Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0038454 (stroke)
 147,016 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Pathogenesis of Alzheimer's disease (AD), which is characterised by accumulation of extracellular deposits of beta-amyloid peptide (Abeta) in the brain, has recently been linked to vascular disorders such as ischemia and stroke. Abeta is constantly produced in the brain from amyloid precursor protein (APP) through its cleavage by beta- and gamma-secretases and certain Abeta species are toxic for neurones. The brain has an endogenous mechanism of Abeta removal via proteolytic degradation and the zinc metalloproteinase neprilysin (NEP) is a critical regulator of Abeta concentration. Down-regulation of NEP could predispose to AD. By comparing the effects of hypoxia and oxidative stress on expression and activity of the Abeta-degrading enzyme NEP in human neuroblastoma NB7 cells and rat primary cortical neurones we have demonstrated that hypoxia reduced NEP expression at the protein and mRNA levels as well as its activity. On contrary in astrocytes hypoxia increased NEP mRNA expression.
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PMID:Effects of hypoxia and oxidative stress on expression of neprilysin in human neuroblastoma cells and rat cortical neurones and astrocytes. 1748 46

The time window in the treatment of ischemic stroke with tissue plasminogen activator (tPA) is narrow, arbitrarily within 3 hours after the onset of symptom. Hemorrhagic transformation resulting from cerebral ischemia may be related to damage of the microvascular basal lamina of the brain, which may in turn cause microvascular fibrin deposition and aggravate cerebral ischemia. Here, we investigated the effect of tPA on the microvascular tissue changes during cerebral ischemia/reperfusion. Sprague-Dawley rats were subjected to focal cerebral ischemia by ligation of the right middle cerebral artery and bilateral common carotid arteries for 90 minutes. Sixty minutes after the onset of ischemia, escalated dosages of tPA from 2.5 to 10 mg/kg or saline were intravenously infused for 60 minutes. Twenty-four hours after reperfusion, the animals were allowed to be killed for examination. Low dosage of tPA (2.5-7.5 mg/kg) reduced post-ischemic brain infarction, suppressed metalloproteinase 2 (MMP-2) activity and restored blood-brain barrier (BBB) integrity. In contrast, high dose of tPA (10 mg/kg) aggravated brain infarction, increased MMP-2 activity and exacerbated BBB disruption. Cerebral ischemia/reperfusion decreased the immunoreactivity of both collagen type IV- and laminin-positive microvessels, whereas the low dosage of tPA (2.5-7.5 mg/kg) attenuated the reduction. When these molecules in whole cortical tissues were analysed, tPA dosage-dependently decreased the total content of collagen type IV, laminin and fibronectin. Although the detailed mechanisms regarding the action of tPA are yet to be investigated, our findings demonstrate that the detrimental effect of tPA was mediated, at least in part, through the destruction of the basal lamina in the cerebral microvessels by activating MMP-2.
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PMID:Effects of tissue plasminogen activator on cerebral microvessels of rats during focal cerebral ischemia and reperfusion. 1750 27

Proteolytic disruption of the extracellular matrix with opening of the blood-brain barrier (BBB) because of matrix metalloproteinases (MMPs) occurs in reperfusion injury after stroke. Matrix metalloproteinase inhibition blocks the early disruption of the BBB, but the long-term consequences of short-term MMP inhibition are not known. Recently, a method to quantify BBB permeability by graphical methods was described, which provides a way to study both early disruption of the BBB and long-term effects on recovery in the same animal. We used a broad-spectrum MMP inhibitor, BB1101, to determine both the usefulness of the Magnetic resonance imaging (MRI) method for treatment studies and the long-term effects on recovery. Magnetic resonance imaging studies were performed in control (N=6) and drug-treated (N=8) groups on a dedicated 4.7-T MRI scanner. Adult Wistar-Kyoto underwent a 2-h middle cerebral artery occlusion followed by an MRI study after 3 h of reperfusion, which consisted of T2- and diffusion-weighted techniques. Additionally, a rapid T1 mapping protocol was also implemented to acquire one pre-gadolinium-diethylenetriaminepentaacetic acid baseline data set followed by postinjection data sets at 3-min intervals for 45 mins. The same animal was imaged again at 48 h for lesion size estimation. Data was postprocessed pixel-wise to generate apparent diffusion coefficient and permeability coefficient maps. Treatment with BB-1101 significantly reduced BBB permeability at 3 h, but failed to reduce lesion size at 48 h. Behavioral studies showed impairment in recovery in treated rats. Magnetic resonance imaging allowed for the monitoring of multiple parameters in the same animal. Our studies showed that BB-1101 was an excellent inhibitor of the BBB damage. However, results show that BB-1101 may be responsible for significant deterioration in neurologic status of treated animals. Although these preliminary results suggest that BB-1101 is useful in reducing early BBB leakage owing to reperfusion injury in stroke, further studies will be needed to determine whether the later detrimental effects can be eliminated by shorter time course of drug delivery.
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PMID:Early beneficial effect of matrix metalloproteinase inhibition on blood-brain barrier permeability as measured by magnetic resonance imaging countered by impaired long-term recovery after stroke in rat brain. 1770 Jun 31

