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)

Atherosclerosis may cause severe stenosis of the arteries supplying the brain, which induces chronic cerebral hypoperfusion. Although an infarction often occurs in the chronically hypoperfused brain area, it has been uncertain whether the stroke severity is attenuated or increased when further decrease of blood flow occurs. To test the hypothesis that chronic cerebral hypoperfusion is protective against the subsequent severe ischemia, we examined the effect of chronic cerebral hypoperfusion on brains subjected to acute focal ischemia. Spontaneous hypertensive rats were subjected to middle cerebral artery occlusion/reperfusion four weeks after bilateral common carotid artery ligation (BCAL) or sham operation. The rats with BCAL had smaller infarctions, determined by 2,3,5-triphenyltetrazolium hydrochloride staining, and less severe neurologic deficits than those with sham operation. The number of DNA-damaged cells, examined by the in situ nick translation study, was significantly reduced in animals with BCAL. Immunoreactivity for apurinic/apyrimidinic endonuclease/redox factor-1, which plays a role in cellular defense mechanism, was markedly increased in those with BCAL. Indirect evidence of extracellular matrix remodeling, which might be associated with adaptive arteriogenesis or angiogenesis, was obtained in the form of increased matrix metalloproteinase-2 activity in them. These findings provide experimental evidence that chronic cerebral hypoperfusion would be protective against subsequent severe ischemic insults.
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PMID:Preconditioning with chronic cerebral hypoperfusion reduces a focal cerebral ischemic injury and increases apurinic/apyrimidinic endonuclease/redox factor-1 and matrix metalloproteinase-2 expression. 1750 7

Stromal cell-derived factor-1 (SDF1) and its chemokine (CXC motif) receptor 4 (CXCR4), along with matrix metalloproteinases (MMPs), regulate bone marrow stromal cell (BMSC) migration. We tested the hypothesis that a nitric oxide donor, DETA-NONOate, increases endogenous ischemic brain SDF1 and BMSC CXCR4 and MMP9 expression, which promotes BMSC migration into ischemic brain and thereby enhances functional outcome after stroke. C57BL/6J mice were subjected to middle cerebral artery occlusion (MCAo), and 24 hours later, the following were intravenously administered (n = 9 mice per group): (a) phosphate-buffered saline; (b) BMSCs (5 x 10(5)); (c) 0.4 mg/kg DETA-NONOate; (d) combination of CXCR4-inhibition BMSCs with DETA-NONOate; and (e) combination of BMSCs with DETA-NONOate. To elucidate the mechanisms underlying combination-enhanced BMSC migration, transwell cocultures of BMSC with mouse brain endothelial cells (MBECs) or astrocytes were performed. Combination treatment significantly improved functional outcome after stroke compared with BMSC monotherapy and MCAo control, and it increased SDF1 expression in the ischemic brain compared with DETA-NONOate monotherapy and MCAo control. The number of BMSCs in the ischemic brain was significantly increased after combination BMSC with DETA-NONOate treatment compared with monotherapy with BMSCs. The number of engrafted BMSCs was significantly correlated with functional outcome after stroke. DETA-NONOate significantly increased BMSC CXCR4 and MMP9 expression and promoted BMSC adhesion and migration to MBECs and astrocytes compared with nontreatment BMSCs. Inhibition of CXCR4 or MMPs in BMSCs significantly decreased DETA-NONOate-induced BMSC adhesion and migration. Our data demonstrate that DETA-NONOate enhanced the therapeutic potency of BMSCs, possibly via upregulation of SDF1/CXCR4 and MMP pathways, and increased BMSC engraftment into the ischemic brain.
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PMID:Nitric oxide donor upregulation of stromal cell-derived factor-1/chemokine (CXC motif) receptor 4 enhances bone marrow stromal cell migration into ischemic brain after stroke. 1764 Dec 43

While recombinant tissue plasminogen activator (rt-PA) is successfully used for thrombolysis in human stroke, it may increase the risk of hemorrhagic complications. We describe the effects of different doses of rt-PA (saline, 0.9, 9, or 18 mg rt-PA/kg body weight) on the extravasation of blood components following experimental cerebral ischemia (3 h, 24 h reperfusion, suture model) in rats. The damage to the blood-brain barrier and the hemoglobin extravasation were quantified by Western blotting and immunohistochemistry. Both were significantly elevated in the ischemic cortex and basal ganglia. As rt-PA doses rose, the hemoglobin content as well as the damage to the blood-brain barrier in the ischemic side also rose significantly (p<0.001). This correlated significantly with the rising MMP-9 (matrix metalloproteinase) after increasing doses of rt-PA. Despite various benefits, rt-PA is responsible for a dose-dependent increase of edema and hemorrhage after cerebral ischemia. Clinicians should consider using the lowest effective dose of rt-PA in stroke patients.
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PMID:rt-PA causes a dose-dependent increase in the extravasation of cellular and non-cellular blood elements after focal cerebral ischemia. 1764 75

