Tissue-type plasminogen activator as a therapeutic target in stroke

Gravanis, Iordanis; Tsirka, Stella E.

doi:10.1517/14728222.12.2.159

Cited by 122 publications

(78 citation statements)

References 133 publications

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“…The tPA/PAI-1 complex is cleared from the circulation by the liver via a scavenging receptor, the low-density lipoprotein receptorrelated protein-1 (LRP). Because of this, tPA has a half-life in the bloodstream in humans of 5 to 10 min [33]. This short half-life prevents tPA from acting on subsequent and continued vessel occlusions that occur.…”

Section: Clinical Options For Stroke Treatment Are Very Limitedmentioning

confidence: 99%

“…tPA has also been combined with mechanical removal of the clot (MERCI™ retriever, a tiny corkscrew threaded through an artery to remove the clot [38], or the Penumbra device, Penumbra, Inc., San Leandro, California, to vacuum the clot bit by bit). These techniques have the drawback that they require arterial catheterization and are therefore more interventional, requiring more specialized personnel and equipment for successful implementation, and may be useful only in large artery occlusions [33]. Additional approaches are to combine tPA thrombolysis with neuroprotective drugs or agents that specifically counteract neurotoxic side effects of tPA (Table 2), although most of these studies are still in the experimental, pre-clinical stages.…”

Section: Clinical Options For Stroke Treatment Are Very Limitedmentioning

confidence: 99%

“…Anistreplase Activated complex of streptokinase with human plasminogen Prepared in inactive anisoylated form, deacylated in circulation to active form with half-life 2 hr, active form has 90 min half-life; used for treatment of myocardial infarction, no information on stroke usage available. Streptokinase [33] Extracellular metalloenzyme produced by ß-hemolytic streptococcus…”

Section: Abbreviationsmentioning

confidence: 99%

“…New trails are ongoing. Desmoteplase (Desmodus salivary plasminogen activator α-1) [30,33,34,87] A plasminogen activator in the saliva of vampire bats…”

Section: Abbreviationsmentioning

confidence: 99%

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Tissue Plasminogen Activator (tPA) and Matrix Metalloproteinases in the Pathogenesis of Stroke: Therapeutic Strategies

Adibhatla

Hatcher²

2008

CNSNDDT

173

135

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Today there exists only one FDA-approved treatment for ischemic stroke; i.e., the serine protease tissue-type plasminogen activator (tPA). In the aftermath of the failed stroke clinical trials with the nitrone spin trap/radical scavenger, NXY-059, a number of articles raised the question: are we doing the right thing? Is the animal research truly translational in identifying new agents for stroke treatment? This review summarizes the current state of affairs with plasminogen activators in thrombolytic therapy. In addition to therapeutic value, potential side effects of tPA also exist that aggravate stroke injury and offset the benefits provided by reperfusion of the occluded artery. Thus, combinational options (ultrasound alone or with microspheres/nanobubbles, mechanical dissociation of clot, activated protein C (APC), plasminogen activator inhibitor-1 (PAI-1), neuroserpin and CDPcholine) that could offset tPA toxic side effects and improve efficacy are also discussed here. Desmoteplase, a plasminogen activator derived from the saliva of Desmodus rotundus vampire bat, antagonizes vascular tPA-induced neurotoxicity by competitively binding to low-density lipoprotein related-receptors (LPR) at the blood-brain barrier (BBB) interface, minimizing the tPA uptake into brain parenchyma. tPA can also activate matrix metalloproteinases (MMPs), a family of endopeptidases comprised of 24 mammalian enzymes that primarily catalyze the turnover and degradation of the extracellular matrix (ECM). MMPs have been implicated in BBB breakdown and neuronal injury in the early times after stroke, but also contribute to vascular remodeling, angiogenesis, neurogenesis and axonal regeneration during the later repair phase after stroke. tPA, directly or by activation of MMP-9, could have beneficial effects on recovery after stroke by promoting neurovascular repair through vascular endothelial growth factor (VEGF). However, any treatment regimen directed at MMPs must consider their pleiotropic nature and the likelihood of either beneficial or detrimental effects that might depend on the timing of the treatment in relation to the stage of brain injury.

