Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.24.3 (collagenase)
18,340 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Neural stem/progenitor cells (NPCs) reside in the subventricular zone (SVZ) and dentate gyrus in the adult mammalian brain. It has been reported that endogenous NPCs are activated after brain insults such as ischemic stroke. We investigated whether proliferation and migration of endogenous NPCs are increased after a collagenase-induced small intracerebral hemorrhage (ICH) near the internal capsule in rats. Bromodeoxyuridin (BrdU) administration for 14 days after ICH (post-labeling) resulted in an increase in the number of BrdU-positive cells as shown in both ipsilateral and contralateral SVZs. BrdU treatment given for 2 days before ICH to label endogenous NPCs (pre-labeling), caused more BrdU-positive cells to be detected in the ipsilateral dorsal striatum (dSTR) compared to those in the contralateral dSTR 14 days after ICH. BrdU- and doublecortin (Dcx)-positive cells were found in the ipsilateral STR. An increase in the number of Dcx-positive migrating immature neurons was found in the dSTR and peri-hemorrhage area 14 days after ICH, and a cluster of Dcx-positive cells was found in the STR around the lesion 28 days after ICH. Matrix metalloproteinase-2 (MMP-2) was strongly expressed in wide area of the injured brain, particularly around the lesion 14 and 28 days after ICH. Dcx- and MMP-2-positive cells were detected in the ipsilateral STR near the lesion. These data suggest that collagenase-induced ICH enhances the proliferation of endogenous NPCs and the migration of newly born neuroblasts toward the hemorrhage area.
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PMID:Increase in neurogenesis and neuroblast migration after a small intracerebral hemorrhage in rats. 1782 9

Spontaneous intracerebral hemorrhage (ICH) is one of the most devastating subtypes of stroke. Since angiogenesis is a fundamental process to brain development and repair by new blood vessel formation from pre-existing ones, mediated by numerous angiogenic factors including vascular endothelial growth factor (VEGF), the goal of the present work is to establish whether there is cerebral angiogenesis in rat brains with collagenase-induced ICH. Investigations were also performed to evaluate whether ICH alters expression of VEGF and its receptors Flt-1 and Flk-1. ICH was induced on adult male Sprague-Dawley rats by stereotactic injection of collagenase type VII into right globus pallidus. Angiogenesis was identified by hematoxylin-eosin stain and double immunolabeling method, and expression of VEGF and the receptors was evaluated by immunohistochemistry and quantitative real time reverse transcription-polymerase chain reaction. New vessels appeared around the hematoma and extended into it from 7 days, and 5-Bromo-2-Deoxyuridine-labeled nuclei in cerebral endothelial cells resided around the hematoma and the labeling peaked from 7 to 14 days. Expression of VEGF, Flt-1 and Flk-1 was observed in cerebral endothelial cells at the hemorrhagic basal ganglion, and increases of their mRNA persisted to 28 days. These findings suggest that ICH can induce cerebral angiogenesis and upregulation of VEGF, Flt-1 and Flk-1 and that modulation of angiogenesis via altering expression of VEGF and its receptors may be a potential strategy for promoting ICH repair.
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PMID:Cerebral angiogenesis after collagenase-induced intracerebral hemorrhage in rats. 1788 90