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

The slow time course of neurodegeneration after brain ischemia/reperfusion opened a realistic time window for the application of protective therapies to prevent spreading of brain damage. In this work, we studied the ability of micromolar concentrations of this flavonoid in the blood to protect against brain damage induced by transient focal cerebral ischemia in rats. Transient focal cerebral ischemia was induced by middle cerebral artery occlusion in adult rats and brain damage has been monitored by 2,3,5-triphenyltetrazolium chloride (TTC) staining, hematoxylin-eosin (H-E) staining, 'in situ' terminal deoxyribonucleotidyl transferase-mediated dUTP-fluorescein nick end labeling (TUNEL), 'in situ' metalloproteinase activity using DQ-gelatin and loss of anti-laminin staining. Intravenous injections of kaempferol, at a dose of 10-15 mumol/L of blood 30 min before the induction of a 60 min ischemia-episode and just after reperfusion, led to >90% and 70-80% (TTC, H-E, TUNEL) decrease of brain damage in the temporal-frontal areas of neocortex and striatum, respectively, but only 40-50% decrease of brain damage was observed in the hippocampus and vicinal caudal areas of the striatum. This treatment with kaempferol also produced a similar reduction of metalloproteinase activation and loss of anti-laminin staining in cortical and striatum infarct areas. Kaempferol treatment efficiently protected against nitrosative-oxidative stress after ischemia/reperfusion, as shown by nearly complete protection against the increase of protein nitrotyrosines, and also afforded strong protection against the increase of apoptotic cell death (TUNEL) and biochemical markers of apoptosis, such as caspase-9 activity and poly-(ADP-ribose) polymerase degradation. On these grounds, a potential new therapeutic role of kaempferol to acute treatment of ischemic stroke is suggested.
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PMID:Blood micromolar concentrations of kaempferol afford protection against ischemia/reperfusion-induced damage in rat brain. 1795 Jul 7

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

An elevated level of Homocysteine (Hcy) is a risk factor for vascular dementia and stroke. Cysthathionine beta Synthase (CBS) gene is involved in the clearance of Hcy. Homozygous individuals for (CBS-/-) die early, but heterozygous for (CBS-/+) survive with high levels of Hcy. The gamma-Amino Butyric Acid (GABA) presents in the central nervous system (CNS) and functions as an inhibitory neurotransmitter. Hcy competes with GABA at the GABA(A) receptor and affects the CNS function. We hypothesize that Hcy causes a decrease in blood flow to the brain due to increase in vascular resistance (VR) because of arterial remodeling in the carotid artery (CA). Blood pressure and blood flow in CA of wild type (WT), CBS-/+, CBS-/+ GABA(A)-/- double knockout, and GABA(A)-/- were measured. CA was stained with trichrome, and the brain permeability was measured. Matrix Metalloproteinases (MMP-2 and MMP-9), tissue inhibitor of metalloproteinase (TIMP-3, TIMP-4), elastin, and collagen-III expression were measured by real-time polymerase chain reaction (RT-PCR). Results showed an increase in VR in CBS-/+/GABA(A)-/-double knockout>CBS-/+/>GABA(A)-/- compared to WT mice. Increased MMP-2, MMP-9, collagen-III and TIMP-3 mRNA levels were found in GABA(A)-/-, CBS-/+, CBS-/+/GABA(A) double knockout compared to WT. The levels of TIMP-4 and elastin were decreased, whereas the levels of MMP-2, MMP-9 and TIMP-3 increased, which indirectly reflected the arterial resistance. These results suggested that Hcy caused arterial remodeling in part, by increase in collagen/elastin ratio thereby increasing VR leading to the decrease in CA blood flow.
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PMID:Homocysteine decreases blood flow to the brain due to vascular resistance in carotid artery. 1872 59