Neuroinflammation is often associated with neurodegenerative diseases, including multiple sclerosis (MS), stroke, Alzheimer's disease, and HIV-1-associated dementia (HAD). The proinflammatory cytokine interleukin-1beta (IL-1beta) is one of the main mediators of inflammation, and IL-1beta expression in the brain is rapidly upregulated in response to acute and chronic insults. IL-1beta is synthesized as biologically inactive precursor (pro-IL-1beta), which is classically processed by caspase-1 [also known as interleukin-converting enzyme (ICE)] into the active, mature cytokine. However, caspase-1/ICE-independent mechanisms of IL-1beta processing have recently been suggested. Here we report that matrix metalloproteinases (MMPs) participate in the maturation process (cleavage and activation) of IL-1beta in an in vivo model of HIV-associated neurodegeneration based on the intracerebroventricular injection of the HIV-1 envelope glycoprotein gp120. We show that, following gp120 exposure, MMP-9 and MMP-2, but not caspase-1/ICE, are rapidly induced. Pharmacological manipulation of MMPs activity, using the broad spectrum MMPs inhibitor GM6001, reduces the increase in IL-1beta immunoreactivity and the neuronal apoptosis induced by gp120. Taken together, these findings point to a critical role for MMPs in IL-1beta increase and consequent neurotoxicity triggered by gp120 in the neocortex of rat and suggest new links between IL-1beta processing and MMP activation during the neuroinflammatory process.
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PMID:Evidence implicating matrix metalloproteinases in the mechanism underlying accumulation of IL-1beta and neuronal apoptosis in the neocortex of HIV/gp120-exposed rats. 1767 75

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

Increased permeability of the blood-brain barrier (BBB) is important in neurological disorders. Neuroinflammation is associated with increased BBB breakdown and brain injury. Tumor necrosis factor (TNF)-alpha is involved in BBB injury and edema formation through a mechanism involving matrix metalloproteinase (MMP) up-regulation. There is emerging evidence indicating that cyclooxygenase (COX) inhibition limits BBB disruption following ischemic stroke and bacterial meningitis, but the mechanisms involved are not known. We used intracerebral injection of TNF-alpha to study the effect of COX inhibition on TNF-alpha-induced BBB breakdown, MMP expression/activity, and oxidative stress. BBB disruption was evaluated by the uptake of (14)C-sucrose into the brain and by magnetic resonance imaging utilizing gadolinium-diethylenetriaminepentaacetic acid as a paramagnetic contrast agent. Using selective inhibitors of each COX isoform, we found that COX-1 activity is more important than COX-2 in BBB opening. TNF-alpha induced a significant up-regulation of gelatinase B (MMP-9), stromelysin-1 (MMP-3), and COX-2. In addition, TNF-alpha significantly depleted glutathione as compared with saline. Indomethacin (10 mg/kg i.p.), an inhibitor of COX-1 and COX-2, reduced BBB damage at 24 h. Indomethacin significantly attenuated MMP-9 and MMP-3 expression and activation and prevented the loss of endogenous radical scavenging capacity following intracerebral injection of TNF-alpha. Our results show for the first time that BBB disruption during neuroinflammation can be significantly reduced by administration of COX inhibitors. Modulation of COX in brain injury by COX inhibitors or agents modulating prostaglandin E(2) formation/signaling may be useful in clinical settings associated with BBB disruption.
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PMID:Cyclooxygenase inhibition limits blood-brain barrier disruption following intracerebral injection of tumor necrosis factor-alpha in the rat. 1770 56

(4-Phenoxyphenylsulfonyl)methylthiirane (inhibitor 1) is a highly selective inhibitor of gelatinases (matrix metalloproteinases 2 and 9), which is showing considerable promise in animal models for cancer and stroke. Despite demonstrated potent, selective, and effective inhibition of gelatinases both in vitro and in vivo, the compound is rapidly metabolized, implying that the likely activity in vivo is due to a metabolite rather than the compound itself. To this end, metabolism of inhibitor 1 was investigated in in vitro systems. Four metabolites were identified by LC/MS-MS and the structures of three of them were further validated by comparison with authentic synthetic samples. One metabolite, 4-(4-thiiranylmethanesulfonylphenoxy)phenol (compound 21), was generated by hydroxylation of the terminal phenyl group of 1. This compound was investigated in kinetics of inhibition of several matrix metalloproteinases. This metabolite was a more potent slow-binding inhibitor of gelatinases (matrix metalloproteinase-2 and matrix metalloproteinase-9) than the parent compound 1, but it also served as a slow-binding inhibitor of matrix metalloproteinase-14, the upstream activator of matrix metalloproteinase-2.
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PMID:Metabolism of a highly selective gelatinase inhibitor generates active metabolite. 1792 22

