scholarly journals Tissue plasminogen activator in central nervous system physiology and pathology

2005 ◽  
Vol 93 (04) ◽  
pp. 655-660 ◽  
Author(s):  
Jerry Melchor ◽  
Sidney Strickland
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Plasminogen Activator ◽  
Tissue Plasminogen Activator ◽  
Neuronal Degeneration ◽  
Fibrin Clot ◽  
Proteolytic Cascade ◽  
Tissue Plasminogen ◽  
System Physiology ◽  
The Brain

SummaryAlthough conventionally associated with fibrin clot degradation, recent work has uncovered new functions for the tissue plasminogen activator (tPA)/plasminogen cascade in central nervous system physiology and pathology. This extracellular proteolytic cascade has been shown to have roles in learning and memory, stress, neuronal degeneration, addiction and Alzheimer’s disease. The current review considers the different ways tPA functions in the brain.

Activation of microglia reveals a non-proteolytic cytokine function for tissue plasminogen activator in the central nervous system

1999 ◽  
Vol 112 (22) ◽  
pp. 4007-4016 ◽  
Author(s):  
A.D. Rogove ◽  
C. Siao ◽  
B. Keyt ◽  
S. Strickland ◽  
S.E. Tsirka
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Plasminogen Activator ◽  
Tissue Plasminogen Activator ◽  
Microglial Activation ◽  
Neuronal Degeneration ◽  
Wild Type ◽  
Tissue Plasminogen ◽  
Cortical Cultures ◽  
The Central Nervous System

Tissue plasminogen activator mediates excitotoxin-induced neurodegeneration and microglial activation in the mouse hippocampus. Here we show that tissue plasminogen activator (tPA) acts in a protease-independent manner to modulate the activation of microglia, the cells of the central nervous system with macrophage properties. Cultured microglia from tPA-deficient mice can phagocytose as efficiently as wild-type microglia. However, tPA-deficient microglia in mixed cortical cultures exhibit attenuated activation in response to lipopolysaccharide, as judged by morphological changes, increased expression of the activation marker F4/80 and the release of the pro-inflammatory cytokine tumor necrosis factor-(α). When tPA is added to tPA deficient cortical cultures prior to endotoxin stimulation, microglial activation is restored to levels comparable to that observed in wild-type cells. Proteolytically-inactive tPA can also restore activation of tPA-deficient microglia in culture and in vivo. However, this inactive enzyme does not restore susceptibility of tPA-deficient hippocampal neurons to excitotoxin-mediated cell death. These results dissociate two different functions of tPA: inactive enzyme can mediate microglial activation, whereas proteolytically-competent protein also promotes neuronal degeneration. Thus tPA is identified as a new cytokine in the central nervous system.

scholarly journals Beyond Clot Dissolution; Role of Tissue Plasminogen Activator in Central Nervous System

2007 ◽  
Vol 15 (1) ◽  
pp. 16-26
Author(s):  
Ji-Woon Kim ◽  
Soon-Young Lee ◽  
So-Hyun Joo ◽  
Mi-Ryoung Song ◽  
Chan-Young Shin
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Plasminogen Activator ◽  
Tissue Plasminogen Activator ◽  
Tissue Plasminogen

Tissue plasminogen activator as a modulator of neuronal survival and function

2002 ◽  
Vol 30 (2) ◽  
pp. 222-225 ◽  
Author(s):  
S. E. Tsirka
Keyword(s):  
Central Nervous System ◽  
Extracellular Matrix ◽  
Nervous System ◽  
Neurite Outgrowth ◽  
Plasminogen Activator ◽  
Tissue Plasminogen Activator ◽  
Cell Surface Receptor ◽  
Mammalian Brain ◽  
Tissue Plasminogen ◽  
Surface Receptor

The tissue plasminogen activator (tPA)/plasmin proteolytic system has been implicated in both physiological and pathological processes in the mammalian brain. The physiological roles include facilitating neurite outgrowth and pathfinding. The pathological role involves mediating a critical step in the progression of excitotoxin-induced neurodegeneration. Mechanistically, tPA appears to function through two pathways. The first pathway proceeds via its well established ability to convert plasminogen into plasmin. Plasmin then either promotes neuronal death via both the degradation of the extracellular matrix and the establishment of chemoattractant gradients for microglia, or facilitates neurite outgrowth through the processing of extracellular matrix proteoglycans. The second pathway for tPA does not involve its proteolytic activity: rather tPA functions as an agonist to stimulate a cell-surface receptor on microglia (the macrophage-like immunocompetent cells of the central nervous system) and results in their activation. Once activated after neuronal injury, microglia contribute to the ensuing neurodegeneration. Using tPA as a link between neurons and microglia, we are focusing on understanding their communication and interactions in the normal and diseased central nervous system.

