Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0014070 (encephalomyelitis)
 13,017 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Matrix metalloproteinases (MMPs) comprise a group of proteolytic enzymes that are implicated in the pathogenesis of inflammatory diseases of the nervous system such as multiple sclerosis. However, the exact function and expression pattern of MMPs in the inflamed nervous system are not known. In the present study we investigated the expression of 92-kDa gelatinase (MMP-9) in spinal cord from animals with adoptive transfer experimental autoimmune encephalomyelitis (AT-EAE), using a semiquantitative competitive reverse transcriptase-polymerase chain reaction assay. Increased levels of MMP-9 mRNA were found with peak values at times of maximum disease severity. Increased mRNA expression was associated with enhanced proteolytic activity of this enzyme, as demonstrated by gelatin zymography. Immunohistochemistry revealed immunoreactivity along the meninges, around blood vessels and within the parenchyma, in diseased but not in normal spinal cord. Furthermore, the expression pattern of five other MMPs was investigated. Matrilysin (MMP-7) was also found to be upregulated with maximum mRNA levels at the peak of the disease. In contrast, mRNAs for collagenase-3, 72-kDa gelatinase, and stromelysin-1 and -3 were not changed. Our findings indicate that 92-kDa gelatinase and matrilysin are selectively upregulated during AT-EAE and thus may contribute to the pathogenesis of inflammatory diseases of the CNS.
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PMID:Matrix metalloproteinase-9 and -7 are regulated in experimental autoimmune encephalomyelitis. 954 96

Matrix metalloproteinases (MMPs) are a family of endopeptidases capable of enzymatic digestion of subendothelial basement membrane and other components of the extracellular matrix. Expression of MMP-2, -3, -7 and -9 is increased around multiple sclerosis plaques and in brain tissue in experimental allergic encephalomyelitis. To measure quantitatively the expression of these MMPs and their endogenous inhibitors (TIMP-1 and -2), we analysed samples from 52 patients with relapsing-remitting and primary progressive multiple sclerosis by ELISA (enzyme-linked immunosorbent assay) and substrate-gel electrophoresis (zymography). MMP-9 was increased over controls in 100% of relapsing-remitting multiple sclerosis cases, with similar levels detected in relapses and clinically stable phases of disease. In primary progressive multiple sclerosis, MMP-9 was increased in 57% of CSF samples, but concentrations were below those encountered in the relapsing-remitting form. The selective upregulation of MMP-9 suggests that T-cells and macrophages invading the brain parenchyma and the CSF space are the predominant source of MMP-9 in multiple sclerosis. TIMPs and other MMPs (MMP-2 and -3) were not upregulated or not detectable (MMP-7) in CSF of patients with relapsing-remitting and primary progressive multiple sclerosis. The sustained increase of MMP-9 in clinically stable multiple sclerosis supports the concept that multiple sclerosis is associated with ongoing proteolysis that may result in progressive tissue damage. The selective inhibition of MMP-9 could be a useful approach for the prevention of disease progression in multiple sclerosis.
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PMID:Matrix metalloproteinase-9 (gelatinase B) is selectively elevated in CSF during relapses and stable phases of multiple sclerosis. 987 83

