UMLS:C0022116 - FACTA Search

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Query: UMLS:C0022116 (ischemia)
91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Results from several studies indicate that cyclooxygenase-2 (COX-2) is involved in ischemic brain injury. The purpose of this study was to evaluate the neuroprotective effects of the selective COX-2 inhibitor nimesulide on cerebral infarction and neurological deficits in a standardized model of transient focal cerebral ischemia in rats. Three doses of nimesulide (3, 6 and 12 mg/kg; i.p.) or vehicle were administered immediately after stroke and additional doses were given at 6, 12, 24, 36 and 48 h after ischemia. In other set of experiments, the effect of nimesulide was studied in a situation in which its first administration was delayed for 3-24 h after ischemia. Total, cortical and subcortical infarct volumes and functional outcome (assessed by neurological deficit score and rotarod performance) were determined 3 days after ischemia. The effect of nimesulide on prostaglandin E(2) (PGE(2)) levels in the injured brain was also investigated. Nimesulide dose-dependently reduced infarct volume and improved functional recovery when compared to vehicle. Of interest is the finding that neuroprotection conferred by nimesulide (reduction of infarct size and neurological deficits and improvement of rotarod performance) was also observed when treatment was delayed until 24 h after ischemia. Further, administration of nimesulide in a delayed treatment paradigm completely abolished PGE(2) accumulation in the postischemic brain, suggesting that COX-2 inhibition is a promising therapeutic strategy for cerebral ischemia to target the late-occurring inflammatory events which amplify initial damage.
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PMID:Wide therapeutic time window for nimesulide neuroprotection in a model of transient focal cerebral ischemia in the rat. 1506 40

Microglia are the major inflammatory cells in the central nervous system and become activated in response to brain injuries such as ischemia, trauma, and neurodegenerative diseases including Alzheimer's disease (AD). Moreover, activated microglia are known to release a variety of proinflammatory cytokines and oxidants such as nitric oxide (NO). Minocycline is a semisynthetic second-generation tetracycline that exerts anti-inflammatory effects that are completely distinct form its antimicrobial action. In this study, the inhibitory effects of minocycline on NO and prostaglandin E2 (PGE2) release was examined in lipopolysaccharides (LPS)-challenged BV2 murine microglial cells. Further, effects of minocycline on inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) expression levels were also determined. The results showed that minocycline significantly inhibited NO and PGE2 production and iNOS and COX-2 expression in BV2 microglial cells. These findings suggest that minocycline should be evaluated as potential therapeutic agent for various pathological conditions due to the excessive activation of microglia.
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PMID:Inhibitory action of minocycline on lipopolysaccharide-induced release of nitric oxide and prostaglandin E2 in BV2 microglial cells. 1508 37

Cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) have been previously implicated in the late phase of cardioprotection associated with opioid-induced and ischemic preconditioning (IPC) in conscious rabbits and COX-2 in isolated rat hearts pretreated with an exogenous delta opioid agonist. However, it is not know if both iNOS and COX-2 mediate the late phase of cardioprotection induced by opioids in the intact blood-perfused rat. Therefore, we investigated the role of COX-2 and iNOS in the delayed phase of protection mediated by delta opioid receptor activation. Rats were pretreated 24 hours prior to an occlusion/reperfusion protocol with the selective non-peptide delta opioid agonists, BW373U86 (BW) and SNC-121 (SNC). NS-398, a selective COX-2 inhibitor was administered after the 24-hour recovery period just prior to index ischemia. The selective iNOS inhibitors, S-methylthiourea (SMT) and aminoguanidine (AG), were administered in conjunction with opioid pretreatment or were also given 24 hours after opioid administration just prior to index ischemia. COX-2 inhibition by NS-398 given 24 hours after opioid administration attenuated the protective effects of both BW and SNC (46 +/- 6 vs. 13 +/- 3 and 51 +/- 5 vs. 29 +/- 2, p < 0.001, respectively). Similarly, inhibition of iNOS following 24 hours of treatment with opioids also attenuated the protective effects of BW and SNC. However, the delayed protective effects of the opioids were not attenuated by pretreatment with the iNOS inhibitors 24 hours prior to the infarct protocol. These results suggest that both COX-2 and iNOS are mediators of delayed protection induced by non-peptide delta opioid agonists. It appears that the trigger effect is not dependent on the activity of iNOS or COX-2 but the late phase of cardioprotection is dependent on the upregulation of these enzymes.
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PMID:COX-2 and iNOS in opioid-induced delayed cardioprotection in the intact rat. 1512 May 66

