Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0917798 (cerebral ischemia)
 17,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Microvascular integrity is lost during focal cerebral ischemia. The degradation of the basal lamina and extracellular matrix are, in part, responsible for the loss of vascular integrity. Matrix metalloproteinases (MMPs) may play a primary role in basal lamina degradation. By using a sensitive modification of gelatin zymography, the authors investigated the activity of MMP-2 and MMP-9 in frozen 10-microm sections of ischemic and nonischemic basal ganglia and plasma samples of 27 non-human primates after middle cerebral artery occlusion/reperfusion (MCAO/R) for various periods. The gelatinolytic activities were compared with parallel cell dUTP incorporation in the ischemic zones of adjacent sections. In the brain, the integrated density of MMP-2 increased significantly by 1 hour after MCAO and was persistently elevated thereafter. Matrix metalloproteinase-2 expression was highly correlated with the extent of neuron injury and the number of injured neurons (r = 0.9763, SE = 0.004, 2P < 0.0008). Matrix metalloproteinase-9 expression only was significantly increased in subjects with hemorrhagic transformation. In plasma, only MMP-9 increased transiently at 2 hours of MCAO. These findings highlight the early potential role of MMP-2 in the degradation of basal lamina leading to neuronal injury, and an association of MMP-9 with hemorrhagic transformation after focal cerebral ischemia.
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PMID:Matrix metalloproteinases increase very early during experimental focal cerebral ischemia. 1036 92

Blood-brain barrier (BBB) disruption is thought to play a critical role in the pathophysiology of ischemia/reperfusion. Matrix metalloproteinases (MMPs) are a family of proteolytic enzymes that can degrade all the components of the extracellular matrix when they are activated. Gelatinase A (MMP-2) and gelatinase B (MMP-9) are able to digest the endothelial basal lamina, which plays a major role in maintaining BBB impermeability. The present study examined the expression and activation of gelatinases before and after transient focal cerebral ischemia (FCI) in mice. Adult male CD1 mice were subjected to 60 min FCI and reperfusion. Zymography was performed from 1 to 23 h after reperfusion using the protein extraction method with detergent extraction and affinity-support purification. MMP-9 expression was also examined by both immunohistochemistry and Western blot analysis, and tissue inhibitors to metalloproteinase-1 was measured by reverse zymography. The BBB opening was evaluated by the Evans blue extravasation method. The 88-kDa activated MMP-9 was absent from the control specimens, while it appeared 3 h after transient ischemia by zymography. At this time point, the BBB permeability alteration was detected in the ischemic brain. Both pro-MMP-9 (96 kDa) and pro-MMP-2 (72 kDa) were seen in the control specimens, and were markedly increased after FCI. A significant induction of MMP-9 was confirmed by both immunohistochemistry and Western blot analysis. The early appearance of activated MMP-9, associated with evidence of BBB permeability alteration, suggests that activation of MMP-9 contributes to the early formation of vasogenic edema after transient FCI.
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PMID:Early appearance of activated matrix metalloproteinase-9 and blood-brain barrier disruption in mice after focal cerebral ischemia and reperfusion. 1052 99

Matrix metalloproteinases (MMPs) are proteolytic enzymes that can degrade the extracellular matrix. MMP-9 and MMP-2 have been implicated in brain injury formation. The authors examined the effect of MMP inhibitor KB-R7785 on brain infarct formation resulting from permanent focal cerebral ischemia in mice. Ischemia was induced by intraluminal middle cerebral artery occlusion (MCAO) in mice under halothane anesthesia. Zymography was conducted to measure the MMPs activity in ischemic brain tissues. Injection of KB-R7785 (100 mg/kg) 30 min before MCAO significantly decreased both MMP-9 activity and infarct volume determined at 24 h. In addition, KB-R7785 injected twice at 1 and 4.5 h after MCAO significantly decreased infarct volume. These results indicate that KB-R7785 has a protective efficacy against focal cerebral ischemia, and our data provide further evidence that MMP-9 contributes to brain infarct formation.
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PMID:Matrix metalloproteinase inhibitor KB-R7785 attenuates brain damage resulting from permanent focal cerebral ischemia in mice. 1135 3

