprehensive search in PubMed and Scopus databases for studies published between January 1, 2012, and October 31, 2023. Studies were selected based on their relevance to neurosurgical conditions and glymphatic function, with both animal and human studies included. Data extraction focused on the methods for quantifying glymphatic function and the main results. A total of 67 articles were included, covering conditions such as idiopathic normal pressure hydrocephalus (iNPH), idiopathic intracranial hypertension (IIH), subarachnoid hemorrhage (SAH), stroke, intracranial tumors, and traumatic brain injury (TBI). Significant glymphatic dysregulation was noted in iNPH and IIH, with evidence of impaired CSF dynamics and delayed clearance. SAH studies indicated glymphatic dysfunction with the potential therapeutic effects of nimodipine and tissue plasminogen activator. In stroke, alterations in glymphatic activity correlated with the extent of edema and neurological recovery. TBI studies highlighted the role of the glymphatic system in post-injury cognitive outcomes. Results indicate that the regulation of aquaporin-4 (AQP4) channels is a critical target for therapeutic intervention. The glymphatic system plays a critical role in the pathophysiology of various neurosurgical conditions, influencing brain edema and CSF dynamics. Targeting the regulation of AQP4 channels presents as a significant therapeutic strategy. Although promising, the translation of these findings into clinical practice requires further human studies. Future research should focus on establishing non-invasive biomarkers for glymphatic function and exploring the long-term effects of glymphatic dysfunction.
Topics: Animals; Humans; Glymphatic System; Neurosurgeons; Tissue Plasminogen Activator; Brain; Subarachnoid Hemorrhage; Brain Injuries, Traumatic; Hydrocephalus; Stroke
PubMed: 38253938
DOI: 10.1007/s10143-024-02291-6 -
Journal of Vascular Surgery Mar 2021Catheter-directed thrombolysis in the treatment of acute lower extremity arterial occlusions often requires several interventional sessions to generate successful...
OBJECTIVE
Catheter-directed thrombolysis in the treatment of acute lower extremity arterial occlusions often requires several interventional sessions to generate successful outcomes. It is typically an expensive procedure, necessitating extended hospital length of stay (LOS) that may be associated with an increase in both local and systemic hemorrhagic complications. Five years ago, we created the fast-track thrombolysis protocol for arteries (FTTP-A) to deal with these concerns. The goal of our protocol is to re-establish patency during the first session of thrombolysis, thus decreasing costs and complications associated with prolonged periods of thrombolytic exposure.
METHODS
A retrospective study of 42 patients who were treated for acute limb ischemia at our institution by FTTP-A from January 2014 to February 2019 was performed. FTTP-A includes periadventitial lidocaine injection at the arterial puncture site under ultrasound guidance, contrast arteriography of the entire targeted segment, pharmacomechanical rheolytic thrombectomy of the occluded arterial segment, tissue plasminogen activator infusion along the occluded segment, balloon maceration of the thrombus, and (if deemed necessary) placement of a stent in an area of significant (≥30%) stenosis that is refractory to balloon angioplasty and thrombolysis. After the stenosis or thrombus is cleared, patients are prescribed an oral anticoagulant agent.
RESULTS
Primary FTTP-A (50 total interventions) was performed in 42 patients. The median age of patients was 67.2 ± 12.2 years (range, 41-98 years), and 54.8% were male; 59.5% of the procedures were performed on the left lower extremity. Initial arterial access was obtained through the common femoral artery in 39 of 42 cases (92.9%); in the remaining 3 cases, it was obtained in a left bypass access site, a right femoral-popliteal graft, and a right femoral-femoral graft. The mean operative time was 148.9 ± 62.9 minutes (range, 83-313 minutes), and the mean volume of tissue plasminogen activator infused was 9.7 ± 4.0 mg (range, 2-20 mg). The median cost including medications and interventional tools was $4673.19 per procedure. The mean postoperative LOS was 3.1 ± 4.5 days (range, 1-25 days). Median postoperative LOS was 1 day. Mean postoperative follow-up was 27 ± 19.2 months (range, 0-62 months). Single-session FTTP-A was successful in 81% (n = 34/42) of patients; the remaining 8 patients (19%) required a single additional session. Of the 42 patients, 34 (81%) required arterial stenting. Periprocedural complications consisted of one patient with hematuria, which resolved, and one patient with thrombocytopenia, which resolved. No patients experienced rethrombosis within 30 days of FTTP-A. During the 5-year study period, there was no significant local or systemic hemorrhage, limb loss, or mortality related to this protocol.
