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Query: UMLS:C0038454 (stroke)
 147,016 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Plasminogen activators are used in thrombolytic stroke therapy. However, it is increasingly recognized that they have other actions besides fibrinolysis. In this study, we assess potential pro-inflammatory effects of tissue-type plasminogen activator (tPA) and urokinase-type plasminogen activator (uPA) in rat cortical astrocytes. Both uPA and tPA induced rapid dose-dependent upregulation in MMP-2 and MMP-9, as demonstrated by zymography of conditioned media. In addition, a multiplex ELISA array demonstrated that patterned responses in chemokines and cytokines were also evoked. Exposure to tPA induced elevations in secreted MIP-2, MCP-1 and GRO/KC. Exposure to uPA induced elevations in secreted IFN-gamma, TNF-alpha, GMCSF, MIP-1alpha, MIP-2, MIP-3alpha, MCP-1, RANTES and fractalkine. These data suggest that plasminogen activators may trigger selected pro-inflammatory responses at the neurovascular interface. Whether these effects influence thrombolytic stroke therapy warrants further investigation.
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PMID:Induction of matrix metalloproteinase, cytokines and chemokines in rat cortical astrocytes exposed to plasminogen activators. 1738 75

Salt-loaded, spontaneously hypertensive stroke-prone rats show progressive increases in blood pressure and proteinuria and accumulate acute-phase proteins in body fluids, modeling events during renal damage. The aim of this study was to assess the pathological events occurring in the kidney of spontaneously hypertensive stroke-prone rats over time and evaluate the effects of statin treatment, which is known to improve renal and cardiovascular outcomes. Kidneys of male spontaneously hypertensive stroke-prone rats euthanized at different stages of proteinuria showed progressive inflammatory cell infiltration, the accumulation of alpha-smooth muscle actin-positive cells, degenerative changes in podocytes, and severe fibrosis. These were accompanied by an imbalance in the plasminogen/plasmin and metalloprotease systems characterized by the increased renal expression of plasminogen activator inhibitor-1, tissue plasminogen activator, and urokinase plasminogen activator; the net result was an increase in plasmin and matrix metalloproteinase (MMP)-2 and a reduction in MMP-9 activity. Chronic treatment with the hydrophilic rosuvastatin had renoprotective effects in terms of morphology and inflammation and prevented the changes in plasmin, MMP-2, and MMP-9 activity. These effects were independent of the changes in blood pressure and plasma lipid levels. Treatment with the lipophilic simvastatin was not renoprotective. These data suggest that rosuvastatin may have potential utility as a therapeutic option in renal diseases that are characterized by inflammation and fibrosis.
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PMID:Rosuvastatin treatment prevents progressive kidney inflammation and fibrosis in stroke-prone rats. 1739 57

Extracellular proteolysis is an important regulatory nexus for coordinating synaptic functional and structural plasticity, but the identity of such proteases is incompletely understood. Matrix metalloproteinases (MMPs) have well-known, mostly deleterious roles in remodeling after injury or stroke, but their role in nonpathological synaptic plasticity and function in intact adult brains has not been extensively investigated. Here we address the role of MMP-9 in hippocampal synaptic plasticity using both gain- and loss-of-function approaches in urethane-anesthetized adult rats. Acute blockade of MMP-9 proteolytic activity with inhibitors or neutralizing antibodies impairs maintenance, but not induction, of long-term potentiation (LTP) at synapses formed between Schaffer-collaterals and area CA1 dendrites. LTP is associated with significant increases in levels of MMP-9 and proteolytic activity within the potentiated neuropil. By introducing a novel application of gelatin-substrate zymography in vivo, we find that LTP is associated with significantly elevated numbers of gelatinolytic puncta in the potentiated neuropil that codistribute with immunolabeling for MMP-9 and for markers of synapses and dendrites. Such increases in proteolytic activity require NMDA receptor activation. Exposing intact area CA1 neurons to recombinant-active MMP-9 induces a slow synaptic potentiation that mutually occludes, and is occluded by, tetanically evoked potentiation. Taken together, our data reveal novel roles for MMP-mediated proteolysis in regulating nonpathological synaptic function and plasticity in mature hippocampus.
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PMID:In vivo roles for matrix metalloproteinase-9 in mature hippocampal synaptic physiology and plasticity. 1749 27

