Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.21.68 (tissue plasminogen activator)
 11,311 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Multiple sclerosis (MS) is an immune-mediated chronic inflammatory demyelinating disease of the central nervous system. It manifests as acute focal inflammatory demyelination and axonal loss with limited remyelination and results in the chronic multifocal sclerotic plaques. Previously published data showed impaired fibrinolysis in MS. Tissue plasminogen activator t-PA is a serine protease that catalyses the activation of plasmin, which mediates the effects of fibrinolytic system. Alu insertion/deletion (I/D) genetic polymorphism in TPA gene in MS patients has not been analysed previously. The major inhibitor of t-PA is plasminogen activator inhibitor-1 (PAI-1). Its gene expression is modulated by functional genetic polymorphism in the promoter (4G/5G). In the present study, an association of two genetic polymorphisms with MS, its progression and subtype were analysed. TPA DD/PAI-1 4G4G genotype combination has reached a borderline significance for reduced risk for MS (OR = 0.543, 95% CI 0.301-0.978, P = 0.04), suggesting a gene-gene interaction. The explanation for this interaction may be a complex interplay between these two pleiotropic proteins within the brain tissue and in plasma.
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PMID:PAI and TPA gene polymorphisms in multiple sclerosis. 1798 6

Inflammatory cell trafficking into the brain complicates several neurological disorders including multiple sclerosis. Normally, reliable brain functioning is maintained and controlled by the blood-brain barrier (BBB), which is essential to restrict the entry of potentially harmful molecules and cells from the blood into the brain. The BBB is a selective barrier formed by dedicated brain endothelial cells and dependent on the presence of intracellular tight junctions. In multiple sclerosis, a severe dysfunction of the BBB is observed, which is key to monocyte infiltration and inflammation in the brain. Proteolytic activity has been associated with these inflammatory processes in the brain. Our studies in plasma of rats indicated that the extracellular protease tissue-type plasminogen activator (tPA) correlates with the clinical signs of experimental allergic encephalomyelitis, a rat model of multiple sclerosis. In this study, we studied the function of the tPA during diapedesis of monocytes through a rat and human brain endothelial barrier. Monocyte-brain endothelial cell coculture experiments showed that monocytes induce the release of tPA by brain endothelial cells, which subsequently activates the signal transduction protein extracellular signal related kinase (ERK1/2), both involved in monocyte diapedesis. Importantly, live imaging and immunoblot analyses of rat brain endothelial cells revealed that tPA and ERK1/2 control the breakdown of the tight junction protein occludin. These studies identify tPA as a novel and relevant pathological mediator of neuroinflammation and provide a potential mechanism for this.
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PMID:Tissue-type plasminogen activator is a regulator of monocyte diapedesis through the brain endothelial barrier. 1871 30

Normal neuronal functioning is dependent on the blood-brain barrier. This barrier is confined to specialized brain endothelial cells lining the inner vessel wall, and tightly controlling transport of nutrients, efflux of potentially harmful molecules and entry of immune cells into the brain. Loss of blood-brain barrier function is an early and significant event which contributes to inflammation in the brain and subsequent progression of neuronal deficits in a number of brain disorders and has been well-documented for the auto-immune disease multiple sclerosis. Extravasation of cells happens by paracellular transport across the endothelial junctions, transcellularly across the endothelial cells, or both, and requires the active participation of endothelial cells. We and others have shown that this process requires the activity of proteases, including tissue-type plasminogen activator. We here describe a novel role for NMDA receptor, a potential cellular target of tissue-type plasminogen activator, in human brain endothelial cells. Our results show that the NMDA receptor subunit 1 (NR1) is expressed in brain endothelial cells, regulates tissue-type plasminogen activator-induced signal transduction and controls the passage of monocytes through the brain endothelial cell barrier. Together, our results hold significant promise for the treatment of chronic inflammation in the brain.
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PMID:The NR1 subunit of NMDA receptor regulates monocyte transmigration through the brain endothelial cell barrier. 2008 11

When in 1947, Astrup and Permin reported that animal tissues contain fibrinokinase, a plasminogen activator, and when Pennica and colleagues (Pennica et al., 1983) cloned and expressed human tissue plasminogen activator (tPA) in Escherichia coli in 1983, they might did not realize how much their pioneer work would impact the life of millions of patients suffering from myocardial infarction or ischemic stroke. Some years after, accumulating evidence shows that tPA is not just a plasminogen activator of endothelial origin. Indeed, the main function of tPA released from the endothelium is to convert fibrin-bound plasminogen into active plasmin, thus dissolving the fibrin meshwork of blood clots. But this serine protease is also expressed by several cell types, and its beneficial and deleterious actions stand beyond fibrinolysis or even proteolysis. We will review here the reported effects and mechanisms of action of tPA in the course of three different pathologies of the central nervous system (CNS): spinal cord injury, ischemic stroke and multiple sclerosis. While these three disorders have distinct aetiologies, they share some pathogenic mechanisms. We will depict the main "good" and "bad" sides of tPA described to date during each of these pathological situations, as well as the proposed mechanisms explaining these effects. We speculate that due to common pathogenic pathways, tPA's actions described in one particular disease could in fact occur in the others. Finally, we will evaluate if tPA could be a therapeutic target for these pathologies. This article is part of a Special Issue entitled 'Post-Traumatic Stress Disorder'.
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PMID:tPA in the injured central nervous system: different scenarios starring the same actor? 2207 61

