Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:Q99542 (matrix metalloproteinase)
 15,999 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Inflammatory leukocytes infiltrate the CNS parenchyma in neuroinflammation. This involves cellular migration across various structures associated with the blood-brain barrier: the vascular endothelium, the glia limitans, and the perivascular space between them. Leukocytes accumulate spontaneously in the perivascular space in brains of transgenic (Tg) mice that overexpress CCL2 under control of a CNS-specific promoter. The Tg mice show no clinical symptoms, even though leukocytes have crossed the endothelial basement membrane. Pertussis toxin (PTx) given i.p. induced encephalopathy and weight loss in Tg mice. We used flow cytometry, ultra-small superparamagnetic iron oxide-enhanced magnetic resonance imaging, and immunofluorescent staining to show that encephalopathy involved leukocyte migration across the glia limitans into the brain parenchyma, identifying this as the critical step in inducing clinical symptoms. Metalloproteinase (MPs) enzymes are implicated in leukocyte infiltration in neuroinflammation. Unmanipulated Tg mice had elevated expression of tissue inhibitor of metalloproteinase-1, matrix metalloproteinase (MMP)-10, and -12 mRNA in the brain. PTx further induced expression of tissue inhibitor of metalloproteinase-1, metalloproteinase disintegrins-12, MMP-8, and -10 in brains of Tg mice. Levels of the microglial-associated MP MMP-15 were not affected in control or PTx-treated Tg mice. PTx also up-regulated expression of proinflammatory cytokines IL-1beta and TNF-alpha mRNA in Tg CNS. Weight loss and parenchymal infiltration, but not perivascular accumulation, were significantly inhibited by the broad-spectrum MP inhibitor BB-94/Batimastat. Our finding that MPs mediate PTx-induced parenchymal infiltration to the chemokine-overexpressing CNS has relevance for the pathogenesis of human diseases involving CNS inflammation, such as multiple sclerosis.
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PMID:Metalloproteinases control brain inflammation induced by pertussis toxin in mice overexpressing the chemokine CCL2 in the central nervous system. 1708 42

Available treatments for multiple sclerosis (MS) require frequent injections and have significant side effects. Proteases generated during inflammation are involved in the induction of tissue damage during inflammatory demyelination in the central nervous system (CNS). The Bowman-Birk Inhibitor (BBI), a soy-derived protease inhibitor with anti-carcinogenic and anti-inflammatory properties, has been shown to be well tolerated in clinical trials for pre-cancerous conditions, such as oral leukoplakia and the inflammatory disease, ulcerative colitis. We hypothesized that BBI may modulate experimental autoimmune encephalomyelitis (EAE), an animal model of MS. The BBI concentrate (BBIC), a soybean extract enriched in BBI, was administered to myelin basic protein (MBP)-immunized Lewis rats by gastric gavage in different treatment regimens, during the induction or the effector phase of disease. BBIC significantly delayed disease onset and suppressed disease severity, clinically and pathologically, in all treatment protocols. Both in vitro and ex vivo, BBIC inhibited MBP-specific proliferation of lymph node cells. BBIC reduced the activity of matrix metalloproteinase (MMP)-2 and -9 in spleen cell supernatants and was detected in the CNS of treated rats. BBIC suppresses EAE, it can be administered orally, and it is safe and relatively inexpensive. It may have a therapeutic role in patients with MS.
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PMID:The protease inhibitor, Bowman-Birk Inhibitor, suppresses experimental autoimmune encephalomyelitis: a potential oral therapy for multiple sclerosis. 1726 95

The matrix metalloproteinases (MMPs) are implicated in the pathology of multiple sclerosis (MS). This review summarizes the consequences of upregulation of MMP members in MS as well as in an animal model of the disease, experimental autoimmune encephalomyelitis (EAE). The pathogenic roles of MMPs are considered, especially in the transmigration of leukocytes into the CNS. We review the evidence that interferon-beta, an immunomodulator that is commonly used in MS, affects MMP expression in the disease. The potential of minocycline as a therapy in MS, based on its activity as an MMP inhibitor, is discussed. Besides affecting MMPs, minocycline may have other actions that help account for its possible utility in MS.
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PMID:Elevation of matrix metalloproteinases (MMPs) in multiple sclerosis and impact of immunomodulators. 1738 65

