Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In traditional Oriental medicine, Uncaria rhynchophylla has been used to lower blood pressure and to relieve various neurological symptoms. However, scientific evidence related to its effectiveness or precise modes of action has not been available. Thus, in the current study, we evaluated neuroprotective effects of U. rhynchophylla after transient global ischemia using 4-vessel occlusion model in rats. Methanol extract of U. rhynchophylla administered intraperitoneally (100-1000 mg/kg at 0 and 90 min after reperfusion) significantly protected hippocampal CA1 neurons against 10 min transient forebrain ischemia. Measurement of neuronal cell density in CA1 region at 7 days after ischemia by Nissl staining revealed more than 70% protection in U. rhynchophylla-treated rats compared to saline-treated animals. In U. rhynchophylla-treated animals, induction of cyclooxygenase-2 in hippocampus at 24 hr after ischemia was significantly inhibited at both mRNA and protein levels. Furthermore, U. rhynchophylla extract inhibited TNF-alpha and nitric oxide production in BV-2 mouse microglial cells in vitro. These anti-inflammatory actions of U. rhynchophylla extract may contribute to its neuroprotective effects.
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PMID:Neuroprotection by methanol extract of Uncaria rhynchophylla against global cerebral ischemia in rats. 1217 11

Opioids confer biphasic (early and late) cardioprotection against myocardial infarction by opening mitochondrial ATP-sensitive K(+) channels. It is unknown whether cyclooxygenase-2 (COX-2), which mediates ischemia-induced late preconditioning, also mediates opioid-induced cardioprotection. Isolated perfused rat hearts were subjected to 20 min of global ischemia followed by 20 min of reperfusion. BW-373U86 (BW), a delta-opioid receptor agonist, was administered 1, 12, or 24 h before death. Recovery of left ventricular developed pressure (LVDP) after ischemia-reperfusion improved when BW was administered 1 or 24 h before ischemia (control: 57 +/- 8, BW 1 h: 75 +/- 5, BW 24 h: 85 +/- 6%) but not when it was administered 12 h before (60 +/- 5%). Levels of 6-keto-PGF(1alpha) (a stable metabolite of PGI(2)) in coronary effluent after 20 min of reperfusion were higher with 24-h BW pretreatment than in controls (1,053 +/- 92 vs. 724 +/- 81 pg/ml), whereas 6-keto-PGF(1alpha) levels at baseline did not differ. Administration of a selective COX-2 inhibitor, NS-398, abolished the late phase of cardioprotection (recovery of LVDP, 53 +/- 8%) and attenuated the increase in PGI(2) (706 +/- 138 pg/ml) but did not block the early phase of cardioprotection. The selective COX-1 inhibitor SC-560 did not affect either phase of protection. Western immunoblotting revealed upregulation of PGI(2) synthase protein 24 h after BW administration without changes in COX-1 and COX-2 protein levels. In conclusion, the late (but not the early) phase of delta-opioid receptor-induced preconditioning is mediated by COX-2. A functional coupling between COX-2 and upregulated PGI(2) synthase appears to underlie this cardioprotective phenomenon in the rat.
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PMID:COX-2-derived prostacyclin mediates opioid-induced late phase of preconditioning in isolated rat hearts. 1238 83

Cyclooxygenase-2 is involved in the inflammatory component of the ischemic cascade, playing an important role in the delayed progression of the brain damage. The present study evaluated the pharmacological effects of the selective cyclooxygenase-2 inhibitor nimesulide on delayed neuronal death of hippocampal CA1 neurons following transient global cerebral ischemia in gerbils. Administration of therapeutically relevant doses of nimesulide (3, 6 and 12 mg/kg; i.p.) 30 min before ischemia and at 6, 12, 24, 48 and 72 h after ischemia significantly (P<0.01) reduced hippocampal neuronal damage. Treatment with a single dose of nimesulide given 30 min before ischemia also resulted in a significant increase in the number of healthy neurons in the hippocampal CA1 sector 7 days after ischemia. Of interest is the finding that nimesulide rescued CA1 pyramidal neurons from ischemic death even when treatment was delayed until 24 h after ischemia (34+/-9% protection). Neuroprotective effect of nimesulide is still evident 30 days after the ischemic episode, providing the first experimental evidence that cyclooxygenase-2 inhibitors confer a long-lasting neuroprotection. Oral administration of nimesulide was also able to significantly reduce brain damage, suggesting that protective effects are independent of the route of administration. The present study confirms the ability of cyclooxygenase-2 inhibitors to reduce brain damage induced by cerebral ischemia and indicates that nimesulide can provide protection when administered for up to 24 h post-ischemia.
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PMID:Neuroprotective efficacy of nimesulide against hippocampal neuronal damage following transient forebrain ischemia. 1239 3

