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

Recent studies demonstrate that progesterone (PROG) significantly reduces cerebral edema and enhances functional recovery from traumatic brain injury (TBI) and stroke in several animal models, but its concrete mechanism is still unknown. This study was designed to investigate the inhibitory effects of PROG on inflammatory response after stroke and its influence on the structure of blood-brain barrier (BBB). In the treatment group, PROG was dissolved in 22.5% 2-hydroxypropyl-bcyclodextrin and given in a dose of 8 mg/kg by intraperitoneal injection 1h and 6h after permanent occlusion of middle cerebral artery (pMCAO). Additional injections of 15 mg/kg were administered subcutaneously once a day after pMCAO. The expression of tumor necrosis factor-alpha (TNF-alpha), matrix metalloproteinase-9 (MMP-9) and claudin5 was measured by western blot technique. Evan's blue extravasation and brain water content in the ipsilateral hemisphere was also detected to evaluate the permeability of BBB. Western blot analysis revealed that the expression of TNF-alpha and MMP-9 were reduced while claudin5 was up-regulated in brain tissues of PROG-treated rats. In addition, examination of BBB permeability also showed that administration of PROG significantly reduced Evan's blue extravasation and brain water content in the ipsilateral hemisphere compared to vehicle-treated rats. Our findings reveal that PROG inhibited the inflammatory response after experimental stroke and mitigated the severity of brain damage, suggesting a role for PROG in the integrity of the BBB and subsequent edema formation following cerebral ischemia.
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PMID:The protective mechanism of progesterone on blood-brain barrier in cerebral ischemia in rats. 1994 39

We investigated the neuroprotective effect of atorvastatin in combination with delayed thrombolytic therapy in a rat model of embolic stroke. Rats subjected to embolic middle cerebral artery (MCA) occlusion were treated with atorvastatin at 4 h, followed by tissue plasminogen activator (tPA) at 6 or 8 h after stroke. The combination of atorvastatin at 4 h and tPA at 6 h significantly decreased the size of the embolus at the origin of the MCA, improved microvascular patency, and reduced infarct volume, but did not increase the incidence of hemorrhagic transformation compared with vehicle-treated control animals. However, monotherapy with tPA at 6 h increased the incidence of hemorrhagic transformation and failed to reduce infarct volume compared with the control group. In addition, adjuvant treatment with atorvastatin at 4 h and with tPA at 6 h reduced tPA-induced upregulation of protease-activated receptor-1, intercellular adhesion molecule-1, and matrix metalloproteinase-9, and concomitantly reduced cerebral microvascular platelet, neutrophil, and fibrin deposition compared with rats treated with tPA alone at 6 h. In conclusion, a combination of atorvastatin and tPA extended the therapeutic window for stroke to 6 h without increasing the incidence of hemorrhagic transformation. Atorvastatin blocked delayed tPA-potentiated adverse cerebral vascular events, which likely contributes to the neuroprotective effect of the combination therapy.
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PMID:Atorvastatin extends the therapeutic window for tPA to 6 h after the onset of embolic stroke in rats. 1963 98

Oxidative stress and matrix metalloproteinases (MMPs) contribute to hemorrhagic transformation after ischemic stroke and brain injury after intracerebral hemorrhage (ICH). The goal of this study was to develop a new model of spontaneous ICH, based on the hypothesis that acute, superimposed on chronic, hypertension produces ICH. We hypothesized that increases in angiotensin II (AngII)-mediated oxidative stress and activation of MMPs are associated with, and may precede, spontaneous ICH during hypertension. In C57BL/6 mice, chronic hypertension was produced with AngII infusion and an inhibitor of nitric oxide synthase. During chronic hypertension, mice with acute hypertension from injections of AngII developed ICH. Oxidative stress and MMP levels increased in the brain even before developing ICH. Active MMPs colocalized with a marker of oxidative stress, especially on cerebral vessels that appeared to lead toward regions with ICH. Incidence of ICH and levels of oxidative stress and MMP-9 were greater in mice with acute hypertension produced by AngII than by norepinephrine. In summary, we have developed an experimental model of ICH during hypertension that may facilitate studies in genetically altered mice. We speculate that acute hypertension, especially when induced by AngII, may be critical in spontaneous ICH during chronic hypertension, possibly through oxidative stress and MMP-9.
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PMID:Spontaneous intracerebral hemorrhage during acute and chronic hypertension in mice. 1972 90