Platelet aggregation plays a key role in hemostasis and thrombosis, and it is partly regulated by a plasma glycoprotein known as von Willebrand factor (VWF). VWF is primarily synthesized in vascular endothelial cells and secreted into the plasma as unusually large multimers. Normally, these VWF multimers are quickly degraded into smaller forms by a plasma metalloproteinase, namely, VWF-cleaving protease. In 2001, the protease was identified as ADAMTS13, a member of the ADAMTS metalloprotease family. Functional deficiency of ADAMTS13 caused by genetic mutation and inhibitory autoantibodies leads to the accumulation of unusually large VWF multimers in the plasma and results in a thrombotic disease known as thrombotic thrombocytopenic purpura (TTP). TTP caused by congenital ADAMTS13 deficiency is called Upshaw-Schulman syndrome (USS). Thus far, more than 80 causative mutations have been identified in the ADAMTS13 gene of the patients with USS. Almost all patients are compound heterozygotes or homozygotes of mutated ADAMTS13. In addition, 11 missense polymorphisms in ADAMTS13 were identified in the general population: some of them are found in populations throughout the world and some in specific ethnic groups. Among these polymorphisms, P475S is the only one that reduces the plasma ADAMTS13 activity. At present, there is no evidence of a relationship between ADAMTS13 polymorphisms and thrombotic diseases such as acute ischemic stroke and acute myocardial infarction; further research is required to clarify whether any relationship exists between them.
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PMID:[Genetic polymorphism of von Willebrand factor (VWF)-cleaving protease, ADAMTS13]. 1906 66

Anti-platelet integrin GPIIIa49-66 antibody (Ab) induces complement-independent platelet oxidative fragmentation and death by generation of platelet peroxide following NADPH oxidase activation. A C-terminal 385-amino acid fragment of ADAMTS-18 (a disintegrin metalloproteinase with thrombospondin motifs produced in endothelial cells) induces oxidative platelet fragmentation in an identical kinetic fashion as anti-GPIIIa49-66 Ab. Endothelial cell ADAMTS-18 secretion is enhanced by thrombin and activated by thrombin cleavage to fragment platelets. Platelet aggregates produced ex vivo with ADP or collagen and fibrinogen are destroyed by the C-terminal ADAMTS-18 fragment. Anti-ADAMTS-18 Ab shortens the tail vein bleeding time. The C-terminal fragment protects against FeCI3-induced carotid artery thrombosis as well as cerebral infarction in a postischemic stroke model. Thus, a new mechanism is proposed for platelet thrombus clearance, via platelet oxidative fragmentation induced by thrombin cleavage of ADAMTS-18.
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PMID:C-terminal ADAMTS-18 fragment induces oxidative platelet fragmentation, dissolves platelet aggregates, and protects against carotid artery occlusion and cerebral stroke. 1952 Aug 14

Extracellular matrix (ECM) and ECM-hydrolytic enzymes play critical roles in reproduction, development, morphogenesis, wound healing, tissue repair, regeneration, and remodeling. They are also involved in pathological processes such as inflammation, arthritis, cardiovascular diseases, stroke, neurodegeneration, metabolic syndrome, and cancer invasion and metastasis. Other reviews summarized the structure and function of ECM-degrading enzymes in cancer and other diseases. This review will focus on current insights of major protease families and other digestive enzymes that play significant roles in ECM remodeling and ECM-related pathologies. For example, the functions of matrix metalloproteinases in modulating adipogenesis, and their subsequent implications in obese patients, are discussed. Recent discovery and characterization of nineteen members of the human disintegrin-metalloproteinase with thrombospondin motif family have revealed new opportunities of investigating these enzymes in human pathologies, especially in the pathogenesis of osteoarthritis. Although kallikrein-3 was discovered many years ago as prostate specific antigen, the biomarker for detecting human prostate cancer and monitoring its recurrence in patients after surgery, fifteen members of the kallikrein family were reported to participate in physiological and pathological processes. Furthermore, exciting research has been carried out on other important ECM-digestive enzymes, including heparanase, cathepsins, hyaluronidases, and matriptases. Research data have suggested that these enzymes are potential therapeutic targets and biomarkers for cancer, arthritis, obesity, diabetic complications, multiple sclerosis, cardiovascular diseases, cerebral vascular diseases, and many other pathological conditions.
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PMID:A fresh prospect of extracellular matrix hydrolytic enzymes and their substrates. 1935 69


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