CONCLUSIONS
FTTP-A appears to be a safe, efficacious, and cost-effective procedure in the resolution of acute lower extremity arterial occlusions.
Topics: Acute Disease; Adult; Aged; Aged, 80 and over; Angioplasty, Balloon; Cost-Benefit Analysis; Drug Costs; Female; Hospital Costs; Humans; Infusions, Intra-Arterial; Ischemia; Length of Stay; Male; Middle Aged; Peripheral Arterial Disease; Retrospective Studies; Stents; Thrombolytic Therapy; Thrombosis; Time Factors; Time-to-Treatment; Tissue Plasminogen Activator; Treatment Outcome; Vascular Patency
PubMed: 32437952
DOI: 10.1016/j.jvs.2020.03.061 -
International Journal of Molecular... Mar 2021Plasminogen activator inhibitor-1 (PAI-1) is the main physiological inhibitor of plasminogen activators (PAs) and is therefore an important inhibitor of the... (Review)
Review
Plasminogen activator inhibitor-1 (PAI-1) is the main physiological inhibitor of plasminogen activators (PAs) and is therefore an important inhibitor of the plasminogen/plasmin system. Being the fast-acting inhibitor of tissue-type PA (tPA), PAI-1 primarily attenuates fibrinolysis. Through inhibition of urokinase-type PA (uPA) and interaction with biological ligands such as vitronectin and cell-surface receptors, the function of PAI-1 extends to pericellular proteolysis, tissue remodeling and other processes including cell migration. This review aims at providing a general overview of the properties of PAI-1 and the role it plays in many biological processes and touches upon the possible use of PAI-1 inhibitors as therapeutics.
Topics: Cardiovascular Diseases; Cell Movement; Fibrinolysis; Fibrosis; Humans; Neoplasm Proteins; Neoplasms; Plasminogen Activator Inhibitor 1; Proteolysis; Urokinase-Type Plasminogen Activator
PubMed: 33800359
DOI: 10.3390/ijms22052721 -
Journal of Thrombosis and Haemostasis :... Jul 2021Twenty-five years ago, intravenous thrombolysis has revolutionized the care of patients with acute ischemic stroke. Since 2015, randomized clinical trials have... (Review)
Review
Twenty-five years ago, intravenous thrombolysis has revolutionized the care of patients with acute ischemic stroke. Since 2015, randomized clinical trials have demonstrated that mechanical thrombectomy improves functional outcome in stroke patients over intravenous thrombolysis alone. More recently, three randomized clinical trials have suggested that mechanical thrombectomy alone is noninferior to a combined strategy with both intravenous thrombolysis and mechanical thrombectomy. In the present review, we will present the last clinical and preclinical studies on the use of thrombolysis in stroke patients in the modern thrombectomy era. At the cost of a potential increased risk of hemorrhagic transformation, thrombolysis may promote arterial recanalization before thrombectomy, improve the rate of successful recanalization after thrombectomy, and restore microcirculation patency downstream of the main thrombus. Besides, new thrombolytic strategies targeting tissue-type plasminogen activator resistant thrombi are being developed, which could strengthen the beneficial effects of thrombolysis without carrying additional pro-hemorrhagic effects. For instance, tenecteplase has shown improved rate of recanalization compared with tissue-type plasminogen activator (alteplase). Beyond fibrinolysis, DNA- and von Willebrand factor-targeted thrombolytic strategies have shown promising results in experimental models of ischemic stroke. New combined strategies, improved thrombolytics, and dedicated clinical trials in selected patients are eagerly awaited to further improve functional outcome in stroke.