Acute myocardial infarction (AMI) is associated with matrix metalloproteinase activation. The plasma concentrations of carboxy-terminal telopeptide of collagen type I (CITP) reflect collagen type I degradation due to matrix metalloproteinase activation. We assessed the role of CITP as an early marker of outcome in AMI. Plasma CITP was measured 72 hours after hospital admission in 432 patients presenting with AMI. The 2 composite end points of the study (death, resuscitated cardiac arrest, recurrent AMI or ischemia, and heart failure or stroke; and death, resuscitated cardiac arrest, or heart failure) and mortality were assessed at 1 year in 4 patient groups stratified by the CITP quartiles. Patients with ST-segment elevation MI represented 75.7% of the population. In-hospital percutaneous coronary intervention was performed in 70.4% of the patients. The mean left ventricular ejection fraction was 53.9 +/- 12.5%. At 1 year of follow-up, high levels of CITP were associated with the occurrence of both composite end points and mortality (p <0.01 for all). Stepwise logistic regression analysis identified CITP as an independent predictor of both composite end points (odds ratio 2.14, 95% confidence interval 1.34 to 3.42, p = 0.001; and odds ratio 3.19, 95% confidence interval 1.50 to 6.81, p = 0.003), along with the Killip class and brain natriuretic peptide levels. In conclusion, high hospital levels of CITP, a marker of collagen degradation and ventricular remodeling, are associated with late mortality and other serious clinical events after AMI.
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PMID:Relation of high concentrations of plasma carboxy-terminal telopeptide of collagen type I with outcome in acute myocardial infarction. 1976 54

Increased matrix metalloproteinase (MMP) activity is implicated in proteolysis of extracellular matrix in ischemic stroke. We recently observed intranuclear MMP activity in ischemic brain neurons at early reperfusion, suggesting a possible role in nuclear matrix proteolysis. Nuclear proteins, poly-ADP-ribose polymerase-1 (PARP-1) and X-ray cross-complementary factor 1 (XRCC1), as well as DNA repair enzymes, are important in DNA fragmentation and cell apoptosis. We hypothesized that intranuclear MMP activity facilitates oxidative injury in neurons during early ischemic insult by cleaving PARP-1 and XRCC1, interfering with DNA repair. We induced a 90-min middle cerebral artery occlusion in rats. Increase activity of MMP-2 and -9, detected in the ischemic neuronal nuclei at 3 h, was associated with DNA fragmentation at 24 and 48 h reperfusion. The intranuclear MMPs cleaved PARP-1. Treatment of the rats with a broad-spectrum MMP inhibitor, BB1101, significantly attenuated ischemia-induced PARP-1 cleavage, increasing its activity. Degradation of XRCC1 caused by ischemic insult in rat brain was also significantly attenuated by BB1101. We found elevation of oxidized DNA, apurinic/apyrimidinic sites, and 8-hydroxy-2'-deoxyguanosine, in ischemic brain cells at 3 h reperfusion. BB1101 markedly attenuated the early increase of oxidized DNA. Using tissue from stroke patients, we found increased intranuclear MMP expression. Our data suggest that intranuclear MMP activity cleaves PARP-1 and XRCC1, interfering with oxidative DNA repair. This novel role for MMPs could contribute to neuronal apoptosis in ischemic injuries.
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PMID:Increased intranuclear matrix metalloproteinase activity in neurons interferes with oxidative DNA repair in focal cerebral ischemia. 1984 Feb 23

Blood-brain barrier (BBB) disruption, resulting from loss of tight junctions (TJ) and activation of matrix metalloproteinases (MMPs), is associated with edema formation in ischemic stroke. Cerebral edema develops in a phasic manner and consists of both vasogenic and cytotoxic components. Although it is contingent on several independent mechanisms, involving hypoxic and inflammatory responses, the single effect of prolonged hypoxia on BBB integrity in vivo was not addressed so far. Exposing mice to normobaric hypoxia (8% oxygen for 48 h) led to a significant increase in vascular permeability associated with diminished expression of the TJ protein occludin. Immunofluorescence studies revealed that hypoxia resulted in disrupted continuity of occludin and zonula occludens-1 (Zo-1) staining with significant gap formation. Hypoxia increased gelatinolytic activity specifically in vascular structures and gel zymography identified MMP-9 as enzymatic source. Treatment with an MMP inhibitor reduced vascular leakage and attenuated disorganization of TJ. Inhibition of vascular endothelial growth factor (VEGF) attenuated vascular leakage and MMP-9 activation induced by hypoxia. In conclusion, our data suggest that hypoxia-induced edema formation is mediated by MMP-9-dependent TJ rearrangement by a mechanism involving VEGF. Therefore, inhibition of MMP-9 might provide the basis for therapeutic strategies to treat brain edema.
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PMID:Matrix metalloproteinase-9 mediates hypoxia-induced vascular leakage in the brain via tight junction rearrangement. 1999 18