The role of extracellular proteolysis in inflammatory demyelination, originally hypothesized as a mechanism for myelin degradation, is increasingly recognized as a pathogenetic step and as a target for therapy in human demyelinating disease. The activation of ubiquitous plasminogen by urokinase (u-PA) and tissue-type plasminogen activator (t-PA), which is associated with various neuropathologies, including multiple sclerosis (MS), is the key initiator of the activation cascade of the four classes of matrix metalloproteinases (MMPs): collagenases, stromelysins, membrane-type metalloproteinases and gelatinases. Spatiotemporal protein and mRNA expression of gelatinase B (MMP-9) and matrilysin (MMP-7) have been documented respectively in MS lesions and in the central nervous system (CNS) of animals developing experimental autoimmune encephalomyelitis (EAE). A close interaction between disease-promoting cytokines and extracellularly acting proteases is deduced from in vitro experiments. Cytokines regulate the balance between the proteases and their respective specific inhibitors at the transcriptional level, while proteolysis is a reciprocal mechanism to enhance (by activation) or downmodulate (by degradation) the specific activities of cytokines. In acute inflammation the contribution of chemokines is hierarchically organised, interleukin-8 (IL-8) and related CXC-chemokines inducing a rapid influx of neutrophils in the acute lesions and an instantaneous exocytosis of gelatinase B granules. This results in sudden and extensive damage to the CNS. In chronic disease involving autoimmune processes CC-chemokines that act mainly on mononuclear cell types appear to be more strictly regulated. As MMPs modify matrix components, promoting extravasation of lymphocytes and monocytes/macrophages and have the potential to generate encephalitogenic peptides from myelin basic protein, novel treatments for demyelinating diseases may be predicted by specific inhibition of these enzymes. Here we review plasminogen activators and the MMP family, in the context of their role in CNS inflammation and demyelination and highlight studies in which intervention in these protease cascades are and may be used to treat demyelinating diseases.
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PMID:Plasminogen activators and matrix metalloproteases, mediators of extracellular proteolysis in inflammatory demyelination of the central nervous system. 1037 31

Induction of EAE can be inhibited or repressed by administration of soluble metalloproteinase inhibitors. We studied the matrix metalloproteinase (MMP) and their tissue inhibitor (TIMP) expression pattern in experimental autoimmune encephalomyelitis (EAE) of the resistant Th2 prone BALB/c mouse, where the disease can be induced with ultrasound-emulsified antigen/adjuvant (son-ag), but not with conventional technique (syr-ag). We found highly elevated expression of MMP-8 (neutrophil collagenase) mRNA and protein in diseased son-ag challenged mice, colocalizing to neutrophil infiltrates found in brain and extensively in the spinal cord submeningeal space. MMP-8 expression has not been found previously in sensitive mouse strains. The infiltrates stained positive also for MMP-9 protein, and brain homogenates from corresponding mice showed MMP-9 activity during overt disease (days 12-16 post-immunization). TIMP-1 gene expression could be detected in CNS samples from diseased son-ag challenged mice but not in syr-ag or control mice, and the TIMP-1 protein colocalized with GFAP-staining. In contrast, in syr-ag mice both TIMP-2 and TIMP-3 gene expression in the spinal cords was elevated. The results show that sonication, but not extrusion, creates an adjuvant formula potent in activating the matrix metalloproteinase cascade similar to sensitive mouse strains, strongly implicating their role in EAE induction in this Th2 prone strain. The study provides the basis for establishment of MMP-specific therapy in this model.
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PMID:Up-regulation of MMP-8 and MMP-9 activity in the BALB/c mouse spinal cord correlates with the severity of experimental autoimmune encephalomyelitis. 1198 14

Multiple sclerosis is characterized by the infiltration of leukocytes into the CNS. As matrix metalloproteinases (MMPs) facilitate the passage of leukocytes across matrix barriers, we tested the hypothesis that targeting MMPs could attenuate neuro-inflammation. We report that minocycline, a widely used generic drug with a good safety record, inhibited MMP activity, reduced production of MMP-9 and decreased the transmigration of T lymphocytes across a fibronectin matrix barrier. In addition, minocycline was efficacious against both mild and severe experimental autoimmune encephalomyelitis (EAE) in mice, an animal model of multiple sclerosis. When severe EAE was produced, minocycline pre-treatment delayed the course of the disease: when maximal disease activity occurred in vehicle-treated EAE mice, minocycline animals were relatively normal and had minimal signs of inflammation and demyelination in the CNS. When tested in mice afflicted with mild EAE, minocycline attenuated the clinical severity of disease throughout the course of treatment. These results indicate that minocycline may constitute a safe and inexpensive therapy for multiple sclerosis.
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PMID:Targeting leukocyte MMPs and transmigration: minocycline as a potential therapy for multiple sclerosis. 1202 18