The high mobility group box-1 (HMGB1), originally identified as an architectural nuclear protein, exhibits an inflammatory cytokine-like activity in the extracellular space. Here we show that treatment with neutralizing anti-HMGB1 monoclonal antibody (mAb; 200 microg, twice) remarkably ameliorated brain infarction induced by 2-h occlusion of the middle cerebral artery in rats, even when the mAb was administered after the start of reperfusion. Consistent with the 90% reduction in infarct size, the accompanying neurological deficits in locomotor function were significantly improved. Anti-HMGB1 mAb inhibited the increased permeability of the blood-brain barrier, the activation of microglia, the expression of TNF-alpha and iNOS, and suppressed the activity of MMP-9, whereas it had little effect on blood flow. Intracerebroventricular injection of HMGB1 increased the severity of infarction. Immunohistochemical study revealed that HMGB1 immunoreactivity in the cell nuclei decreased or disappeared in the affected areas, suggesting the release of HMGB1 into the extracellular space. These results indicate that HMGB1 plays a critical role in the development of brain infarction through the amplification of plural inflammatory responses in the ischemic region and could be an outstandingly suitable target for the treatment. Intravenous injection of neutralizing anti-HMGB1 mAb provides a novel therapeutic strategy for ischemic stroke.
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PMID:Anti-high mobility group box 1 monoclonal antibody ameliorates brain infarction induced by transient ischemia in rats. 1762 15

While recombinant tissue plasminogen activator (rt-PA) is successfully used for thrombolysis in human stroke, it may increase the risk of hemorrhagic complications. We describe the effects of different doses of rt-PA (saline, 0.9, 9, or 18 mg rt-PA/kg body weight) on the extravasation of blood components following experimental cerebral ischemia (3 h, 24 h reperfusion, suture model) in rats. The damage to the blood-brain barrier and the hemoglobin extravasation were quantified by Western blotting and immunohistochemistry. Both were significantly elevated in the ischemic cortex and basal ganglia. As rt-PA doses rose, the hemoglobin content as well as the damage to the blood-brain barrier in the ischemic side also rose significantly (p<0.001). This correlated significantly with the rising MMP-9 (matrix metalloproteinase) after increasing doses of rt-PA. Despite various benefits, rt-PA is responsible for a dose-dependent increase of edema and hemorrhage after cerebral ischemia. Clinicians should consider using the lowest effective dose of rt-PA in stroke patients.
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PMID:rt-PA causes a dose-dependent increase in the extravasation of cellular and non-cellular blood elements after focal cerebral ischemia. 1764 75

Abnormal expression of matrix metalloproteinases (MMPs) has been implicated in the pathophysiology of neuroinflammatory processes that accompany most central nervous system disease. In particular, early upregulation of the gelatinases MMP-2 and MMP-9 has been shown to contribute to disruption of the blood-brain barrier and to death of neurons in ischemic stroke. In situ zymography reveals a significant increase in gelatinolytic MMPs activity in the ischemic brain hemisphere after 2-h middle cerebral artery occlusion (MCAo) followed by 2-h reperfusion in rat. Accordingly, gel zymography demonstrates that expression and activity of MMP-2 and MMP-9 are enhanced in cortex and striatum ipsilateral to the ischemic insult. The latter effect appears to be instrumental for development of delayed brain damage since administration of a broad spectrum, highly specific MMPs inhibitor, GM6001, but not by its negative control, results in a significant (50%) reduction in ischemic brain volume. Increased gelatinase activity in the ischemic cortex coincides with elevation (166% vs sham) of mature interleukin-1beta (IL-1beta) after 2-h reperfusion and this does not appear to implicate a caspase-1-dependent processing of pro(31kDa)-IL-1beta to yield mature (17kDa) IL-1beta. More importantly, when administered at a neuroprotective dose GM6001 abolishes the early IL-1beta increase in the ischemic cortex and reduces the cleavage of the cytokine proform supporting the deduction that MMPs may initiate IL-1beta processing. In conclusion, development of tissue damage that follows transient ischemia implicates a crucial interplay between MMPs and mediators of neuroinflammation (e.g., IL-1beta), and this further underscores the therapeutic potential of MMPs inhibitors in the treatment of stroke.
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PMID:Early upregulation of matrix metalloproteinases following reperfusion triggers neuroinflammatory mediators in brain ischemia in rat. 1767 60

