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)

Heat shock proteins (HSPs) are reported to reduce inflammation and apoptosis in a variety of brain insults. Geranylgeranylacetone (GGA), developed as an antiulcer in Japan, has been known to induce HSP70 and to exert cytoprotective effects. In this study, we investigated whether GGA, as a specific HSP inducer, exerts therapeutic effects in experimentally induced intracerebral hemorrhage (ICH). ICH was induced with male Sprague-Dawley rats via the collagenase infusion. GGA (800 mg/kg) was administered via oral tube according to various schedules of treatment. The treatment with GGA, beginning before the induction of ICH and continuing until day 3, showed the reduction of brain water content and the increased level of HSP70 protein, as compared to the treatment with vehicle, although GGA started after the induction of ICH or administered as a single dose before ICH failed to up-regulate HSP70 and to reduce brain edema. The rats treated with GGA exhibited better functional recovery than those treated with vehicle. In the pre- and post- treatment group, inflammatory cells and cell death in the perihematomal regions were found to have been decreased. The treatment of GGA inhibited the mRNA expression of MMP-9, uPA, IL-6 and MIP-1, with concomitant increment of eNOS and phosphorylated STAT3 and Akt after ICH. We demonstrated that GGA induced a reduction in the brain edema along with marked inhibitory effects on inflammation and cell death after ICH.
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PMID:Pharmacological induction of heat shock protein exerts neuroprotective effects in experimental intracerebral hemorrhage. 1720 4

Thrombin is thought to play an important role in brain damage associated with intracerebral hemorrhage (ICH). We previously showed that activation of mitogen-activated protein (MAP) kinases and recruitment of microglia are crucial for thrombin-induced shrinkage of the striatal tissue in vitro and thrombin-induced striatal damage in vivo. Here we investigated whether the same mechanisms are involved in ICH-induced brain injury. A substantial loss of neurons was observed in the center and the peripheral region of hematoma at 3 days after ICH induced by intrastriatal injection of collagenase in adult rats. Intracerebroventricular injection of argatroban or cycloheximide, both of which prevent thrombin cytotoxicity in vitro, exhibited a significant neuroprotective effect against ICH-induced injury. ICH-induced neuron loss was also prevented by a MAP kinase kinase inhibitor (PD98059) and a c-Jun N-terminal kinase inhibitor (SP600125). These drugs had no effect on hematoma size or ICH-induced brain edema. Activation of extracellular signal-regulated kinase in response to ICH was observed in both neurons and microglia. Despite their neuroprotective effects, MAP kinase inhibitors did not decrease the number of terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL)-positive cells appearing after ICH. Identification of cell types revealed that TUNEL staining occurred prominently in neurons but not in microglia, whereas inhibition of MAP kinases resulted in appearance of TUNEL staining in microglia. These results suggest that thrombin and the activation of MAP kinases are involved in ICH-induced neuronal injury, and that neuroprotective effects of MAP kinases are in part mediated by arrestment of microglial activities.
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PMID:Involvement of thrombin and mitogen-activated protein kinase pathways in hemorrhagic brain injury. 1749 98

Angiotensin II exerts its central nervous system effects primarily via its receptors AT1 and AT2, and it participates in the pathogenesis of ischemia via AT1. The selective AT1 receptor blocker (ARB) is used in the hypertension treatment, and it exerts a variety of pleiotropic effects, including antioxidative, antiapoptotic, and anti-inflammatory effects. In this study, we investigated the therapeutic effect of the ARB telmisartan in experimental intracerebral hemorrhage (ICH) in normotensive rats. ICH was induced via the collagenase infusion or autologous blood injection. Either telmisartan at 30 mg/kg/dose or phosphate-buffered saline was orally administered 2 h after ICH induction. We evaluated hemorrhage volume, brain water content, and functional recovery, and we performed the histological analysis for terminal deoxynucleotidyl transferase dUTP nick-end labeling, leukocyte infiltration, and microglia activation. A variety of intracellular signals, in terms of oxidative stress, apoptotic molecules, and inflammatory mediators, were also measured. Telmisartan reduced hemorrhage volume, brain edema, and inflammatory or apoptotic cells in the perihematomal area. Telmisartan was noted to induce the expression of endothelial nitric-oxide synthase and peroxisome proliferator-activated receptor gamma and decrease oxidative stress, apoptotic signal, tumor necrosis factor-alpha, and cyclooxygenase-2 expression. The telmisartan-treated rats exhibited less pronounced neurological deficits and recovered better. Thus, telmisartan seems to offer neural protection, including antiapoptosis, anti-inflammatory, and antioxidant benefits in the intracerebral hemorrhage rat model.
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PMID:Blockade of AT1 receptor reduces apoptosis, inflammation, and oxidative stress in normotensive rats with intracerebral hemorrhage. 1753 8

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

Many studies have indicated leukocytes are a major contributor to brain injuries caused by intracerebral hemorrhage (ICH). Leukocyte-expressed CD18 is important for neutrophil-endothelial interactions in the vasculature, and CD18 deficiency protects against ischemia-reperfusion injury. We investigated whether CD18 deficiency provides protection against ICH-induced brain injury. Male wild-type (WT) CD18(+/+) mice and CD18(-/-) -knockout mice were used in this study. ICH was induced by a collagenase injection. Mortality, neurological function, brain edema, and myeloperoxidase (MPO) activity as well as tissue expression of nitrotyrosine and MPO were evaluated 24 hr after ICH. We discovered significantly reduced brain edema and diminished mortality with a concomitant decrease in MPO and nitrotyrosine immunoreactivity in brains of CD18-knockout mice.
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PMID:Reduced brain injury in CD18-deficient mice after experimental intracerebral hemorrhage. 1861 43