The present study investigates the immunological effects of a combination treatment of mitoxantrone and the cardioprotector dexrazoxane in experimental autoimmune encephalomyelitis (EAE). Mitoxantrone, an anthracycline-derived immunosuppressive drug has been approved recently for treatment of very active multiple sclerosis (MS). Its prolonged use is limited due to its cardiotoxic properties. Dexrazoxane (DZR (S)-(+)-1,2-bis (3,5.dioxopiperazinyl)propane, ICRF-187) is an iron III chelator which in animal models and in cancer patients reduces anthracycline and mitoxantrone induced cardiotoxicity when given immediately before these agents. We examined the immunological effects of dexrazoxane in combination with mitoxantrone in experimental autoimmune encephalomyelitis (EAE) in Lewis rats. EAE was induced by active immunization with myelin basic protein (MBP) or by adoptive transfer of MBP specific T cells (AT-EAE). The clinical course, spinal cord pathology, activity of metalloproteinases (MMP-2 and MMP-9) and T cell apoptosis were assessed. Monotherapy with DZR ameliorated slightly the course of actively induced EAE and AT-EAE. The combination of DZR and mitoxantrone was superior to mitoxantrone given alone. Clinical amelioration ran in parallel with the marked reduction of inflammatory infiltration which was nearly abolished by the combination treatment. DZR did not affect the activity of metalloproteinase 9 and did not increase the proportion of apoptotic lymph node cells ex vivo or T cells in situ. We conclude that in addition to its cardioprotective role, DZR augments mitoxantrone-mediated immunosuppressive effects in animal models of human central nervous system (CNS) autoimmune disease. Clinical trials in MS patients are warranted to evaluate the unexpected immunosuppressive efficacy of DZR as add-on treatment.
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PMID:The cardioprotector dexrazoxane augments therapeutic efficacy of mitoxantrone in experimental autoimmune encephalomyelitis. 1467 64

Increasing evidence suggests that enhanced production of reactive oxygen species (ROS) activates the MAP kinases, c-Jun N-terminal protein kinase (JNK) and mitogen-activated protein kinase MAPK (p38). These phosphorylated intermediates at the stress-activated pathway induce expression of matrix metalloproteinases (MMPs), leading to inflammatory responses and pathological damages involved in the etiology of multiple sclerosis (MS). Here we report that N-acetylcysteine amide (AD4) crosses the blood-brain barrier (BBB), chelates Cu(2+), which catalyzes free radical formation, and prevents ROS-induced activation of JNK, p38 and MMP-9. In the myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE), a mouse model of MS, oral administration of AD4 drastically reduced the clinical signs, inflammation, MMP-9 activity, and protected axons from demylination damages. In agreement with the in vitro studies, we propose that ROS scavenging by AD4 in MOG-treated animals prevented MMP's induction and subsequent damages through inhibition of MAPK pathway. The low toxicity of AD4 coupled with BBB penetration makes this compound an excellent potential candidate for the therapy of MS and other neurodegenerative disorders.
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PMID:A low molecular weight copper chelator crosses the blood-brain barrier and attenuates experimental autoimmune encephalomyelitis. 1514 17