Effective stroke therapies require recanalization of occluded cerebral blood vessels. However, reperfusion can cause neurovascular injury, leading to cerebral edema, brain hemorrhage, and neuronal death by apoptosis/necrosis. These complications, which result from excess production of reactive oxygen species in mitochondria, significantly limit the benefits of stroke therapies. We have developed a focal stroke model using mice deficient in mitochondrial manganese-superoxide dismutase (SOD2-/+) to investigate neurovascular endothelial damage that occurs during reperfusion. Following focal stroke and reperfusion, SOD2-/+ mice had delayed blood-brain barrier breakdown, associated with activation of matrix metalloproteinase and high brain hemorrhage rates, whereas a decrease in apoptosis and hemorrhage was observed in SOD2 overexpressors. Thus, induction and activation of SOD2 is a novel strategy for neurovascular protection after ischemia/reperfusion. Our recent study identified the signal transducer and activator of transcription 3 (STAT3) as a transcription factor of the mouse SOD2 gene. During reperfusion, activation of STAT3 and its recruitment into the SOD2 gene were blocked, resulting in increased oxidative stress and neuronal apoptosis. In contrast, pharmacological activation of STAT3 induced SOD2 expression, which limits ischemic neuronal death. Our studies point to antioxidant-based neurovascular protective strategies as potential treatments to expand the therapeutic window of currently approved therapies.
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PMID:Reperfusion and neurovascular dysfunction in stroke: from basic mechanisms to potential strategies for neuroprotection. 2015 89

In this study, we examined the relationship between tissue and blood levels of matrix metalloproteinase (MMP)-2 and MMP-9 through gelatin zymography at multiple time points after experimental stroke. We additionally investigated the association between these levels and the evidence of blood-cerebrospinal fluid (CSF) barrier (BCSFB) and blood-brain barrier (BBB) disruption on post-contrast fluid-attenuated inversion-recovery (FLAIR) imaging. Increased plasma MMP-9 was associated with BCSFB disruption at 1h post-reperfusion. Ventricular enhancement ipsilateral to the stroke was 500+/-100%, significantly higher than sham, 24, and 48 h groups. Increased tissue MMP-2 and MMP-9 were associated with BBB disruption at 48 h post-reperfusion. Parenchymal enhancement was 60+/-20% for a volume equivalent to 260+/-80 mm(3). Although the percent enhancement was comparable across groups, the volume of enhancing lesion was significantly higher at 48 h (260+/-80 mm(3), 100%) in comparison to 1 h (8+/-3 mm(3), 3%) and 24 h (51 mm(3), 18%). These findings support the use of imaging markers of BCSFB and BBB status as indirect measures of MMP regulation in the blood and brain tissue. The methods presented herein should be useful in understanding the link between MMPs, barrier integrity, and subsequent hemorrhagic transformation.
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PMID:Increased plasma and tissue MMP levels are associated with BCSFB and BBB disruption evident on post-contrast FLAIR after experimental stroke. 2019 80

Neurovascular injury comprises a wide spectrum of pathophysiology that underlies the progression of brain injury after cerebral ischemia. Recently, it has been shown that activation of the integrin-associated protein CD47 mediates the development of blood-brain barrier injury and edema after cerebral ischemia. However, the mechanisms that mediate these complex neurovascular effects of CD47 remain to be elucidated. Here, we compare the effects of CD47 signaling in brain endothelial cells, astrocytes, and pericytes. Exposure to 4N1 K, a specific CD47-activating peptide derived from the major CD47 ligand thrombospondin-1, upregulated two major neurovascular mediators, vascular endothelial growth factor (VEGF) and matrix metalloproteinase-9 (MMP-9), in brain endothelial cells and astrocytes. No changes were detected in pericytes. These findings may provide a potential mechanism for CD47-induced changes in blood-brain barrier homeostasis, and further suggest that CD47 may be a relevant neurovascular target in stroke.
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PMID:Induction of vascular endothelial growth factor and matrix metalloproteinase-9 via CD47 signaling in neurovascular cells. 2036 20

There is only 1 US Food and Drug Administration-approved drug for acute ischemic stroke: tissue plasminogen activator (tPA). Due to a short time window and fear of intracerebral hemorrhage (ICH), tPA remains underutilized. There is great interest in developing combination drugs to use with tPA to improve the odds of a favorable recovery and to reduce the risk of ICH. Minocycline is a broad-spectrum antibiotic that has been found to be a neuroprotective agent in preclinical ischemic stroke models. Minocycline inhibits matrix metalloproteinase-9, a biomarker for ICH associated with tPA use. Minocycline is also an anti-inflammatory agent and inhibits poly (ADP-ribose) polymerase-1. Minocycline has been safe and well tolerated in the clinical trials conducted to date.
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PMID:Repurposing an old drug to improve the use and safety of tissue plasminogen activator for acute ischemic stroke: minocycline. 2041 Aug 69


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