Minocycline has immunomodulatory and neuroprotective activities in vitro and in an animal model of multiple sclerosis (MS). We have previously reported that minocycline decreased gadolinium-enhancing activity over six months in a small trial of patients with active relapsing-remitting MS (RRMS). Here we report the impact of oral minocycline on clinical and magnetic resonance imaging (MRI) outcomes and serum immune molecules in this cohort over 24 months of open-label minocycline treatment. Despite a moderately high pretreatment annualized relapse rate (1.3/year pre-enrolment; 1.2/year during a three-month baseline period) prior to treatment, no relapses occurred between months 6 and 24. Also, despite very active MRI activity pretreatment (19/40 scans had gadolinium-enhancing activity during a three-month run-in), the only patient with gadolinium-enhancing lesions on MRI at 12 and 24 months was on half-dose minocycline. Levels of the p40 subunit of interleukin (IL)-12, which at high levels might antagonize the proinflammatory IL-12 receptor, were elevated over 18 months of treatment, as were levels of soluble vascular cell adhesion molecule-1. The activity of matrix metalloproteinase-9 was decreased by treatment. Thus, clinical and MRI outcomes are supported by systemic immunological changes and call for further investigation of minocycline in MS.
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PMID:The clinical response to minocycline in multiple sclerosis is accompanied by beneficial immune changes: a pilot study. 1746 74

Early in the pathogenesis of multiple sclerosis, the blood-brain barrier is compromised, which leads to deposition of the plasma proteins fibronectin and vitronectin in cerebral parenchyma. In light of our previous finding that microglial activation in vitro is strongly promoted by fibronectin and vitronectin, we set out to examine the possibility that modulation of microglial activation by fibronectin or vitronectin is an important regulatory mechanism in vivo. In an experimental autoimmune encephalomyelitis mouse model of demyelination, total brain levels of fibronectin and vitronectin were strongly increased and there was a close relationship between fibronectin and vitronectin deposition, microglial activation, and microglial expression of matrix metalloproteinase-9. In murine cell culture, flow cytometry for MHC class I and gelatin zymography revealed that microglial activation and expression of pro-matrix metalloproteinase-9 were significantly increased by fibronectin and vitronectin. Function-blocking studies showed that the influence of fibronectin and vitronectin was mediated by the alpha(5)beta(1) and alpha(v)beta(5) integrins, respectively. Taken together, this work suggests that fibronectin and vitronectin deposition during demyelinating disease is an important influence on microglial activation state. Furthermore, it provides the first evidence that the alpha(5)beta(1) and alpha(v)beta(5) integrins are important mediators of microglial activation.
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PMID:Fibronectin- and vitronectin-induced microglial activation and matrix metalloproteinase-9 expression is mediated by integrins alpha5beta1 and alphavbeta5. 1754 54

In patients with multiple sclerosis (MS), activation of immune cells and breakdown of the blood-brain barrier (BBB) lead to demyelination and axon injury. Although repairing damage to neurons is not possible, immunomodulating therapies can reduce the inflammatory processes that lead to demyelination. Interferon-beta (IFN-beta) is a polypeptide, normally produced by fibroblasts, that has antiviral and antiproliferative effects. Binding of IFN-beta to its receptor induces a complex transcriptional response. In immune cells (the most likely target of IFN-beta's therapeutic effect in MS), IFN-beta reduces antigen presentation and T-cell proliferation, alters cytokine and matrix metalloproteinase (MMP) expression, and restores suppressor function. Therapeutic forms of IFN-beta can be produced in bacterial expression systems (IFN-beta1b) or in mammalian cells (IFN-beta1a). These forms have some differences in their amino acid sequence and posttranslational modifications, but the transcriptional response to IFN- beta1b and IFN-beta1a appears to be similar, if not indistinguishable. However, the biological response and the clinical effect do vary with changes in the dosing frequency of IFN-beta. In clinical trials, IFN-beta1a IM administered weekly elicits a transient biological response compared to IFN-beta1b administered SC every other day or IFN-beta1a (administered SC three times per week). Comparative clinical trials suggest that the differences in the biological response are clinically meaningful: more frequent IFN-beta administration produces superior clinical responses.
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PMID:Interferon-beta: mechanism of action and dosing issues. 1756 48

We investigated whether polyunsaturated fatty acids (PUFA), which might be a useful complementary therapy among patients with multiple sclerosis (MS), are able to modulate matrix metalloproteinase (MMP) production in microglial cultures. MMPs are myelinotoxic factors. Primary cultures of rat microglia were treated with different doses of omega-3 (omega-3) PUFA or purified fish oil, containing a mixture of omega-3 and omega-6 PUFA, and simultaneously activated by exposure to lipopolysaccharide (LPS). Culture supernatants were subjected to zymography and Western blot analysis for the assessment of MMP-2 and MMP-9 levels. Increased amounts of MMP-9, but not of the constitutively expressed MMP-2, were observed in supernatants from LPS-treated microglia in comparison with non-treated control cells. The treatment with both omega-3 PUFA and fish oil dose-dependently inhibited the LPS-induced production of MMP-9. Our results suggest that a low fat diet supplemented with omega-3 PUFA may become recommended for the well being of MS patients under therapy.
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PMID:Inhibitory effect of polyunsaturated fatty acids on MMP-9 release from microglial cells--implications for complementary multiple sclerosis treatment. 1762 13