Intracerebral hemorrhage (ICH) is associated with stroke and head trauma. Different experimental models are used, but it is unclear to what extent the tissue responses are comparable. The purpose of this study was to compare the temporal responses to brain hemorrhages created by injection of autologous whole blood, collagenase digestion of blood vessels, and avulsion of cerebral blood vessels. Adult rats were subjected to ICH. Rats were perfusion fixed with paraformaldehyde 1 hour to 28 days later. Hematoxylin and eosin, Fluoro-Jade, immunohistochemical, and TUNEL staining were used to allow quantification of damaged and dying neurons, neutrophils, CD8alpha immunoreactive lymphocytes, and RCA-1 positive microglia/macrophages, adjacent to the hemorrhagic lesion. In all models, eosinophilic neurons peaked between 2 and 3 days. TUNEL positive cells were observed maximal at 2 days in blood injection model, 3 days in vessel avulsion model, between 1 and 7 days in the collagenase injection model, and were evident in small quantities in 21 to 28 days in 3 models. Neutrophils appeared briefly from 1 to 3 days in all models, but they were substantially lower in the cortical vessel avulsion model, perhaps owing to the devitalized nature of the tissue. Influx of CD8alpha immunoreactive lymphocytes were maximal at 2 to 3 days in the autologous injection model, 3 to 7 days in other 2 models, and persisted for 21 to 28 days in all models. The microglial/macrophage reaction peaked between 2 and 3 days in the blood injection model and at 3 to 7 days in other 2 models, and persisted for weeks in all groups. These results suggest that different models of ICH are associated with similar temporal patterns of cell death and inflammation. However, the relative magnitude of these changes differs.
J Stroke Cerebrovasc Dis
PMID:Comparison of brain cell death and inflammatory reaction in three models of intracerebral hemorrhage in adult rats. 1790 20

Blood-brain barrier (BBB) formed by brain microvascular endothelial cells (BMVEC) regulates the passage of molecules and leukocytes in and out of the brain. Activation of matrix metalloproteinases (MMPs) and alteration of basement membrane (BM) associated with BBB injury was documented in stroke patients. While chronic alcoholism is a risk factor for developing stroke, underlying mechanisms are not well understood. We hypothesized that ethanol (EtOH)-induced protein tyrosine kinase (PTK) signaling resulted a loss of BBB integrity via MMPs activation and degradation of BM component, collagen IV. Treatment of BMVEC with EtOH or acetaldehyde (AA) for 2-48 h increased MMP-1, -2 and -9 activities or decreased the levels of tissue inhibitors of MMPs (TIMP-1, -2) in a PTK-dependent manner without affecting protein tyrosine phosphatase activity. Enhanced PTK activity after EtOH exposure correlated with increased phosphorylated proteins of selective receptor and nonreceptor PTKs. Up-regulation of MMPs activities and protein contents paralleled a decrease in collagen IV content, and inhibitors of EtOH metabolism, MMP-2 and -9, or PTK reversed all these effects. Using human BMVEC assembled into BBB models, we found that EtOH/AA diminished barrier tightness, augmented permeability, and monocyte migration across the BBB via activation of PTKs and MMPs. These findings suggest that alcohol associated BBB injury could be mediated by MMPs via BM protein degradation and could serve as a comorbidity factor for neurological disorders like stroke or neuroinflammation. Furthermore, our preliminary experiments indicated that human astrocytes secreted high levels of MMP-1 and -9 following exposure to EtOH, suggesting the role of BM protein degradation and BBB compromise as a result of glial activation by ethanol. These results provide better understanding of multifaceted effects of alcohol on the brain and could help develop new therapeutic interventions.
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PMID:Activation of protein tyrosine kinases and matrix metalloproteinases causes blood-brain barrier injury: Novel mechanism for neurodegeneration associated with alcohol abuse. 1794 53

Neural stem cell (NSC) transplantation has been investigated as a means to reconstitute the damaged brain after stroke. In this study, however, we investigated the effect on acute cerebral and peripheral inflammation after intracerebral haemorrhage (ICH). NSCs (H1 clone) from fetal human brain were injected intravenously (NSCs-iv, 5 million cells) or intracerebrally (NSCs-ic, 1 million cells) at 2 or 24 h after collagenase-induced ICH in a rat model. Only NSCs-iv-2 h resulted in fewer initial neurologic deteriorations and reduced brain oedema formation, inflammatory infiltrations (OX-42, myeloperoxidase) and apoptosis (activated caspase-3, TUNEL) compared to the vehicle-injected control animals. Rat neurosphere-iv-2 h, but not human fibroblast-iv-2 h, also reduced the brain oedema and the initial neurologic deficits. Human NSCs-iv-2 h also attenuated both cerebral and splenic activations of tumour necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), and nuclear factor-kappa B (NF-kappaB). However, we observed only a few stem cells in brain sections of the NSCs-iv-2 h group; in the main, they were detected in marginal zone of spleens. To investigate whether NSCs interact with spleen to reduce cerebral inflammation, we performed a splenectomy prior to ICH induction, which eliminated the effect of NSCs-iv-2 h transplantation on brain water content and inflammatory infiltrations. NSCs also inhibited in vitro macrophage activations after lipopolysaccharide stimulation in a cell-to-cell contact dependent manner. In summary, early intravenous NSC injection displayed anti-inflammatory functionality that promoted neuroprotection, mainly by interrupting splenic inflammatory responses after ICH.
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PMID:Anti-inflammatory mechanism of intravascular neural stem cell transplantation in haemorrhagic stroke. 1866 89