Tissue plasminogen activator and neuroserpin are widely expressed in the human central nervous system

2004 ◽  
Vol 92 (08) ◽  
pp. 358-368 ◽  
Author(s):  
Andres Kulla ◽  
Aadu Simisker ◽  
Vappu Sirén ◽  
Daniel Lawrence ◽  
Toomas Asser ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Plasminogen Activator ◽  
Tissue Plasminogen Activator ◽  
Brain Regions ◽  
Protein Levels ◽  
Tissue Arrays ◽  
Tissue Plasminogen ◽  
The Central Nervous System ◽  
Anatomic Locations

SummaryTissue plasminogen activator (tPA) is increasingly recognized to play important roles in various physiological and pathological processes in the central nervous system (CNS). Much of the data on the involvement of plasminogen activators in neurophysiology and -pathology have been derived from studies on experimental animals. We have now performed a systematic characterization of the expression of tPA and its inhibitor, neuroserpin, in normal human CNS. Brain and spinal cord samples from 30-36 anatomic locations covering all major brain regions were collected at 9 autopsies of donors with no neurological disease. Tissues were embedded in paraffin and tissue arrays were constructed. In two cases parallel samples were snap-frozen for biochemical analysis. Expression and activity profiling of tPA and neuroserpin were performed by immunohistochemistry, in situ hybridization, immunocapture and zymography assays. In the adult CNS, tPA was expressed at the mRNA and protein levels in many types of neurons, in particular in thalamus, cortex of cerebellum, pontine nuclei, neocortex, limbic system, and medulla oblongata. Interestingly, tPA was often co-expressed with its CNS inhibitor, neuroserpin. Despite overlapping expression of tPA and neuroserpin, zymography and immunocapture assays demonstrated that human neural tissue is a rich source of active tPA. Our analysis documents a detailed map of expression of tPA and its inhibitor in the human CNS and is compatible with the view that tPA is a key player in CNS physiology and pathology.

ACTIVATION PATHWAYS OF PLASMINOGEN BY UROKINASE AND TISSUE PLASMINOGEN ACTIVATOR IN THE PLASMA OR CLOTTED PLASMA: COMAPRISON WITH PURIFIED SYSTEMS

1987 ◽  
Author(s):  
Y Makino ◽  
M Yoshida ◽  
Y Takada ◽  
A Takada
Keyword(s):  
Plasminogen Activator ◽  
Tissue Plasminogen Activator ◽  
Fibrin Clot ◽  
Activation Process ◽  
Plasma Clot ◽  
Native Form ◽  
Tissue Plasminogen ◽  
Cross Linkage ◽  
Activation Pathways

The activation pathways of a native plasminogen (Glu-plg) were studied in the plasma and purified systems. When purified Glu-plg was activated by urokinase (UK) or tissue plasminogen activator (t-PA), the activation of Glu-plg proceeded very slowly in the presence of fibrinogen, but rapidly in the presence of non crosslinked or cross-linked fibrin. Little formation of modified pig (Lys-plg) was observed in the presence of fibrinogen, but significant amounts of Lys-plg were formed in the presence of fibrin clot. The addition of α2antiplasmin (α2AP) to the mixture of Glu-plg, UK or t-PA, and fibrinogen or fibrin resulted in little formation of Lys-plg in the presence of fibrinogen but significant formation of Lys-plg in the presence of non cross-linked or cross linked fibrin. Alphapantiplasmin did not prevent the formation of Lys-plg from Glu-plg by plasmin in the presence of fibrin regardless of possible cross-linkage of α2AP to fibrin. In contrast to purified system, the activation of Glu-plg by UK or t-PA in the presence of plasma clot resulted in little formation of Lys pig The addition of thrombin and Ca++ to the plasma activated by UK or t-PA resulted in little formation of Lys-plg. These results suggest that Glu-plg was mainly directly activated by UK or t-PA to Glu-plasmin (then Lys-plasmin) in the plasma or plasma clot (non cross-linked or cross-linked), and that some of Glu-plg was converted to Lys-plg by preformed plasmin after UK or t-PA induced activation of Glu-plg in the presence of fibrin. It should be stressed that not all the molecules of Glu-plg were converted to Lys-plg in the presence of fibrin before their activation by activators. Some amounts of Glu-plg were present throughout the activation process in its native form.

scholarly journals Fibrinolysis With TPA Alone Is Only One Third As Effective As It Should Be

2020 ◽  
Vol 5 (3) ◽  
pp. 1-3
Author(s):  
Victor Gurewich ◽  
Keyword(s):  
Myocardial Infarction ◽  
Acute Myocardial Infarction ◽  
Plasminogen Activator ◽  
Tissue Plasminogen Activator ◽  
Mechanism Of Action ◽  
Fibrin Clot ◽  
Efficient Mechanism ◽  
Tissue Plasminogen

Therapeutic fibrinolysis has used tissue Plasminogen Activator (tPA) alone since 1987,when tPA was first approved for the treatment of Acute Myocardial Infarction (AMI). The use of Tpa was based on the belief that it was responsible for fibrinolysis. However, this assumption should have been put into question from the outset when tPA was found to have the same efficacy as Streptokinase (SK). This was unexpected, since SK has an indirect, less efficient mechanism of action and SK has no fibrin clot affinity, in contrast to tPA. Nevertheless, the 30-day AMI mortality with tPA and SK were identical in the first two trials.

Sign in / Sign up

Export Citation Format

Share Document