Mediators of extracellular matrix proteins degradation, the matrix metalloproteinases (MMPs), involved in inflammation as well as facilitation of process outgrowth of oligodendrocytes are interesting targets for neural repair. Recent data reported their activation after seizures, cerebral ischemia and spinal cord injury. The present study was designed to localize at cellular level the gelatinase activity by in situ zymography in a rat spinal cord contusion model. The kinetic of gelatinase activation was monitored by in situ zymography on 20 microm cryostat sections. The fluorescein-quenched DQ gelatin digestion yielded cleaved fluorescent peptides enabling the detection of gelatinase activity at cellular level. Twenty four hours and 48 h after injury, a strong gelatinase activity was detected at the lesion site in and around vascular structures and infiltrated cells. A preincubation with either MMP-2 or MMP-9 antibodies significantly decreases the gelatinase activity pattern, suggesting the involvement of at least both MMPs. Our results are consistent with a role for MMPs in the blood spinal barrier disruption, the leukocytes infiltration, the disruption of the extracellular matrix and the clearance of debris.
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PMID:Matrix metalloproteinases: potential therapeutic target in spinal cord injury. 1138 63

Matrix metalloproteinases (MMPs) may contribute to tissue damage after cerebral ischemia. In this study, wildtype and MMP-2 knockout mice were subjected to permanent and transient (2 h) occlusions of the middle cerebral artery. Gelatin zymography showed that MMP-9 levels were increased in all brains after ischemia. MMP-2 levels did not show a significant increase in wildtype mice, and were not detectable in knockout mice. Laser doppler flowmetry demonstrated equivalent ischemic reductions in perfusion in wildtype and knockout mice. In both permanent and transient occlusion paradigms, there were no statistically significant differences between wildtype and knockout mice in terms of 24 h ischemic lesion volumes. These data suggest that MMP-2 does not contribute to acute tissue damage in this model of focal ischemia.
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PMID:Matrix metalloproteinase 2 gene knockout has no effect on acute brain injury after focal ischemia. 1158 20

Matrix metalloproteinases (MMPs) degrade the extracellular matrix and carry out key functions during development and after injury. By means of zymography, Western blot and immunohistochemistry, we studied MMP-2 (gelatinase A) and MMP-9 (gelatinase B) in rat brain after focal cerebral ischemia. The control rat brain showed constitutive MMP-2 and, to a lesser extent, MMP-9, which were mainly present as prozymogens. MMP-2 protein was located in the cell body of neurons, glia, and endothelium, whereas MMP-9 was associated to neurons and myelinated fibre tracts. Ischemia greatly increased MMP activation in two temporal waves, in the first one, MMP-9 protein was induced from 4 h to 4 days, and also a small and short-lasting increase in MMP-2 was detected at 4 h. The second wave showed a massive increase in MMP-2 protein expression and activation by day 4, which was compatible with abundant MMP-2 in reactive microglia/macrophages. Our results are compatible with progressive induction of MMP-9 proform, likely in neurons, shortly after ischemia. For MMP-2, the results suggest a discrete production immediately after reperfusion, while a very enhanced expression and activation of MMP-2 attributable to microglia/macrophages occurs on day 4, and it might contribute to the phagocytic action of these reactive cells.
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PMID:Expression and activation of matrix metalloproteinase-2 and -9 in rat brain after transient focal cerebral ischemia. 1159 52

Neuroinflammation induces a complex molecular cascade that leads to the proteolysis of cells. Matrix metalloproteinases (MMPs) attack all components of the extracellular matrix in a number of neuroinflammatory diseases and cause a delayed opening of the blood-brain barrier (BBB). Earlier, we showed that lipopolysaccharide (LPS) disrupted the BBB through the action of gelatinase B (MMP-9). In a study of cerebral ischemia, gelatinase A (MMP-2) was seen in astrocytic end-feet and stromelysin-1 (MMP-3) in microglia. Since other MMPs may be important in LPS-induced injury, we studied the gene transcription and cellular localization of several MMPs and an inflammatory mediator, tumor necrosis factor (TNF-alpha), using competitive polymerase chain reaction (PCR) and immunohistochemical methods. Significantly elevated levels of MMP-2 and -3 mRNA were observed in LPS-injected brains by 2 h after injection as compared to non-injected brain tissue (P<0.05). By 8 h post-LPS injection, gene expression of MMP-2 and -3 had declined in both saline- and LPS-injected tissue, while TNF-alpha mRNA levels rose significantly. Immunohistochemistry of control brains confirmed the earlier observation of MMP-2 immunoreactivity in processes abutting cerebral blood vessels, which increased after LPS injection. The expression of MMP-9 and MMP-3 was localized mainly to the cerebrovasculature in LPS-stimulated brain tissue, predominantly in the perivascular cells of the basal lamina near the site of injection. Both of these proteinases were present at the site of LPS injection at 8 h, but MMP-2 was absent. Our results show that MMP genes are up-regulated prior to the induction of cytokines such as TNF-alpha, and that MMP proteins are prominent around blood vessels in LPS-induced neuroinflammation.
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PMID:Stromelysin-1 and gelatinase A are upregulated before TNF-alpha in LPS-stimulated neuroinflammation. 1192 34