Topics: Brain Ischemia; Fibrinolysis; Fibrinolytic Agents; Humans; Ischemic Stroke; Stroke; Thrombectomy; Thrombolytic Therapy; Tissue Plasminogen Activator; Treatment Outcome
PubMed: 33834615
DOI: 10.1111/jth.15336 -
International Journal of Molecular... Apr 2021Fibrinolysis is a crucial physiological process that helps to maintain a hemostatic balance by counteracting excessive thrombosis. The components of the fibrinolytic... (Review)
Review
Fibrinolysis is a crucial physiological process that helps to maintain a hemostatic balance by counteracting excessive thrombosis. The components of the fibrinolytic system are well established and are associated with a wide array of physiological and pathophysiological processes. The aberrant expression of several components, especially urokinase-type plasminogen activator (uPA), its cognate receptor uPAR, and plasminogen activator inhibitor-1 (PAI-1), has shown a direct correlation with increased tumor growth, invasiveness, and metastasis. As a result, targeting the fibrinolytic system has been of great interest in the field of cancer biology. Even though there is a plethora of encouraging preclinical evidence on the potential therapeutic benefits of targeting the key oncogenic components of the fibrinolytic system, none of them made it from "bench to bedside" due to a limited number of clinical trials on them. This review summarizes our existing understanding of the various diagnostic and therapeutic strategies targeting the fibrinolytic system during cancer.
Topics: Animals; Antineoplastic Agents; Fibrinolysis; Humans; Neoplasms; Plasminogen Activator Inhibitor 1; Receptors, Urokinase Plasminogen Activator; Urokinase-Type Plasminogen Activator
PubMed: 33921923
DOI: 10.3390/ijms22094358 -
Medical Hypotheses May 2020Parkinson's disease (PD) is a progressive degenerative nervous system disorder and is the second most common neurodegenerative disorder in the elderly population. The...
Parkinson's disease (PD) is a progressive degenerative nervous system disorder and is the second most common neurodegenerative disorder in the elderly population. The disease originates from the loss of dopamine-producing neurons in the substantia nigra in the brain, resulting in unregulated activity of the basal ganglia. Αlpha-synuclein (α-syn) is a protein found to aggregate in the substantia nigra region of patients with PD, forming Lewy Body inclusions; its aggregation may contribute to neuronal cell death in PD. This work hypothesizes about the synergistic relationship between α-syn aggregation and neuroinflammation to up-regulate expression of the serine protease inhibitor (serpin) plasminogen activator inhibitor-1 (PAI-1). The protease, plasmin, has been shown to cleave extracellular α-syn (including its monomeric, oligomeric, and fibrillary forms), resulting in less aggregation and Lewy Body formation. The zymogen plasminogen is converted to its active serine protease form, plasmin, either by tissue plasminogen activator (tPA) or by urokinase plasminogen activator (uPA) bound to urokinase receptor (uPAR). Both tPA and uPA/uPAR are inhibited by PAI-1. Thus, when PAI-1 levels increase, less plasmin is generated, which would lead to reduced proteolysis of α-syn. Expression of PAI-1 is increased both in inflammatory environments and in the presence of extracellular α-syn aggregates. This scenario suggests a pathological amplification loop: increased extracellular α-syn aggregation activates an inflammatory response from microglia and astrocytes, increasing PAI-1 levels, and decreasing the generation of plasmin. With reduced plasmin, less α-syn can be cleaved, and aggregation continues, sustaining the pathological process. Understanding this putative pathogenic loop could provide insight into the means by which neurodegeneration progresses in PD, and it may offer possible novel therapeutic strategies.