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

Accumulating data suggest that matrix metalloproteinases (MMPs), in particular MMP-2 and MMP-9, are deleterious after acute ischaemic stroke. A beneficial effect of MMPs in the repairing phases of cerebral ischaemia has also been proposed. This study investigated the relationship between MMP-2 and MMP-9 and stroke subtypes, clinical recovery and haemorrhagic transformation (HT). We measured MMP-9 and MMP-2 plasma levels in 29 patients with ischaemic stroke at days one and seven. MMP-2 levels increased only in lacunar strokes, whilst MMP-9 increased only in patients with more severe stroke. Basal MMP-2 levels were higher in patients with stable or recovering symptoms whilst MMP-9 values at day seven were correlated with worse clinical outcome. No differences related to the presence of HT were found. This study sustains a different behaviour of MMPs after ischaemic stroke. MMP-2 seems to be expressed early and related to better outcome, whilst MMP-9 seems to be late and related to more severe stroke.
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PMID:Different roles of matrix metalloproteinases-2 and -9 after human ischaemic stroke. 1769 Aug 45

Increased permeability of the blood-brain barrier (BBB) is important in neurological disorders. Neuroinflammation is associated with increased BBB breakdown and brain injury. Tumor necrosis factor (TNF)-alpha is involved in BBB injury and edema formation through a mechanism involving matrix metalloproteinase (MMP) up-regulation. There is emerging evidence indicating that cyclooxygenase (COX) inhibition limits BBB disruption following ischemic stroke and bacterial meningitis, but the mechanisms involved are not known. We used intracerebral injection of TNF-alpha to study the effect of COX inhibition on TNF-alpha-induced BBB breakdown, MMP expression/activity, and oxidative stress. BBB disruption was evaluated by the uptake of (14)C-sucrose into the brain and by magnetic resonance imaging utilizing gadolinium-diethylenetriaminepentaacetic acid as a paramagnetic contrast agent. Using selective inhibitors of each COX isoform, we found that COX-1 activity is more important than COX-2 in BBB opening. TNF-alpha induced a significant up-regulation of gelatinase B (MMP-9), stromelysin-1 (MMP-3), and COX-2. In addition, TNF-alpha significantly depleted glutathione as compared with saline. Indomethacin (10 mg/kg i.p.), an inhibitor of COX-1 and COX-2, reduced BBB damage at 24 h. Indomethacin significantly attenuated MMP-9 and MMP-3 expression and activation and prevented the loss of endogenous radical scavenging capacity following intracerebral injection of TNF-alpha. Our results show for the first time that BBB disruption during neuroinflammation can be significantly reduced by administration of COX inhibitors. Modulation of COX in brain injury by COX inhibitors or agents modulating prostaglandin E(2) formation/signaling may be useful in clinical settings associated with BBB disruption.
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PMID:Cyclooxygenase inhibition limits blood-brain barrier disruption following intracerebral injection of tumor necrosis factor-alpha in the rat. 1770 56

Recent evidence has demonstrated that thrombin plays an important role in the development of brain edema by the blood-brain barrier disruption in intracerebral hemorrhage. Matrix metalloproteinases (MMPs), a family of proteolytic enzymes that degrade the extracellular matrix, are implicated in blood-brain barrier disruption. In this study, we examined whether thrombin injection into the brain parenchyma induces the MMP-9 expression in rats. Anesthetized adult rats received an injection of 10 U of thrombin into the basal ganglia. At 12, 24, and 72 hours after the thrombin injection, brain water content and the expression of MMP-9 messenger RNA (mRNA) and protein were determined. The effect of a specific thrombin inhibitor (hirudin) on MMP-9 expression and brain edema formation and general administration of synthetic MMPs inhibitor (GM6001) on brain edema formation were also examined for linking the injury and up-regulation of MMP-9. The brain water contents in the basal ganglia and overlying cortex were rapidly increased at 12 hours, maximized at 24 hours, and slightly decreased at 72 hours. The gelatinase activity of MMP-9 determined with gelatin zymography was detected in the basal ganglia and cortex at 12 hours, maximally expressed at 24 hours, and remained strong 72 hours after thrombin injection. The expression of MMP-9 mRNA in the cortex determined with reverse transcription-polymerase chain reaction was clearly seen at 12 and 24 hours, and became weak 72 hours after thrombin injection. Co-injection of thrombin and hirudin almost completely inhibited the brain edema formation and expressions of MMP-9 mRNA and protein. Administration of broad-spectrum metalloproteinase inhibitor GM6001 significantly reduced the brain edema formation in this model. These results indicate that intraparenchymal thrombin induces brain edema formation through MMP-9 expression in rats. Inhibition of MMPs activity may provide an approach to potentially reduce ongoing edema after intracerebral hemorrhage.
J Stroke Cerebrovasc Dis
PMID:Expression of matrix metalloproteinase-9 in thrombin-induced brain edema formation in rats. 1790 58


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