Chronic cerebral hypoperfusion, a mild ischemic condition is associated with advancing age and severity of dementia; however, no unanimous therapy has been established to alleviate related neurological symptoms. We imposed a permanent, bilateral occlusion of the common carotid arteries of rats (n=18) to create cerebral hypoperfusion. A mitochondrial ATP-sensitive K+ channel opener diazoxide (DZ, 5 mg/kg) or its solvent dimethyl sulphoxide (DMSO) were administered i.p. (0.25 ml) on five consecutive days after surgery. Sham-operated animals (n=18) served as control for the surgery, while nontreated rats were used as control for the treatments. Three months after the onset of cerebral hypoperfusion, the rats were tested in a hippocampus-related learning paradigm, the Morris water maze. Subsequently, the animals were sacrificed and neurons, astrocytes and microglia were labeled with immunocytochemistry in the dorsal hippocampus. DMSO and diazoxide dissolved in DMSO restored cerebral hypoperfusion-related learning dysfunction and prevented cyclooxygenase-2-positive neuron loss in the dentate gyrus. Cerebral hypoperfusion led to reduced astrocyte proliferation, which was not clearly affected by the treatment. Microglia activation was considerably enhanced by cerebral hypoperfusion, which was completely prevented by diazoxide dissolved in DMSO, but not by DMSO alone. We conclude that diazoxide can moderate ischemia-related neuroinflammation by suppressing microglial activation. Furthermore, we suggest that DMSO is a neuroprotective chemical in ischemic conditions, and it must be considerately used as a solvent for water-insoluble compounds in experimental animal models.
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PMID:Diazoxide and dimethyl sulphoxide prevent cerebral hypoperfusion-related learning dysfunction and brain damage after carotid artery occlusion. 1514 63

Transient glucose deprivation (TGD) has been shown to induce a resistance to a subsequent ischemia and reperfusion injury in the heart. Induction of cyclooxygenase-2 (COX-2) and heme oxygenase-1 (HO-1) is known to mediate the powerful defensive adaptation of the heart against oxidative stress. In this study, we found that a 30-min incubation in the absence of glucose resulted in a rapid increased expression of COX-2 and HO-1 in cardiac fibroblasts as examined by real-time quantitative polymerase chain reaction (PCR) and western blot analysis. Interestingly, TGD increased the generation of reactive oxygen species (ROS) and caused the transient phosphorylation of p38 mitogen-activated protein kinase (MAPK) as well as the translocation of protein kinase C (PKC)- from the cytosolic to the membrane fraction. However, no significant change in the distribution of PKC-delta isoform was observed compared with the control. Pretreatment of the cells with an antioxidant, N-acetylcysteine (NAC), resulted in the inhibition of p38 MAPK phosphorylation and PKC- translocation during TGD. In addition, the induction of COX-2 and HO-1 expression by TGD was prevented by pretreatment with NAC or SB203580, a p38 MAPK inhibitor. Surprisingly, pretreatment with chelerythrine, an inhibitor of PKC, strongly augmented the HO-1 mRNA expression but blocked the COX-2 mRNA induction by TGD. These results demonstrate that briefly removing glucose from cultured cardiac fibroblasts induces COX-2 and HO-1 expression via generation of ROS and p38 MAPK phosphorylation, while the translocation of PKC- to the membrane fraction may participate in the induction of COX-2 but not in the HO-1 expression.
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PMID:Transient glucose deprivation causes upregulation of heme oxygenase-1 and cyclooxygenase-2 expression in cardiac fibroblasts. 1515 23

Cyclooxygenase-2 inhibitors protect against excitotoxicity in vitro yet provide conflicting results in in vivo models of ischemia. To bridge the gap in understanding the discrepancies among these studies, the effects of different cyclooxygenase-2 inhibitors were studied in an in vitro model of ischemia. Oxygen-glucose deprivation (OGD) induced cyclooxygenase-2 protein expression in neuronal cortical cultures. Cyclooxygenase-2 inhibitors exhibited opposing effects on neuronal death induced by OGD. The acidic sulfonamides, N-(2-cyclohexyloxy-4-nitrophenyl) methanesulfonamide (NS-398) and N-(4-nitro-2-phenoxyphenyl)-methanesulfonamide (nimesulide), aggravated neuronal death by enhancing OGD-induced increases in extracellular glutamate and intracellular Ca2+ levels. In contrast, 1-[(4-methylsulfonyl)phenyl]-3-tri-fluoromethyl-5-(4-fluorophenyl)pyrazole (SC-58125) dose-dependently protected cultures against OGD by suppressing increases in extracellular glutamate and intracellular Ca2+ levels. The NS-398-induced aggravation of neuronal death was lost if the inhibitor was added only following the OGD. The timing of inhibitor application also determined its effects on N-methyl-D-aspartate (NMDA)-induced excitoxicity. NS-398 was protective when added both during and post-NMDA exposure, but not if NS-398 was also applied for 60 min prior to the insult. In contrast, SC-58125 afforded protection against NMDA in the presence or absence of a pre-incubation period. This study demonstrates that certain cyclooxygenase-2 inhibitors have opposing effects on neuronal survival depending on the timing of application and the nature of the insult. These results may account for the discrepancies among previous studies which used different inhibitors and different models of neurotoxicity.
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PMID:Opposing effects of cyclooxygenase-2 selective inhibitors on oxygen-glucose deprivation-induced neurotoxicity. 1518 63

