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.

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.

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 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 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 Effect of intrafollicular indomethacin injection on gonadotropin surge-induced expression of select extracellular matrix degrading enzymes and their inhibitors in bovine preovulatory follicles

Reproduction ◽  
2006 ◽  
Vol 131 (3) ◽  
pp. 533-543 ◽  
Author(s):  
Qinglei Li ◽  
Fermin Jimenez-Krassel ◽  
Yasuhiro Kobayashi ◽  
James J Ireland ◽  
George W Smith
Keyword(s):  
Extracellular Matrix ◽  
Plasminogen Activator ◽  
Tissue Plasminogen Activator ◽  
Follicular Fluid ◽  
Tissue Inhibitor Of Metalloproteinase ◽  
Tissue Inhibitor ◽  
Preovulatory Follicles ◽  
Tissue Plasminogen ◽  
Gonadotropin Surge ◽  
Matrix Degrading Enzymes

A growing body of evidence supports an obligatory role for intrafollicular prostanoids in the mechanism of ovulation. However, the prostanoid-dependent mediators of the follicular extracellular matrix degradation required for ovulation are unknown. The objectives of this study were to determine the cellular compartment(s) in which the gonadotropin surge-induced regulation of select extracellular matrix degrading enzymes and their cognate inhibitors occurs in bovine preovulatory follicles, and to test whether such regulation is blocked by intrafollicular administration of the prostanoid synthesis and ovulation inhibitor, indomethacin (INDO). Follicular fluid prostaglandin E2concentrations were elevated in diluent-treated follicles before ovulation (24 h after GnRH injection), but the increase was blocked in INDO-treated follicles. Real-time PCR analysis revealed the specific follicular cell types where gonadotropin surge-induced increases in mRNA abundance for members of the matrix metalloproteinase/tissue inhibitor of metalloproteinase and plasminogen activator families occurred. INDO treatment increased thecal cell mRNA for tissue inhibitor of metalloproteinase-4 and its protein abundance in the apex of preovulatory follicles before ovulation, but suppressed granulosal cell mRNA and activity for tissue plasminogen activator in follicular fluid and the follicle apex. Plasmin activity was also suppressed in the follicular fluid of INDO-treated follicles. Effects of INDO injection on select matrix metalloproteinases were not observed. The results suggest that gonadotropin surge-induced regulation of tissue inhibitor of metalloproteinase-4 and tissue plasminogen activator may be prostanoid dependent, and support a potential role for increased tissue plasminogen activator expression and decreased tissue inhibitor of metalloproteinase-4 expression in the mechanism of ovulation.

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