Neuroinflammation is often associated with neurodegenerative diseases, including multiple sclerosis (MS), stroke, Alzheimer's disease, and HIV-1-associated dementia (HAD). The proinflammatory cytokine interleukin-1beta (IL-1beta) is one of the main mediators of inflammation, and IL-1beta expression in the brain is rapidly upregulated in response to acute and chronic insults. IL-1beta is synthesized as biologically inactive precursor (pro-IL-1beta), which is classically processed by caspase-1 [also known as interleukin-converting enzyme (ICE)] into the active, mature cytokine. However, caspase-1/ICE-independent mechanisms of IL-1beta processing have recently been suggested. Here we report that matrix metalloproteinases (MMPs) participate in the maturation process (cleavage and activation) of IL-1beta in an in vivo model of HIV-associated neurodegeneration based on the intracerebroventricular injection of the HIV-1 envelope glycoprotein gp120. We show that, following gp120 exposure, MMP-9 and MMP-2, but not caspase-1/ICE, are rapidly induced. Pharmacological manipulation of MMPs activity, using the broad spectrum MMPs inhibitor GM6001, reduces the increase in IL-1beta immunoreactivity and the neuronal apoptosis induced by gp120. Taken together, these findings point to a critical role for MMPs in IL-1beta increase and consequent neurotoxicity triggered by gp120 in the neocortex of rat and suggest new links between IL-1beta processing and MMP activation during the neuroinflammatory process.
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PMID:Evidence implicating matrix metalloproteinases in the mechanism underlying accumulation of IL-1beta and neuronal apoptosis in the neocortex of HIV/gp120-exposed rats. 1767 75

The matrix metalloproteinases (MMPs) are important enzymes that regulate developmental processes, maintain normal physiology in adulthood and have reparative roles at specific stages after an insult to the nervous system. Conversely, the concordant presence and significant upregulation of several MMP members in virtually all neurological conditions result in pathology. Thus, the MMPs have diverse functions, capable of mediating repair and recovery on the one hand and being involved in producing injury on the other. Therefore, targeting MMPs in neurological conditions has become a complicated challenge. This article highlights the beneficial roles of MMPs in normal and reparative processes within the nervous system and discusses the detriments of MMPs encountered in pathology. We review the availability of MMP inhibitors for clinical use and propose that an important consideration for these inhibitors is timing and duration of their use. With acute injuries where a massive upregulation of several MMPs are observed in the early periods after the insult, early and short-term use of broad spectrum MMP inhibitors would seem logical. In chronic conditions where recurrent insults to the CNS are accompanied by prolonged upregulation of MMPs, thereby necessitating the chronic use of medications, the beneficial effects of MMPs in repair may be compromised by the long-term application of MMP inhibitors. In this review we have used spinal cord injury and multiple sclerosis as examples of acute and chronic neurological conditions, respectively, and we consider the use of MMP inhibitors in these states.
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PMID:Targeting MMPs in acute and chronic neurological conditions. 1792 May 39

Inflammation occurs rapidly in response to acute brain insults such as stroke, haemorrhage or trauma, and can be sustained for long periods of time, for example in Alzheimer's or Parkinson's diseases and multiple sclerosis. Experimental evidence indicates that inflammation plays a major role in neurodegeneration under these conditions, and that the cytokine IL-1 (interleukin-1) is a pivotal mediator. IL-1 is expressed rapidly in response to neuronal injury, predominantly by microglia, and elevated levels of endogenous or exogenous IL-1 markedly exacerbate injury. The naturally occurring IL-1RA (IL-1 receptor antagonist) markedly inhibits ischaemic, excitotoxic and traumatic brain injury in rodents, and has shown promise in a Phase II clinical trial in stroke patients. The mechanisms of IL-1 expression, release and action in neurodegeneration are not fully elucidated and appear multiple. Systemic IL-1 markedly enhances ischaemic brain injury via release of neutrophils into circulation, neutrophil adhesion to injured cerebrovasculature and CNS (central nervous system) invasion, and cell death via activation of matrix metalloproteinase-9. IL-1 also influences the release of toxins from glial and endothelial cells. Neuronal responses to excitotoxins and physiological factors may have an impact on neuronal survival. IL-1RA, delivered peripherally, can enter the CNS in animals and humans and has no adverse effects in stroke or subarachnoid haemorrhage patients, but shows potential benefit in acute stroke patients.
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PMID:Interleukin-1 and inflammatory neurodegeneration. 1795 93


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