Inflammation occurs rapidly in response to acute brain insults such as stroke, haemorrhage or trauma, and can be sustained for long periods of time, for example in Alzheimer's or Parkinson's diseases and multiple sclerosis. Experimental evidence indicates that inflammation plays a major role in neurodegeneration under these conditions, and that the cytokine IL-1 (interleukin-1) is a pivotal mediator. IL-1 is expressed rapidly in response to neuronal injury, predominantly by microglia, and elevated levels of endogenous or exogenous IL-1 markedly exacerbate injury. The naturally occurring IL-1RA (IL-1 receptor antagonist) markedly inhibits ischaemic, excitotoxic and traumatic brain injury in rodents, and has shown promise in a Phase II clinical trial in stroke patients. The mechanisms of IL-1 expression, release and action in neurodegeneration are not fully elucidated and appear multiple. Systemic IL-1 markedly enhances ischaemic brain injury via release of neutrophils into circulation, neutrophil adhesion to injured cerebrovasculature and CNS (central nervous system) invasion, and cell death via activation of matrix metalloproteinase-9. IL-1 also influences the release of toxins from glial and endothelial cells. Neuronal responses to excitotoxins and physiological factors may have an impact on neuronal survival. IL-1RA, delivered peripherally, can enter the CNS in animals and humans and has no adverse effects in stroke or subarachnoid haemorrhage patients, but shows potential benefit in acute stroke patients.
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PMID:Interleukin-1 and inflammatory neurodegeneration. 1795 93

Although recombinant tissue plasminogen activator (rt-PA) is successfully used for thrombolysis in human stroke, it may increase the risk of haemorrhagic complications. It was shown that the matrix metalloproteinase (MMP) system is critically involved in basal lamina degradation after middle cerebral artery occlusion and reperfusion following rt-PA administration. We describe the effects of different doses of rt-PA (saline, 0.9, 9, or 18 mg rt-PA/kg body weight) on the MMPs, their specific inhibitors (TIMPs), and also their inducer protein EMMPRIN following experimental cerebral ischemia (3 hours [h], 24 h reperfusion, suture model) in rats. The amount of MMP-2 and -9 was measured by gelatine zymography, TIMP-1 and -2 by reverse gelatine zymography, and the content of EMMPRIN and the basal lamina component collagen type IV by Western blotting. The amount of both MMPs steadily rose with increasing doses of rt-PA (p<0.05). In contrast, their endogenous inhibitors TIMPs decreased (p<0.001). A balance between the proteases and their inhibitors was achieved at the low dose of 0.9 mg/kg rt-PA in the rats, which significantly coincided with the demonstrated protection of collagen type IV degradation at this dose. The inducer protein EMMPRIN increased in parallel to its substrate MMP-2. Exogenous rt-PA leads to an increase of the MMP-inducing system by EMMPRIN, and a rise of the degrading MMPs follows. However, at low to moderate doses of rt-PA the microvascular basal lamina was protected, probably due to inhibition of MMP-2 and MMP-9 by the upregulation of their inhibitors. This strongly supports use of the lowest effective dosage of rt-PA available.
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PMID:Matrix metalloproteinase (MMP) induction and inhibition at different doses of recombinant tissue plasminogen activator following experimental stroke. 1800 May 99

Beneficial effects of thiazolidinediones, peroxisome proliferator-activated receptor gamma (PPARgamma) agonists, on cardiovascular injuries have been reported. However, the effects of these agonists on left ventricular (LV) hypertrophy have not been clarified. To investigate whether pioglitazone improves LV hypertrophy, we used 32-week-old stroke-prone spontaneously hypertensive rats (SHR-SP) that had been treated or not treated with pioglitazone (10 mg/kg/day) for 8 weeks, and Wistar Kyoto rats (WKY). We evaluated LV geometry by echocardiography; myocyte hypertrophy, tissue fibrosis, and appearance of myofibroblasts by histological examination; mRNA expression by real-time polymerase chain reaction (PCR); protein expression by Western blot; activities of matrix metalloproteinase (MMP) by zymography; and production of reactive oxygen species (ROS) by electron spin resonance spectroscopy or thiobarbituric acid reactive substances (TBARS). SHR-SP showed concentric hypertrophy of the LV, but WKY did not. The myocyte diameter, fraction of tissue fibrosis, and number of myofibroblasts were greater in SHR-SP. mRNA expressions of collagen type I and type III, tissue growth factor (TGF)-beta1, and brain natriuretic peptide (BNP); protein expression of connective tissue growth factor (CTGF); activities of MMP2 and MMP9; and ROS were increased in SHR-SP. Pioglitazone did not decrease blood pressure, but partially normalized LV geometry in addition to decreasing myocyte diameter, interstitial fibrosis and number of myofibroblasts; mRNA levels of collagen type I and BNP; MMP2 activity; and protein level of CTGF. However, the mRNA level of collagen type III and TGF-beta1, MMP9 activity, and ROS production were not improved. In conclusion, pioglitazone reversed the concentric LV remodeling independently from blood pressure or oxidative stress in chronic hypertension.
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PMID:Beneficial effects of pioglitazone on left ventricular hypertrophy in genetically hypertensive rats. 1803 80


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