Exercise reduces ischemia and reperfusion (I/R) injury in the rat stroke model. We investigated whether pre-ischemic exercise ameliorates blood-brain barrier (BBB) dysfunction in stroke by reducing matrix metalloproteinase (MMP)-9 expression and strengthening basal lamina. Adult male Sprague-Dawley rats were subjected to a 30 min exercise program on a treadmill 5 days a week for 3 weeks. Stroke was induced by a 2-h middle cerebral artery (MCA) occlusion using an intraluminal filament in the exercised and non-exercised groups. Brain infarction was measured and neurological deficits were scored. BBB dysfunction was determined by examining brain edema and Evans Blue extravasation. Expression of collagen IV, the major component of basal lamina essential for maintenance of the endothelial permeability barrier, was quantitatively detected by Western blot and immunocytochemistry. Ex vivo techniques were used to compare collagen IV-labeled vessels in response to ischemic insult. Temporal relationship of expression of MMP-9 and its endogenous inhibitor, the tissue inhibitors of metalloproteinase-1 (TIMP-1), was determined by real-time PCR for mRNA and Western blot for protein during reperfusion. Brain edema and Evans Blue leakage were both significantly (P<0.01) reduced after stroke in the exercised group, in association with reduced brain infarct volume and neurological deficits. Western blot analysis indicated that exercise enhanced collagen IV expression and reduced the collagen loss after stroke. Immunocytochemistry demonstrated that collagen IV-labeled vessels were significantly (P<0.01) increased in exercised rats. In the ex vivo study, after exercised brains were incubated with ischemic brain tissue, a significantly (P<0.01) higher level of collagen IV-labeled vessels was observed as compared with non-exercised brains following the same treatment. The ex vivo study also revealed a key role of MMP-9 in exercise-strengthened collagen IV expression against I/R injury. TIMP-1 protein levels were significantly (P<0.01) increased by exercise. Our results indicate that pre-ischemic exercise reduces brain injury by improving BBB function and enhancing basal lamina integrity in stroke. This study suggests that the neuroprotective effect of physical exercise is associated with an imbalance of MMP-9 and TIMP-1 expression.
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PMID:Pre-ischemic exercise reduces matrix metalloproteinase-9 expression and ameliorates blood-brain barrier dysfunction in stroke. 1816 Feb 27

Estrogen influences not only the incidence of stroke, but also the amount of injury sustained from a stroke including intracerebral hemorrhage (ICH). In this study we tested whether delayed 17beta-estradiol (E2) treatment affects recovery following striatal ICH. Female rats were trained and tested on several behavioral tests to assess skilled reaching, spontaneous forelimb usage and walking ability. Two weeks following ovariectomy, rats were subjected to a moderate-sized ICH via infusion of collagenase into the striatum. One week later they were implanted with either an E2 pellet (0.36 mg; 60-day release) or they underwent a sham procedure. They were further divided into groups that received either environmental enrichment (EE) rehabilitation therapy (group housing in a complex cage with ramps, tunnels, etc.) or a control condition (group housing in a standard cage). Rats were then behaviorally evaluated out to 8 weeks post-ICH and then euthanized. Neither EE nor E2 affected lesion size, which averaged 62.8 mm(3) across all groups. The EE therapy improved recovery on some tests (e.g., traversing a horizontal ladder) whereas E2 treatment did not notably affect either spontaneous or EE-facilitated recovery. Thus, E2 fails to improve recovery or protect against brain injury when given after a 1-week delay in contrast to its clear neuroprotective effects when given before or soon after ICH.
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PMID:Failure of estradiol to improve spontaneous or rehabilitation-facilitated recovery after hemorrhagic stroke in rats. 1817 74