Aberrations in neural signaling, converging to and diverging from oxidative metabolism and blood supply, contribute to the initiation and maintenance of inflammatory responses, neuronal degeneration, and age-related cognitive decline in Alzheimer's disease (AD). Hypoxia/ischemia triggers phospholipase A2, leading to the accumulation of free arachidonic and docosahexaenoic acids (AA, DHA), as well as that of lysophospholipids. Some of these bioactive lipid messengers in turn give rise to several downstream lipid messengers, such as platelet-activating factor (PAF) and ecosanoids (prostaglandins and leukotrienes). Eicosanoid synthesis is highly regulated in hypoxia and in reperfusion subsequent to ischemia. As one of the consequences, mitochondrial function is disrupted and reactive oxygen species (ROS) both contribute to the expansion of cellular inflammatory responses and reduce the expression of genes required to maintain synaptic structure and function. On the other hand, pro-inflammatory genes are up-regulated. One of these, the inducible cyclooxygenase-2 (COX-2), along with oxygen-starved mitochondria, comprise the major sources of ROS in the brain during hypoxia, ischemia, and reperfusion. One outcome is a sustained metabolic stress that drives progressive dysfunction, apoptosis and/or necrosis, and brain cell death. How hypoxia modulates oxygen-sensitive gene expression is not well understood. Pro-inflammatory gene families that contribute to neurodegeneration are transiently activated in part by the heterodimeric oxygen-sensitive DNA-binding proteins nuclear factor for kappa B (NF-kappaB) and hypoxia-inducible factor-alpha (HIF-1alpha). Here the authors summarize current studies supporting the hypothesis that synaptically-derived lipid messengers play significant roles in ischemic stroke and that hypoxia is an important contributor to the onset and progression of AD neurodegeneration.
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PMID:Hypoxia signaling to genes: significance in Alzheimer's disease. 1242 61

Signal transducers and activators of transcription (STAT) proteins are a family of transcription factors that play a crucial role in growth and differentiation in a variety of cell types. Among them, STAT1, which is expressed in the brain and directly activated by reactive oxygen species, participates in the regulation of cytokine-signaling and cellular responses, particularly to interferon-gamma. Very little, however, is known about the importance of STAT1 during brain injury. The authors found that STAT1 was phosphorylated at tyrosine and serine727 and translocated into neuronal nuclei within hours after middle cerebral artery occlusion. At later time points, STAT1 immunoreactivity colocalized with TUNEL-positive neurons, thereby suggesting a role in cell death. In mice genetically deficient in STAT1 expression, the volume of ischemic brain injury was reduced, neurologic deficits were less severe, and TUNEL-positive neurons were also less numerous compared with wild-type mice. STAT1-knockout mice showed increased phosphorylated Akt and decreased procaspase-3 cleavage. Major strain differences in phosphorylated STAT3 or cyclooxygenase-2 protein expression were not found after ischemia. These results indicate that STAT1 is activated and translocated within ischemic neurons and may contribute to brain injury by regulating transcription and phosphorylation of proteins related to apoptosis and cell death.
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PMID:STAT1 is activated in neurons after ischemia and contributes to ischemic brain injury. 1243 88

Cyclooxygenase-2 (COX-2) plays an important role in the development of injury during cerebral ischemia and inhibition of its activity can reduce infarct size. COX-2 expression during acute ischemia is caused by activation of post-synaptic glutamate receptors, which occurs during spreading depression and ischemic depolarization. Both of these phenomena cause a reduction in the apparent diffusion coefficient of water (ADC), which can be detected with diffusion-weighted magnetic resonance imaging. The reduction is believed to be caused by cellular swelling that occurs as cells depolarize. The goal of this work was to determine the spatial relationship between cyclooxygenase-2 mRNA (cox-2) expression, c-fos mRNA expression and ADC reduction during acute focal cerebral ischemia. Adult rats were subjected to either 30- or 60-min permanent occlusion of the middle cerebral artery. A 2-Tesla scanner was used to acquire diffusion-weighted echo-planar images throughout the ischemic period, which were used to calculate ADC maps. Cox-2 and c-fos mRNA were detected with (35)S in situ hybridization. The results indicate that, for rats subjected to 60-min ischemia, cox-2 was observed in superficial layers of cortex, where transient ADC reduction and c-fos expression were observed. The same was true for most rats subjected to 30-min ischemia. However, in a small number of rats of the 30-min group, cox-2 mRNA expression was observed in regions exhibiting transient and persistent ADC reduction with no c-fos expression. The results suggest that cox-2 mRNA expression during acute MCA occlusion is caused by either or both spreading depression and transient ischemic depolarization.
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PMID:Cyclooxygenase-2 mRNA expression is associated with c-fos mRNA expression and transient water ADC reduction detected with diffusion MRI during acute focal ischemia in rats. 1253 84