Topics: Aged; Humans; Lewy Bodies; Parkinson Disease; Plasminogen Activator Inhibitor 1; Receptors, Urokinase Plasminogen Activator; Tissue Plasminogen Activator; Urokinase-Type Plasminogen Activator; alpha-Synuclein
PubMed: 32035284
DOI: 10.1016/j.mehy.2020.109602 -
Neuroscience Mar 2024The neurovascular unit (NVU) is assembled by endothelial cells (ECs) and pericytes, and encased by a basement membrane (BM) surveilled by microglia and surrounded by... (Review)
Review
The neurovascular unit (NVU) is assembled by endothelial cells (ECs) and pericytes, and encased by a basement membrane (BM) surveilled by microglia and surrounded by perivascular astrocytes (PVA), which in turn are in contact with synapses. Cerebral ischemia induces the rapid release of the serine proteinase tissue-type plasminogen activator (tPA) from endothelial cells, perivascular astrocytes, microglia and neurons. Owning to its ability to catalyze the conversion of plasminogen into plasmin, in the intravascular space tPA functions as a fibrinolytic enzyme. In contrast, the release of astrocytic, microglial and neuronal tPA have a plethora of effects that not always require the generation of plasmin. In the ischemic brain tPA increases the permeability of the NVU, induces microglial activation, participates in the recycling of glutamate, and has various effects on neuronal survival. These effects are mediated by different receptors, notably subunits of the N-methyl-D-aspartate receptor (NMDAR) and the low-density lipoprotein receptor-related protein-1 (LRP-1). Here we review data on the role of tPA in the NVU under non-ischemic and ischemic conditions, and analyze how this knowledge may lead to the development of potential strategies for the treatment of acute ischemic stroke patients.
Topics: Humans; Tissue Plasminogen Activator; Fibrinolysin; Ischemic Stroke; Endothelial Cells; Brain Ischemia; Brain; Fibrinolytic Agents
PubMed: 37574107
DOI: 10.1016/j.neuroscience.2023.08.011 -
Blood Dec 2022Recombinant human tissue plasminogen activator (rh-tPA) is an important thrombolytic agent for treatment of acute ischemic stroke. It requires fibrin binding for...
Recombinant human tissue plasminogen activator (rh-tPA) is an important thrombolytic agent for treatment of acute ischemic stroke. It requires fibrin binding for plasminogen activation. In contrast, Microlyse, a novel thrombolytic agent, requires von Willebrand factor (VWF) binding for plasminogen activation. We compared rh-tPA with Microlyse, administered 20 minutes after inducing thrombosis, in 2 randomized blinded acute ischemic stroke mouse models. Thrombosis was induced in the middle cerebral artery with different experimental triggers. Where thrombin infusion generates fibrin-rich thrombi, topical FeCl3 application generates platelet-rich thrombi. In the fibrin-rich model, both rh-tPA and Microlyse increased cortical reperfusion (determined by laser speckle imaging) 10 minutes after therapy administration (35.8 ± 17.1%; P = .001 39.3 ± 13.1%; P < .0001; 15.6 ± 7.5%, respectively, vs vehicle). In addition, both thrombolytic agents reduced cerebral lesion volume (determined by magnetic resonance imaging) after 24 hours (18.9 ± 11.2 mm3; P = .033; 16.1 ± 13.9 mm3; P = .018; 26.6 ± 5.6 mm3, respectively, vs vehicle). In the platelet-rich model, neither rh-tPA nor Microlyse increased cortical reperfusion 10 minutes after therapy (7.6 ± 8.8%; P = .216; 16.3 ± 13.9%; P = .151; 10.1 ± 7.9%, respectively, vs vehicle). However, Microlyse, but not rh-tPA, decreased cerebral lesion volumes (13.9 ± 11.4 mm3; P < .001; 23.6 ± 11.1 mm3; P = .188; 30.3 ± 10.9 mm3, respectively, vs vehicle). These findings support broad applicability of Microlyse in ischemic stroke, irrespective of the thrombus composition.
Topics: Mice; Humans; Animals; Tissue Plasminogen Activator; Fibrinolytic Agents; von Willebrand Factor; Ischemic Stroke; Thrombosis; Thromboembolism; Fibrin; Thrombolytic Therapy; Plasminogen; Stroke
PubMed: 35960811
DOI: 10.1182/blood.2022016342 -
European Journal of Pharmaceutics and... Nov 2023Tissue-type plasminogen activator (tPA) is the gold standard for emergency treatment of ischemic stroke, which is the third leading cause of death worldwide. Major...