Each year about 650,000 Europeans die from stroke and a similar number lives with the sequelae of multiple sclerosis (MS). Stroke and MS differ in their etiology. Although cause and likewise clinical presentation set the two diseases apart, they share common downstream mechanisms that lead to damage and recovery. Demyelination and axonal injury are characteristics of MS but are also observed in stroke. Conversely, hallmarks of stroke, such as vascular impairment and neurodegeneration, are found in MS. However, the most conspicuous common feature is the marked neuroinflammatory response, marked by glia cell activation and immune cell influx. In MS and stroke the blood-brain barrier is disrupted allowing bone marrow-derived macrophages to invade the brain in support of the resident microglia. In addition, there is a massive invasion of auto-reactive T-cells into the brain of patients with MS. Though less pronounced a similar phenomenon is also found in ischemic lesions. Not surprisingly, the two diseases also resemble each other at the level of gene expression and the biosynthesis of other proinflammatory mediators. While MS has traditionally been considered to be an autoimmune neuroinflammatory disorder, the role of inflammation for cerebral ischemia has only been recognized later. In the case of MS the long track record as neuroinflammatory disease has paid off with respect to treatment options. There are now about a dozen of approved drugs for the treatment of MS that specifically target neuroinflammation by modulating the immune system. Interestingly, experimental work demonstrated that drugs that are in routine use to mitigate neuroinflammation in MS may also work in stroke models. Examples include Fingolimod, glatiramer acetate, and antibodies blocking the leukocyte integrin VLA-4. Moreover, therapeutic strategies that were discovered in experimental autoimmune encephalomyelitis (EAE), the animal model of MS, turned out to be also effective in experimental stroke models. This suggests that previous achievements in MS research may be relevant for stroke. Interestingly, the converse is equally true. Concepts on the neurovascular unit that were developed in a stroke context turned out to be applicable to neuroinflammatory research in MS. Examples include work on the important role of the vascular basement membrane and the BBB for the invasion of immune cells into the brain. Furthermore, tissue plasminogen activator (tPA), the only established drug treatment in acute stroke, modulates the pathogenesis of MS. Endogenous tPA is released from endothelium and astroglia and acts on the BBB, microglia and other neuroinflammatory cells. Thus, the vascular perspective of stroke research provides important input into the mechanisms on how endothelial cells and the BBB regulate inflammation in MS, particularly the invasion of immune cells into the CNS. In the current review we will first discuss pathogenesis of both diseases and current treatment regimens and will provide a detailed overview on pathways of immune cell migration across the barriers of the CNS and the role of activated astrocytes in this process. This article is part of a Special Issue entitled: Neuro Inflammation edited by Helga E. de Vries and Markus Schwaninger.
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PMID:Immune cell trafficking across the barriers of the central nervous system in multiple sclerosis and stroke. 2652 83

Multiple sclerosis is among the most common causes of neurological disability in young adults. Here we provide the preclinical proof of concept of the benefit of a novel strategy of treatment for multiple sclerosis targeting neuroendothelial N-methyl-D-aspartate glutamate receptors. We designed a monoclonal antibody against N-methyl-D-aspartate receptors, which targets a regulatory site of the GluN1 subunit of N-methyl-D-aspartate receptor sensitive to the protease tissue plasminogen activator. This antibody reverted the effect of tissue plasminogen activator on N-methyl-D-aspartate receptor function without affecting basal N-methyl-D-aspartate receptor activity (n = 21, P < 0.01). This antibody bound N-methyl-D-aspartate receptors on the luminal surface of neurovascular endothelium in human tissues and in mouse, at the vicinity of tight junctions of the blood-spinal cord barrier. Noteworthy, it reduced human leucocyte transmigration in an in vitro model of the blood-brain barrier (n = 12, P < 0.05). When injected during the effector phase of MOG-induced experimental autoimmune encephalomyelitis (n = 24), it blocked the progression of neurological impairments, reducing cumulative clinical score (P < 0.001) and mean peak score (P < 0.001). This effect was observed in wild-type animals but not in tissue plasminogen activator knock-out animals (n = 10). This therapeutic effect was associated to a preservation of the blood-spinal cord barrier (n = 6, P < 0.001), leading to reduced leucocyte infiltration (n = 6, P < 0.001). Overall, this study unveils a critical function of endothelial N-methyl-D-aspartate receptor in multiple sclerosis, and highlights the therapeutic potential of strategies targeting the protease-regulated site of N-methyl-D-aspartate receptor.
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PMID:Neuroendothelial NMDA receptors as therapeutic targets in experimental autoimmune encephalomyelitis. 2743 92


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