The Janus kinase (JAK)-signal transducers and activators of transcription (STAT) pathway is a stress-responsive mechanism that transduces signals from the cell surface to the nucleus, thereby modulating gene expression. Recent studies have demonstrated that myocardial ischemia and reperfusion induce rapid activation of this pathway. Although the functional consequences of this event remain to be elucidated, there is emerging evidence that JAK-STAT signaling plays an important role in the development of the cardioprotected phenotype associated with ischemic preconditioning. Specifically, brief episodes of myocardial ischemia/reperfusion activate JAK1 and JAK2, followed by recruitment of STAT1 and STAT3, resulting in transcriptional upregulation of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), which then mediate the infarct-sparing effects of the late phase of preconditioning. The present review focuses on this novel cardioprotective role of JAK-STAT signaling and on its potential exploitation for developing therapeutic strategies aimed at limiting ischemia/reperfusion injury.
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PMID:Role of the JAK-STAT pathway in protection against myocardial ischemia/reperfusion injury. 1258 43

We determined whether up to 24 h of ischemia could induce the expression of cyclooxygenase-2 (COX-2) in the brain of nonhuman primates. Randomized animals were subjected to either a 2 h ischemia (group II; n=3) or a 24 h ischemia (group III; n=3). Three animals in group I served as controls. In group III, regional cerebral blood flow (CBF) and the cerebral glucose metabolic rate (CMRglc) were evaluated using positron emission tomography. Upregulation of COX-2 mRNA expression was observed after 2 h of ischemia, but disappeared by 24 h in the ischemic temporal cortex, in which both CMRglc and CBF were markedly reduced. In the ischemic parietal cortex, where CMRglc was preserved, COX-2 expression persisted even 24 h after ischemia. This study is the first to demonstrate neuronal COX-2 induction within potentially viable hypoperfused brain areas in nonhuman primates.
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PMID:Post-ischemic cyclooxygenase-2 expression is regulated by the extent of cerebral blood flow reduction in non-human primates. 1267 38

Although the inducible isoform of NO synthase (iNOS) mediates late preconditioning (PC), it is unknown whether iNOS gene transfer can replicate the cardioprotective effects of late PC, and the role of this protein in myocardial ischemia is controversial. Thus, the cDNA for human iNOS was cloned behind the Rous sarcoma virus (RSV) promoter to create adenovirus (Ad) 5/iNOS lacking E1, E2a, and E3 regions. Intramyocardial injection of Ad5/iNOS in mice increased local iNOS protein expression and activity and markedly reduced infarct size. The infarct-sparing effects of Ad5/iNOS were at least as powerful as those of ischemic PC. The increased iNOS expression was associated with increased cyclooxygenase-2 (COX-2) protein expression and prostanoid levels. Pretreatment with the COX-2-selective inhibitor NS-398 completely abrogated the infarct-sparing actions of Ad5/iNOS, demonstrating that COX-2 is an obligatory downstream effector of iNOS-dependent cardioprotection. We conclude that gene transfer of iNOS (an enzyme commonly thought to be detrimental) affords powerful cardioprotection the magnitude of which is equivalent to that of late PC. This is the first report that upregulation of iNOS, in itself, is sufficient to reduce infarct size. The results provide proof-of-principle for gene therapy against ischemia/reperfusion injury, which increases local myocardial NO synthase levels without the need for continuous intravenous infusion of NO donors and without altering systemic hemodynamics. The data also reveal the existence of a close coupling between iNOS and COX-2, whereby induction of the former enzyme leads to secondary induction of the latter, which in turn mediates the cytoprotective effects of iNOS. We propose that iNOS and COX-2 form a stress-responsive functional module that mitigates ischemia/reperfusion injury.
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PMID:Gene therapy with inducible nitric oxide synthase protects against myocardial infarction via a cyclooxygenase-2-dependent mechanism. 1270 42

Ascorbic acid (vitamin C) has been suggested to protect cerebral tissue in a variety of pathophysiological situations such as head trauma, ischemia or Alzheimer's disease. Most of these protective actions have been attributed to the antioxidative capacity of ascorbic acid. Besides the presence of elevated levels of oxygen radicals, prostaglandins produced by neurones and microglial cells seem to play an important role in prolonged tissue damage. We investigated whether ascorbic acid alone inhibits prostaglandin E2 (PGE2) synthesis and may augment the inhibitory effect of acetylsalicylic acid on prostaglandin synthesis. Ascorbic acid dose-dependently inhibited PGE2 synthesis in lipopolysaccharide-treated primary rat microglial cells (IC50 = 3.70 micro m). In combination with acetylsalicylic acid (IC50 = 1.85 micro m), ascorbic acid augmented the inhibitory effect of acetylsalicylic acid on PGE2 synthesis (IC50 = 0.25 micro m in combination with 100 micro m ascorbic acid). Ascorbic acid alone or in combination with acetylsalicylic acid did not inhibit cyclooxygenase-2 (COX-2) protein synthesis but inhibited COX-2 enzyme activity. Our results show that ascorbic acid and acetylsalicylic acid act synergistically in inhibiting PGE2 synthesis, which may help to explain a possible protective effect of ascorbic acid in various brain diseases.
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PMID:Synergistic inhibitory effect of ascorbic acid and acetylsalicylic acid on prostaglandin E2 release in primary rat microglia. 1280 37


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