Prompted by our recent observations of increased MMP-8 and MMP-9 with simultaneous downregulation of tissue inhibitor of metalloproteinase-2 (TIMP-2) and TIMP-3 mRNA levels in the central nervous system (CNS) of mice with severe experimental autoimmune encephalomyelitis (EAE), we used Semliki Forest virus (SFV) to transfer and express recombinant murine TIMP-1-3 genes in the CNS. TIMP-1, TIMP-2 and TIMP-3 expression was confirmed in cultured cells and in the CNS of infected mice. Following intraperitoneal infection with 10(6) plaque-forming units (PFU) of SFV-TIMP, focal TIMP protein expression was achieved throughout the brain. Although already treatment with empty vector inhibited development of EAE to some extent, the expression of TIMP-2 by the virus significantly enhanced the inhibition. TIMP-3-administered mice also had lower disease grade, but the inhibition was not statistically significant. In contrast, SFV-TIMP-1 had no effect, similar to co-infection with TIMP-2 and TIMP-3. We found TIMP-2 expression also by non-infected CNS-resident cells surrounding the virus-positive areas, suggesting a bystander TIMP-2 induction. These data strengthen the view that matrix metalloproteinases are involved in the pathogenesis of EAE and provide clear evidence that virus-mediated delivery of their protein inhibitors can be effective in preventing the clinical disease. TIMPs might be candidates for novel treatment regimens in CNS autoimmune disorders, such as multiple sclerosis.
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PMID:Treatment of experimental autoimmune encephalomyelitis with a neurotropic alphavirus vector expressing tissue inhibitor of metalloproteinase-2. 1537 62

Matrix metalloproteinase-2 (MMP-2; gelatinase A) is known to degrade a broad range of extracellular matrix components and chemokines, and has important roles in the processes of cell migration, invasion, and involution during development, as well as during tumor growth and metastasis and in inflammation and repair. To better elucidate the roles of this matrix metalloproteinase in the development and progression of experimental autoimmune encephalomyelitis, we used MMP-2-deficient (KO) mice. Surprisingly, we found that MMP-2 KO mice exhibited an earlier onset and more severe disease than did their wild-type (WT) counterparts. WT mice engrafted with MMP-2 KO bone marrow exhibited a similar earlier onset and more severe clinical disease score than WT mice engrafted with WT bone marrow. Lymphocytes derived from MMP-2 KO mice exhibited increased transmigration through endothelial cell monolayers as well as through collagen type IV and laminin-coated BD BIOCOAT inserts, which correlated with a 3-fold increase in expression of MMP-9 and was abrogated by inhibition of MMP activity. We demonstrated a correlation between expression levels of MMP-9 and MT1-MMP expression and suggest a signaling pathway involving tethering of MMP-2 to MT1-MMP as a modulator of MMP-9 expression. Last, we discuss other possible MMP-2-mediated mechanisms which may contribute to the observed phenotype.
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PMID:MMP-2 null mice exhibit an early onset and severe experimental autoimmune encephalomyelitis due to an increase in MMP-9 expression and activity. 1552 13

The tyrosine kinase receptor RON and its ligand, macrophage stimulating protein (MSP), exert inhibitory effects on systemic innate immunity, but their CNS expression and impact on human neuroinflammatory diseases are unknown were RON and MSP present in human brain perivascular macrophages and microglia, but RON mRNA and protein abundance in the CNS were diminished in both MS patients and the MS animal model, experimental autoimmune encephalomyelitis (EAE). Treatment of differentiated human monocytoid cells with MSP resulted in significant reduction of interleukin (IL)-1beta, tumor necrosis factor (TNF)-alpha and MMP-9 mRNA levels, whereas minimal effects were observed in human astrocytes. After induction of EAE, RON knockout and heterozygote animals exhibited significantly increased CNS proinflammatory gene (TNF-alpha, MMP-12) expression compared with wild-type littermate controls, although IL-4 levels were suppressed in both RON-deficient groups. Neurological disease in RON-deficient animals showed a more rapid onset with overall worsened severity, together with exacerbated demyelination, axonal injury, and neuroinflammation after EAE induction. The proto-oncogene, c-Cbl, which modulates ubiquitylation of RON, was increased in glia in both MS brains and EAE spinal cords. Thus, the MSP-RON pathway represents a novel regulatory mechanism within the CNS by which innate immunity and its pathogenic effects could be targeted for future therapeutic interventions.
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PMID:RON-regulated innate immunity is protective in an animal model of multiple sclerosis. 1592 40


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