To determine the activity of matrix metalloproteinases (MMP), especially MMP-2 and MMP-9, which play an important role in ischemic stroke and intracerebral hemorrhage, we adapted a simple and rapid method for localizing gelatinase activity to a gelatin film in situ-overlay technique previously used in cancer research. Ten micrometer cryosections of rat brain from controls and animals subjected to 3 h of ischemia and 48 h of reperfusion (suture model for transient cerebral ischemia) were used. After thawing, a gelatin film with a polyester base was put on the slide, incubated for 24 h at 37 degrees C, stained with Ponceau S, and then discolored in bi-distilled water. Non-staining areas on the film corresponded to lysis zones, caused by activated MMPs. This was proven by MMP incubation at various concentrations on the plain gelatin film and pretreatment with EDTA (an MMP inhibitor), which prevents lysis zones in normal and ischemic brains. As confirmatory tests, SDS-PAGE zymography was used to define MMP activity, and also MMP-2 immunohistochemistry to detect the possibly cellular origin of MMPs. Normal rat brain exhibited a low background activity, which was visible as a light halo-like lysis zone over and around the brain. Areas in normal brain with medium MMP activity were within the white matter (corpus callosum, anterior commissure, and cerebellum). Ischemic brain exhibited high activity lysis zones within the infarcted area (detected by microtubuli associated protein-2 staining). These zones consisted of microscopically small lysis holes with a diameter of about 10-20 microm. Immunohistochemistry showed that especially microvessels expressed MMP antigen. SDS-PAGE zymography differentiated between a high level of activated MMPs in the ischemic area and a low level in the non-ischemic basal ganglia. The gelatin film in situ-overlay technique is able to localize MMP activity in ischemic rat brain tissue on a microscopic level.
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PMID:A gelatin in situ-overlay technique localizes brain matrix metalloproteinase activity in experimental focal cerebral ischemia. 1204 62

Spatial and temporal relations between metalloproteinase (MMP-2 and MMP-9) activation and laminin degradation in gerbil hippocampus after transient cerebral ischemia has been studied. Activity of MMPs was determined by gelatin zymography in homogenates from dorsal (DP, an equivalent of CA1 sector) and abdominal (AbP, containing CA2-4 and gyrus dentatus) parts of hippocampus. A significant activation of both investigated metalloproteinases was found at 72 h of recovery. Whereas MMP-2 up-regulation did not show any spatial preferences, the increase of MMP-9 activity was observed exclusively in DP. Activation of MMP-9 at this time point correlated spatially with degradation of laminin-protein of extracellular matrix. These results show that MMP pathway may function as a component of delayed neuronal death cascade in the apoptogenic CA1 sector after transient global ischemia.
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PMID:Involvement of MMPs in delayed neuronal death after global ischemia. 1220 Oct 33

While recombinant tissue plasminogen activator (rt-PA) is successfully used in human ischemic stroke, it may also cause hemorrhagic complications. Animal experiments have shown that hemorrhages are related to microvascular basal lamina damage. We investigated the effects of different doses of rt-PA on the brain microvasculature. Experimental cerebral ischemia in rats was induced for 3 h and followed by 24 h reperfusion (suture model). Each group of rats (n = 6) received either treatment (0.9, 9, or 18 mg rt-PA/kg body weight) or saline (control group) at the end of ischemia. The loss of microvascular basal lamina antigen collagen type IV was measured by Western blot of the ischemic and non-ischemic basal ganglia and cortex. Compared with the contralateral non-ischemic area, collagen type IV was significantly reduced in the ischemic area: (basal ganglia/cortex) 43% +/- 9% / 64% +/- 4 %. Low/moderate doses of rt-PA had a protective effect: 0.9 mg 79% +/- 3% / 89% +/- 6%, 9 mg 72% +/- 9%/ 81% +/- 12% (p < 0.05). Higher doses of rt-PA (18 mg) had a similar effect as seen in untreated controls: 57% +/- 11% / 59% +/- 9% (p < 0.05, Anova). MMP-9 and MMP-2, measured by gelatine zymography, steadily increased over higher doses of rt-PA: MMP-9 (basal ganglia/cortex): control 115% +/- 4% / 123% +/- 3% compared with 18 mg rt-PA 146% +/- 5%/ 162% +/- 6% (p < 0.05) and MMP-2: control 109% +/- 4%/ 116% +/- 5% and 18 mg rt-PA 222% +/- 15%/ 252% +/- 2% (p < 0.05). Low to moderate doses of rt-PA protect the microvascular basal lamina, whereas high doses of rt-PA have the opposite effect, probably due to increased coactivation of MMP-2 and MMP-9.
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PMID:Recombinant human tissue plasminogen activator protects the basal lamina in experimental focal cerebral ischemia. 1278 21


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