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Section: Clinical Options For Stroke Treatment Are Very Limitedmentioning

confidence: 99%

Section: Clinical Options For Stroke Treatment Are Very Limitedmentioning

confidence: 99%

Section: Abbreviationsmentioning

confidence: 99%

“…New trails are ongoing. Desmoteplase (Desmodus salivary plasminogen activator α-1) [30,33,34,87] A plasminogen activator in the saliva of vampire bats…”

Section: Abbreviationsmentioning

confidence: 99%

See 2 more Smart Citations

Tissue Plasminogen Activator (tPA) and Matrix Metalloproteinases in the Pathogenesis of Stroke: Therapeutic Strategies

Adibhatla

Hatcher²

2008

CNSNDDT

173

135

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“…Furthermore, the KLK1-kinin system, which influences the permeability of the blood-brain barrier, is activated in stroke (Wagner et al 2002). Given the growing evidence supporting coincident alterations in KLKs and thrombostasis enzymes in a range of CNS disorders, including Alzheimer's (Zarghooni et al 2002;Paul et al 2007), stroke (Chao and Chao 2006;Gravanis and Tsirka 2008), trauma (Festoff et al 2004;Scarisbrick et al 2006b), and MS (Gveric et al 2001;Scarisbrick et al 2002Scarisbrick et al , 2008Terayama et al 2005), there appears to be tremendous potential for the intersection of these two important protease families. KLK6 is up-regulated in response to CNS damage and in concert with the demyelination/remyelination processes that take place after such damage (Scarisbrick et al 1997;He et al 2001;Terayama et al 2004).…”

Section: Discussionmentioning

confidence: 99%

Activation profiles of human kallikrein‐related peptidases by proteases of the thrombostasis axis

et al. 2008

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The human kallikrein-related peptidases (KLKs) comprise 15 members (KLK1-15) and are the single largest family of serine proteases. The KLKs are utilized, or proposed, as clinically important biomarkers and therapeutic targets of interest in cancer and neurodegenerative disease. All KLKs appear to be secreted as inactive pro-forms (pro-KLKs) that are activated extracellularly by specific proteolytic release of their N-terminal pro-peptide. This processing is a key step in the regulation of KLK function. Much recent work has been devoted to elucidating the potential for activation cascades between members of the KLK family, with physiologically relevant KLK regulatory cascades now described in skin desquamation and semen liquefaction. Despite this expanding knowledge of KLK regulation, details regarding the potential for functional intersection of KLKs with other regulatory proteases are essentially unknown. To elucidate such interaction potential, we have characterized the ability of proteases associated with thrombostasis to hydrolyze the pro-peptide sequences of the KLK family using a previously described pro-KLK fusion protein system. A subset of positive hydrolysis results were subsequently quantified with proteolytic assays using intact recombinant pro-KLK proteins. Pro-KLK6 and 14 can be activated by both plasmin and uPA, with plasmin being the best activator of pro-KLK6 identified to date. Pro-KLK11 and 12 can be activated by a broad-spectrum of thrombostasis proteases, with thrombin exhibiting a high degree of selectivity for pro-KLK12. The results show that proteases of the thrombostasis family can efficiently activate specific pro-KLKs, demonstrating the potential for important regulatory interactions between these two major protease families.

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Stroke

Auer

Meher

2022

Encyclopedia of Life Sciences

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Blood vessels supplying the brain can either be blocked or broken, giving rise to the two kinds of stroke: infarcts and haemorrhages. The symptoms and their permanence depend on how much brain tissue is destroyed and in what location. Key Concepts Stroke is the third leading cause of death. There are two types of strokes: haemorrhagic or ischemic. The occlusive substance in ischemia arises from carotid atherosclerosis or underlying heart disease. ‘Time is Brain’: treating a patient in a timely manner is crucial for preventing increased neuronal loss. tPA is an effective clot‐busting drug, however, it can only be administered within 4.5 h of symptom onset. Endovascular therapy, a mechanical clot‐retrieving technique, is proven to be far more superior to tPA treatment. Brain swelling from oedema occurs secondary to stroke. There are two types of oedema that occurs poststroke, vasogenic or cytotoxic and are known to partly arise from the cerebrospinal fluid in and around the brain. Strokes can lead to severe long‐term motor, sensory and cognitive impairments. Stroke rehabilitation remains essential for relearning skills and regaining functional independence poststroke.

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Tissue-type plasminogen activator as a therapeutic target in stroke

Cited by 122 publications

References 133 publications

Tissue Plasminogen Activator (tPA) and Matrix Metalloproteinases in the Pathogenesis of Stroke: Therapeutic Strategies

Tissue Plasminogen Activator (tPA) and Matrix Metalloproteinases in the Pathogenesis of Stroke: Therapeutic Strategies

Activation profiles of human kallikrein‐related peptidases by proteases of the thrombostasis axis

Stroke

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