Cerebrospinal fluid plasminogen activator inhibitor-1 in patients with neurological disease.

Akenami, F.O.T.; Koskiniemi, Marjaleena; Färkkilä, M.; Vaheri, Antti

doi:10.1136/jcp.50.2.157

Cited by 38 publications

(27 citation statements)

References 31 publications

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“…It has also been proposed that tPA acts as a cytokine in the central nervous system, as it can activate microglial cells in vitro independent of its proteinase activity [69]. The plasminogen activators and their inhibitors also play important roles in pathological events in the nervous system, as indicated by the involvement of tPA in excitotoxic cell death and ischaemia (discussed above in relation to neuroserpin), their participation in inflammation and demyelination [70] and an increase in PAI-1 levels in the cerebrospinal fluid in correlation with neurological diseases such as encephalitis and multiple sclerosis [71]. The interactions between thrombin, its receptors (proteinase activated receptors, PAR, 1-4) and its serpin inhibitor PN-1 are also recognised to play fundamental roles in the development, maintenance and pathology of the nervous system [72,73].…”

Section: Neuroserpin In Context: Extracellular Serpins and Serine Promentioning

confidence: 99%

Neuroserpin: a serpin to think about

Miranda

Lomas

2006

Cell. Mol. Life Sci.

115

100

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Proteinases and their inhibitors play important roles in neural development, homeostasis and disease. Neuroserpin is a member of the serine proteinase inhibitor (serpin) superfamily that is secreted from the growth cones of neurons and inhibits the enzyme tissue-type plasminogen activator (tPA). The temporal and spatial pattern of neuroserpin expression suggests a role in synaptogenesis and is most prominent in areas of the brain that participate in learning, memory and behaviour. Neuroserpin also provides neuronal protection in pathologies such as cerebral ischaemia and epilepsy by preventing excessive activity of tPA. Point mutations in neuroserpin cause aberrant conformational transitions and the formation of loop-sheet polymers that are retained within the endoplasmic reticulum of neurons, forming inclusion bodies that underlie an autosomal dominant dementia that we have called familial encephalopathy with neuroserpin inclusion bodies or FENIB. We review here the role of neuroserpin and other proteinase inhibitors in brain development, function and disease.

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Section: Neuroserpin In Context: Extracellular Serpins and Serine Promentioning

confidence: 99%

Neuroserpin: a serpin to think about

Miranda

Lomas

2006

Cell. Mol. Life Sci.

115

100

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“…Further, PAI-1, which inhibits tPA, while present in very low levels in plasma, is rapidly induced by pro-inflammatory cytokines IL-1β and TNF-α [159]. As a result, while tPA has been reported to be elevated in CSF of MS patients by 10-fold relative to controls [4], and in MS lesions [55], the concomitant increase in PAI-1, along with formation of tPA:PAI-1 complexes in MS tissues, serves to decrease active tPA, thereby decreasing fibrinolytic activity and contributing to fibrin deposition [47,99]. Suggestive of a role in axon injury, tPA is co-localized in MS lesions with demyelinated axons that stain positively for nonphosphorylated neurofilament and fibrin [99, 100].…”

Section: Plasminogenmentioning

confidence: 99%

“…The other major fibrinolytic protease, uPA, along with its endogenous inhibitor α2-antiplasmin, is seen in MS CSF and is localized to neurons in areas of demyelination [4,55]. High levels of uPA, uPA receptor (uPAR), and PAI-1 occur in acute MS lesions in association with mononuclear cells and foamy macrophages suggestive of a role in facilitation of CNS cellular infiltration [7,55,99].…”

Section: Plasminogenmentioning

confidence: 99%

The Multiple Sclerosis Degradome: Enzymatic Cascades in Development and Progression of Central Nervous System Inflammatory Disease

Scarisbrick

2008

Current Topics in Microbiology and Immunology

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An array of studies implicate different classes of protease and their endogenous inhibitors in multiple sclerosis (MS) pathogenesis based on expression patterns in MS lesions, sera, and/or cerebrospinal fluid (CSF). Growing evidence exists regarding their mechanistic roles in inflammatory and neurodegenerative aspects of this disease. Proteolytic events participate in demyelination, axon injury, apoptosis, and development of the inflammatory response including immune cell activation and extravasation, cytokine and chemokine activation/inactivation, complement activation, and epitope spreading. The potential significance of proteolytic activity to MS therefore relates not only to their potential use as important biomarkers of disease activity, but additionally as prospective therapeutic targets. Experimental data indicate that understanding the net physiological consequence of altered protease levels in MS development and progression necessitates understanding protease activity in the context of substrates, endogenous inhibitors, and proteolytic cascade interactions, which together make up the MS degradome. This review will focus on evidence regarding the potential physiologic role of those protease families already identified as markers of disease activity in MS; that is, the metallo-, serine, and cysteine proteases.

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“…Influx of fibrin(ogen) is associated with up-regulated activity of tissue plasminogen activator (tPA), the key fibrinolytic enzyme. In MS, tPA activation is matched by a significant increase in the specific inhibitor plasminogen activator inhibitor-1 (PAI-1), preventing the efficient clearance of fibrin [2,5,6]. In EAE, an animal model of MS, mice deficient in tPA suffer an early onset and more severe form of disease that is associated with high levels of PAI-1 and inefficient fibrin removal [1].…”

Section: Introductionmentioning

confidence: 99%

Chronic relapsing experimental allergic encephalomyelitis (CREAE) in plasminogen activator inhibitor‐1 knockout mice: the effect of fibrinolysis during neuroinflammation

East

Gverić

Baker

et al. 2007

Neuropathology Appl Neurobio

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During neuroinflammation in multiple sclerosis (MS) fibrinogen, not normally present in the brain or spinal cord, enters the central nervous system through a compromised blood-brain barrier. Fibrin deposited on axons is ineffectively removed by tissue plasminogen activator (tPA), a key contributory factor being the upregulation of plasminogen activator inhibitor-1 (PAI-1). Aims: This study investigated the role of PAI-1 during experimental neuroinflammatory disease. Methods: Chronic relapsing experimental allergic encephalomyelitis (CREAE), a model of MS, was induced with spinal cord homogenate in PAI-1 knockout (PAI-1 -/-) and wild type (WT) mice, backcrossed onto the Biozzi background. Results: Disease incidence and clinical severity were reduced in PAI-1 -/-mice, with animals developing clinical signs significantly later than WTs. Clinical relapses were absent in PAI-1 -/-mice and the subsequent reduction in neuroinflammation was coupled with a higher capacity for fibrinolysis in spinal cord samples from PAI-1 -/-mice, in association with increased tPA activity. Axonal damage was less apparent in PAI-1 -/-mice than in WTs, implicating fibrin in both inflammatory and degenerative events during CREAE. Conclusions: PAI-1 is a potential target for therapy in neuroinflammatory degenerative diseases, allowing effective fibrin removal and potentially reducing relapse rate and axonal damage.

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Cerebrospinal fluid plasminogen activator inhibitor-1 in patients with neurological disease.

Abstract: Aim-To study cerebrospinal fluid (CSF) concentrations of plasminogen activator inhibitor type-1 (PAI-1) in patients with neurological disease.

Cited by 38 publications

References 31 publications

Neuroserpin: a serpin to think about

Neuroserpin: a serpin to think about

The Multiple Sclerosis Degradome: Enzymatic Cascades in Development and Progression of Central Nervous System Inflammatory Disease

Chronic relapsing experimental allergic encephalomyelitis (CREAE) in plasminogen activator inhibitor‐1 knockout mice: the effect of fibrinolysis during neuroinflammation

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