Tissue-type plasminogen activator (tPA) is the gold standard for emergency treatment of ischemic stroke, which is the third leading cause of death worldwide. Major challenges of tPA therapy are its rapid elimination by plasminogen activator inhibitor-1 (PAI-1) and hepatic clearance, leading to the use of high doses and consequent serious side effects, including internal bleeding, swelling and low blood pressure. In this regard, we developed three polyethylene glycol (PEG)ylated tPA bioconjugates based on the recombinant human tPA drug Alteplase using site-specific conjugation strategies. The first bioconjugate with PEGylation at the N-terminus of tPA performed by reductive alkylation showed a reduced proteolytic activity of 68 % compared to wild type tPA. PEGylation at the single-free cysteine of tPA with linear and branched PEG revealed similar proteolytic activities as the wild-type protein. Moreover, both bioconjugates with PEG-cysteine-modification showed 2-fold slower inhibition kinetics by PAI-1. All bioconjugates increased in hydrodynamic size as a critical requirement for half-life extension.
Topics: Humans; Tissue Plasminogen Activator; Plasminogen Activator Inhibitor 1; Cysteine
PubMed: 37783360
DOI: 10.1016/j.ejpb.2023.09.017 -
The Oncologist Aug 2021Clinical outcomes of patients with glioma are still poor, even after standard treatments, including surgery combined with radiotherapy and chemotherapy. New therapeutic...
BACKGROUND
Clinical outcomes of patients with glioma are still poor, even after standard treatments, including surgery combined with radiotherapy and chemotherapy. New therapeutic strategies and targets for glioma are urgently needed. Plasminogen activator urokinase receptor (PLAUR), a highly glycosylated integral membrane protein, is reported to modulate plasminogen activation and extracellular matrix degradation in many malignant cancers, but its role in gliomas remains unclear.
METHODS
Glioma samples with mRNA sequencing data and clinical information from the Chinese Glioma Genome Atlas (n = 310) data set and The Cancer Genome Atlas (n = 611) data set were collected for this study. Analyses using Kaplan-Meier plots, time-dependent receiver operating characteristic curves, Cox regression, and nomograms were conducted to evaluate the prognostic performance of PLAUR expression. Analyses using Metascape, ESTIMATE, EPIC, and immunohistochemical staining were performed to reveal the potential biological mechanism. The statistical analysis and graphical work were completed using SPSS, R language, and GraphPad Prism.
RESULTS
PLAUR was highly expressed in phenotypes associated with glioma malignancy and could serve as an independent prognostic indicator. Functional analysis revealed the correlation between PLAUR and immune response. Further studies found that samples with higher PLAUR expression were infiltrated with fewer CD8 T cells and many more M2 macrophages. Strong positive correlation was demonstrated between PLAUR expression and some immunosuppressive markers, including immune checkpoints and cytokines. These findings were also confirmed in patient samples.
CONCLUSION
Our results elucidated the clinical significance and immunosuppressive effect of PLAUR in gliomas, which might provide some clues in glioma immunotherapy.
IMPLICATIONS FOR PRACTICE
Although the efficacy of immunotherapy has been verified in other tumors, its application in glioma is impeded because of the unique microenvironment. Tumor-associated macrophages, which are particularly abundant in a glioma mass, contribute much to the immunosuppressive microenvironment and offer new opportunities in glioma immunotherapy. The results of this study identified plasminogen activator urokinase receptor (PLAUR) expression as a potential marker to predict the infiltration of macrophages and the status of immune microenvironment in patients with glioma, suggesting that treatment decisions could be based on PLAUR level when administering immunotherapeutics. The soluble PLAUR in blood and other body fluids would make this approach easy to implement in the clinic.
Topics: Biomarkers; Glioma; Humans; Plasminogen Activators; Prognosis; Receptors, Urokinase Plasminogen Activator; Tumor Microenvironment; Urokinase-Type Plasminogen Activator
PubMed: 33687124
DOI: 10.1002/onco.13750