Intracerebral hemorrhage (ICH) remains a major medical problem and currently has no effective treatment. Hemorrhaged blood is highly toxic to the brain, and catabolism of the pro-oxidant heme, mainly released from hemoglobin, is critical for the resolution of hematoma after ICH. The degradation of the pro-oxidant heme is controlled by heme oxygenase (HO). We have previously reported a neuroprotective role for HO2 in early brain injury after ICH; however, in vivo data that specifically address the role of HO2 in brain edema and neuroinflammation after ICH are absent. Here, we tested the hypothesis that HO2 deletion would exacerbate ICH-induced brain edema, neuroinflammation, and oxidative damage. We subjected wild-type (WT) and HO2 knockout ((-/-)) mice to the collagenase-induced ICH model. Interestingly, HO2(-/-) mice had enhanced brain swelling and neuronal death, although HO2 deletion did not increase collagenase-induced bleeding; the exacerbation of brain injury in HO2(-/-) mice was also associated with increases in neutrophil infiltration, microglial/macrophage and astrocyte activation, DNA damage, peroxynitrite production, and cytochrome c immunoreactivity. In addition, we found that hemispheric enlargement was more sensitive than brain water content in the detection of subtle changes in brain edema formation in this model. Combined, these novel findings extend our previous observations and demonstrate that HO2 deficiency increases brain swelling, neuroinflammation, and oxidative damage. The results provide additional evidence that HO2 plays a critical protective role against ICH-induced early brain injury.
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PMID:Heme oxygenase 2 deficiency increases brain swelling and inflammation after intracerebral hemorrhage. 1867 96

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

Free radical mechanisms are involved in secondary brain injury after intracerebral hemorrhage (ICH). Since melatonin is a potent free radical scavenger and indirect antioxidant, the objective of this study was to evaluate whether melatonin administration would attenuate oxidative stress, brain edema, and neurological deficits in a rat model of ICH. Animals were assigned into groups consisting of sham (needle trauma), vehicle, and melatonin (15 or 150 mg/kg). All injections occurred through the intraperitoneal route, at either 15 min or 3 h after collagenase ICH induction. Then, lipid peroxidation, neurological scoring (18-point system), and brain water content were evaluated at 24h post-ICH. Results demonstrated dramatically increased lipid peroxidation after collagenase-induced ICH; however, melatonin treatment effectively attenuated this lipid peroxidation. Nonetheless, neurological scoring and brain water content in the right basal ganglia was without significant difference between any treatment regimens (15 or 150 mg/kg of melatonin) or time points of drug administration (15 min or 3 h post-ICH). Therefore, melatonin reduced oxidative stress but did not change extent of brain edema or neurologic deficits.
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PMID:The antioxidant effects of melatonin after intracerebral hemorrhage in rats. 1906 75

The use of exogenous superoxide dismutase (SOD) and catalase (CAT) has been previously evaluated against various reactive oxygen species-mediated brain injuries, especially those associated with ischemia/ reperfusion. In this study, we investigated effects of these enzymatic antioxidants on intracerebral hemorrhage (ICH)-induced brain injury. A total of 65 male Sprague-Dawley rats (300-380 g) were divided into a sham group, an untreated ICH group, 3 groups of ICH rats treated with lecithinized SOD (PC-SOD) at doses of 0.1, 0.3, and 1 mg/kg, and a group treated with polyethylene glycol conjugated CAT (PEG-CAT) at a dose of 10,000 U/kg. An additional group of ICH rats received a combination of PC-SOD (1 mg/kg) and PEG-CAT (10,000 U/kg). ICH was induced by collagenase injection. All drugs were administered intravenously immediately after ICH induction. Brain injury was evaluated by scoring neurological function and measuring brain edema at 24 h after ICH induction. Our results demonstrated that ICH caused significant neurological deficit associated with remarkable brain edema. Treatment with PC-SOD, PEG-CAT, or PC-SOD in combination with PEG-CAT did not reduce brain edema or neurological deficit after ICH. We conclude that intravenously administered PC-SOD and/or PEG-CAT do not reduce brain injury in the collagenase-induced ICH rat model.
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PMID:Effects of superoxide dismutase and catalase derivates on intracerebral hemorrhage-induced brain injury in rats. 1906 78

Experimental studies of intracerebral hemorrhage (ICH) point toward leukocytes as a major contributor to ICH-induced brain injury. Leukocyte and endothelial cell adhesion molecules are responsible for injurious neutrophil-endothelial cell interactions in vasculature. Since deficiency of leukocyte-expressed CD18 protects against ischemia-reperfusion injury, we hypothesized that such deficiency may have similar effect in ICH-induced injury. Our aim was to investigate whether CD18 deficiency affords neuroprotection by decreasing ICH-induced brain injury, thereby improving neurological function and reducing mortality. A total of 20 males wild-type CDI8+/+ mice and 12 CD18-/- knockout mice were used in our study. ICH was induced by collagenase injection. Mortality, neurological function, and brain edema were measured at 24h after ICH. Data were analyzed by ANOVA, Chi-square, and Student t-test. Differences of p < 0.05 were considered statistically significant. Our study showed that the increase in brain water content caused by ICH was significantly smaller in CD18 knockout mice compared with wild-type mice (p < 0.05, Student t-test). This result correlated with a tendency toward improvement of neurological function and a decrease in mortality. We conclude that CD18 deficiency significantly reduces brain edema after ICH, which corresponds with a trend toward reduction in neurological deficit and mortality.
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PMID:Deficiency of CD18 gene reduces brain edema in experimental intracerebral hemorrhage in mice. 1906 88


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