scholarly journals Tissue-type plasminogen activator induces opening of the blood-brain barrier via the LDL receptor–related protein

2003 ◽  
Vol 112 (10) ◽  
pp. 1533-1540 ◽  
Author(s):  
Manuel Yepes ◽  
Maria Sandkvist ◽  
Elizabeth G. Moore ◽  
Thomas H. Bugge ◽  
Dudley K. Strickland ◽  
...  
Keyword(s):  
Plasminogen Activator ◽  
Blood Brain Barrier ◽  
Ldl Receptor ◽  
Brain Barrier ◽  
Tissue Type ◽  
Related Protein ◽  
Tissue Type Plasminogen Activator ◽  
Blood Brain ◽  
Type Plasminogen Activator

scholarly journals Plasmin-Dependent Modulation of the Blood–Brain Barrier: A Major Consideration during tPA-Induced Thrombolysis?

2014 ◽  
Vol 34 (8) ◽  
pp. 1283-1296 ◽  
Author(s):  
Be'eri Niego ◽  
Robert L Medcalf
Keyword(s):  
Ischemic Stroke ◽  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Tissue Type ◽  
Ischemic Event ◽  
Tissue Type Plasminogen Activator ◽  
Rational Case ◽  
Blood Brain ◽  
Type Plasminogen Activator ◽  
Major Consideration

Plasmin, the principal downstream product of tissue-type plasminogen activator (tPA), is known for its potent fibrin-degrading capacity but is also recognized for many non-fibrinolytic activities. Curiously, plasmin has not been conclusively linked to blood–brain barrier (BBB) disruption during recombinant tPA (rtPA)-induced thrombolysis in ischemic stroke. This is surprising given the substantial involvement of tPA in the modulation of BBB permeability and the co-existence of tPA and plasminogen in both blood and brain throughout the ischemic event. Here, we review the work that argues a role for plasmin together with endogenous tPA or rtPA in BBB alteration, presenting the overall controversy around the topic yet creating a rational case for an involvement of plasmin in this process.

Tissue-type plasminogen activator induces TNF-α-mediated preconditioning of the blood-brain barrier

2021 ◽  
pp. 0271678X2110603
Author(s):  
Ariel Diaz ◽  
Yena Woo ◽  
Cynthia Martin-Jimenez ◽  
Paola Merino ◽  
Enrique Torre ◽  
...  
Keyword(s):  
Plasminogen Activator ◽  
Blood Brain Barrier ◽  
Neuronal Survival ◽  
Ischemic Tolerance ◽  
Brain Barrier ◽  
Tissue Type ◽  
Ischemic Insult ◽  
Tissue Type Plasminogen Activator ◽  
Type Plasminogen Activator ◽  
Tnf Α

Ischemic tolerance is a phenomenon whereby transient exposure to a non-injurious preconditioning stimulus triggers resistance to a subsequent lethal ischemic insult. Despite the fact that not only neurons but also astrocytes and endothelial cells have a unique response to preconditioning stimuli, current research has been focused mostly on the effect of preconditioning on neuronal death. Thus, it is unclear if the blood-brain barrier (BBB) can be preconditioned independently of an effect on neuronal survival. The release of tissue-type plasminogen activator (tPA) from perivascular astrocytes in response to an ischemic insult increases the permeability of the BBB. In line with these observations, treatment with recombinant tPA increases the permeability of the BBB and genetic deficiency of tPA attenuates the development of post-ischemic edema. Here we show that tPA induces ischemic tolerance in the BBB independently of an effect on neuronal survival. We found that tPA renders the BBB resistant to an ischemic injury by inducing TNF-α-mediated astrocytic activation and increasing the abundance of aquaporin-4-immunoreactive astrocytic end-feet processes in the neurovascular unit. This is a new role for tPA, that does not require plasmin generation, and with potential therapeutic implications for patients with cerebrovascular disease.

Tissue-type plasminogen activator-binding RNA aptamers inhibiting low-density lipoprotein receptor family-mediated internalisation

2015 ◽  
Vol 114 (07) ◽  
pp. 139-149 ◽  
Author(s):  
Kenneth A. Bøtkjær ◽  
Nicky Helsen ◽  
Peter A. Andreasen ◽  
Daniel M. Dupont ◽  
Nils Bjerregaard
Keyword(s):  
Plasminogen Activator ◽  
Low Density Lipoprotein ◽  
Ldl Receptor ◽  
Density Lipoprotein ◽  
Tissue Type ◽  
Clot Lysis ◽  
Low Density ◽  
Tissue Type Plasminogen Activator ◽  
Type Plasminogen Activator ◽  
Receptor Family

SummaryRecombinant tissue-type plasminogen activator (tPA, trade name Alteplase), currently the only drug approved by the US Food and Drug Administration and the European Medicines Agency for the treatment of cerebral ischaemic stroke, has been implicated in a number of adverse effects reportedly mediated by interactions with the low-density lipo-protein (LDL) family receptors, including neuronal cell death and an increased risk of cerebral haemorrhage. The tissue-type plasminogen activator is the principal initiator of thrombolysis in human physiology, an effect that is mediated directly via localised activation of the plasmin zymogen plasminogen at the surface of fibrin clots in the vascular lumen. Here, we sought to identify a ligand to tPA capable of inhibiting the relevant LDL family receptors without interfering with the fibrinolytic activity of tPA. Systematic evolution of ligands by exponential enrichment (SELEX) was employed to isolate tPA-binding RNA aptamers, which were characterised in biochemical assays of tPA association to low density lipoprotein receptor-related protein-1 (LRP-1, an LDL receptor family member); tPA-mediated in vitro and ex vivo clot lysis; and tPA-mediated plasminogen activation in the absence and presence of a stimulating soluble fibrin fragment. Two aptamers, K18 and K32, had minimal effects on clot lysis, but were able to efficiently inhibit tPA-LRP-1 association and LDL receptor family-mediated endocytosis in human vascular endothelial cells and astrocytes. These observations suggest that coadministration alongside tPA may be a viable strategy to improve the safety of thrombolytic treatment of cerebral ischaemic stroke by restricting tPA activity to the vascular lumen.

scholarly journals Clearance of Alzheimer’s amyloid-β1-40 peptide from brain by LDL receptor–related protein-1 at the blood-brain barrier

2000 ◽  
Vol 106 (12) ◽  
pp. 1489-1499 ◽  
Author(s):  
Masayoshi Shibata ◽  
Shinya Yamada ◽  
S. Ram Kumar ◽  
Miguel Calero ◽  
James Bading ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Ldl Receptor ◽  
Brain Barrier ◽  
Related Protein ◽  
Blood Brain
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