Recombinant tissue plasminogen activator (t-PA), the only approved stroke treatment, is used for clot lysis within the occluded brain artery. Unfortunately, matrix metalloproteinase-9 (MMP-9) concentration increases after t-PA treatment and has been related to hemorrhagic transformation after ischemic stroke. Although the exact cellular source of brain MMP-9 remains unknown, invading, inflammatory cells, such as neutrophils, release MMP-9 to cross the blood brain barrier. Therefore, we hypothesize that the most feared side effect of stroke reperfusion therapy, brain hemorrhage, is related to t-PA-induced MMP-9 release by neutrophils. We show by means of ELISA that t-PA treatment promotes MMP-9, MMP-8, and tissue inhibitor metalloproteinase-2 release from human neutrophils ex vivo within 10 and 30 min. Moreover, by zymography and Western blot, we observed that neutrophils are emptied of MMP-9 content after t-PA treatment at those times. Finally, total internal reflection fluorescent imaging allowed us to observe the t-PA effect on neutrophils, showing the promotion of degranulation on these cells in vivo. Our data suggest that neutrophils are good candidates to be the main source of MMP-9 following t-PA stroke treatment and in consequence, partially responsible for thrombolysis-related brain bleedings.
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PMID:Tissue plasminogen activator (t-PA) promotes neutrophil degranulation and MMP-9 release. 1839 Sep 30

Stem cell therapy seems promising in reducing deficits after focal cerebral ischemia. As stroke may result from intracerebral hemorrhage (ICH) in up to 20% we investigated whether human processed lipoaspirate mesenchymal stem cells (PLA-MSC) influence the functional outcome, migration behavior and the activation of endogenous progenitor cells. Experimental ICH was induced by stereotactic administration of collagenase in rats randomly assigned to the control or treatment group. The latter received 3 x 10(6) PLA-MSC by intravenous (i.v.) injection 24h after ICH induction. The outcome was continuously monitored using the RotaRod test over a period of 4 weeks. Morphometric analysis of ICH was performed consecutively by magnetic resonance imaging (MRI) studies and immunohistochemical analysis. The RotaRod test revealed a significant 1.5-fold improvement (p<0.005) in functional outcome for the PLA-MSC treated group after 4 weeks compared to controls. Histological and MRI assessment of lesion size showed no difference between the two groups. Although i.v. injected human cells could not be detected in the post mortem brain, evaluation of the number of endogenous progenitor cells revealed a twofold increase in the treated animals compared to controls. Treatment with PLA-MSC improved the functional outcome significantly in an experimental ICH model. This effect was achieved by stimulation of endogenous progenitor cells rather than integration and differentiation of the infused PLA-MSC.
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PMID:Lipoaspirate-derived adult mesenchymal stem cells improve functional outcome during intracerebral hemorrhage by proliferation of endogenous progenitor cells stem cells in intracerebral hemorrhages. 1869 31

S100B, a 21-kD Ca(2+) binding protein expressed in Schwann cells and astroglia, has often been reported as a promising biomarker for ischemic stroke. In addition to ischemic stroke, the peripheral S100B level may also be useful as a biomarker for intracerebral hemorrhage (ICH). However, the kinetics and characterization of peripheral S100B in patients or experimental animal models with ICH have not been carefully examined. The present study investigated the kinetics and characteristics of the serum S100B level in a rat collagenase-induced ICH model. The serum S100B kinetics and the time-course of brain edema and hematoma formation were examined. Then, the correlations between the elevated serum S100B level and brain edema or hematoma formation were investigated. A transient elevation of serum S100B that peaked at 6 h after ICH induction was observed. The single measurement of serum S100B at 6 h after ICH induction was significantly correlated with brain edema formation and the maximal extent of the hematoma volumes. These results suggest the significance of serum S100B as a biomarker of brain damage resulting from ICH.
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PMID:Serum S100B, brain edema, and hematoma formation in a rat model of collagenase-induced hemorrhagic stroke. 1902 32


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