Inflammatory response following cerebral ischemia/reperfusion plays a key pathogenic role in ischemic cerebral damage. Nitric oxide (NO), cyclooxygenase-2 (COX-2) and myeloperoxidase (MPO) are important inflammatory mediators. Neuronal NO synthase (nNOS) is a major initial source of excessive NO during ischemia/reperfusion. Induction of COX-2 and infiltration of polymorphonuclear cells expressing MPO are critical factors in delayed inflammatory damage. Previously, we demonstrated that administration of melatonin before ischemia significantly reduced the infarct volume in a rat middle cerebral artery occlusion (MCAO) stroke model. In this study, we examined the effect of pretreatment with melatonin at 5 mg/kg on the immunoreactivity (ir) for nNOS, COX-2, MPO, and glial fibrillary acidic protein (GFAP) at 24, 48, and 72 hr after right-sided endovascular MCAO for 1 hr in adult male Sprague-Dawley rats. Melatonin did not affect the hemodynamic parameters. When compared with rats with sham MCAO, ischemia/reperfusion led to an ipsilateral increase in cells with positive ir for nNOS (similar at all times) and in ir-GFAP (similar at all times). Ischemia/reperfusion led to appearance of cells with positive ir for COX-2 (greatest at 24 hr with a tendency to increase again at 72 hr) or MPO (greatest at 24 hr). A single dose of melatonin significantly lessened the ipsilateral increase in cells with positive ir for nNOS, COX-2 or MPO, but did not influence the ipsilateral change in ir-GFAP. Our results suggest that melatonin treatment mediates neuroprotection against ischemia/reperfusion injury partly via inhibition of the consequential inflammatory response.
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PMID:Pretreatment with melatonin exerts anti-inflammatory effects against ischemia/reperfusion injury in a rat middle cerebral artery occlusion stroke model. 1529 66

Hepatic ischemia and reperfusion (I/R) predisposes the liver to secondary stresses such as endotoxemia, possibly via dysregulation of the hepatic microcirculation secondary to an imbalanced regulation of the vascular stress genes. In this study, the effect of hepatic I/R on the hepatic vasoregulatory gene expression in response to endotoxin was determined. Rats were subjected to 90 min of hepatic ischemia and 6 h of reperfusion. Lipopolysaccharide (LPS, 1 mg/kg) was injected intraperitoneally after reperfusion. Plasma and liver samples were obtained 6 h after reperfusion for serum aminotransferase assays and RT-PCR analysis of the mRNA for the genes of interest: endothelin-1 (ET-1), its receptors ET A and ET B, endothelial nitric oxide synthase (eNOS), inducible nitric oxide synthase (iNOS), heme oxygenase-1 (HO-1), cyclooxygenase-2 (COX-2), and tumor necrosis factor-alpha (TNF-alpha). The activities of serum aminotransferases were significantly increased in the I/R group. This increase was markedly potentiated by LPS treatment. The ET-1 mRNA was increased by LPS alone, and this increase was significantly greater in both the I/R alone and I/R + LPS groups compared to the sham. There were no significant differences in ET A receptor mRNA levels among any of the experimental groups. ET B mRNA was increased by both LPS alone and I/R alone, with no significant difference between the I/R alone and I/R + LPS groups. The eNOS and HO-1 transcripts were increased by I/R alone and further increased by I/R + LPS. The iNOS mRNA levels were increased by I/R alone, but increased significantly more by both LPS alone and I/R + LPS compared to I/R alone. The TNF-alpha mRNA levels showed no change with I/R alone, but were increased by both LPS alone and I/R + LPS. The COX-2 expression was increased significantly by I/R alone and significantly more by I/R + LPS. Taken collectively, significantly greater induction of the vasodilator genes over the constriction forces was observed with I/R + LPS. These results may partly explain the increased susceptibility of ischemic livers to injury as a result of endotoxemia.
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PMID:Expression of hepatic vascular stress genes following ischemia/reperfusion and subsequent endotoxemia. 1535 6

The selective cyclooxygenase-2 (COX-2) inhibitor has been reported to have antiinflammatory, neuroprotective, and antioxidant effects in ischemia models. In this study, the authors examined whether a selective COX-2 inhibitor (celecoxib) reduces cerebral inflammation and edema after intracerebral hemorrhage (ICH), and whether functional recovery is sustained with longer treatment. ICH was induced using collagenase in adult rats. Celecoxib (10 or 20 mg/kg) was administered intraperitoneally 20 minutes, 6 hours, and 24 hours after ICH and then daily thereafter. Seventy-two hours after ICH induction, the rats were killed for histologic assessment and measurement of brain edema and prostaglandin E2. Behavioral tests were performed before and 1, 7, 14, 21, and 28 days after ICH. The brain water content of celecoxib-treated rats decreased both in lesioned and nonlesioned hemispheres in a dose-dependent manner. Compared with the ICH-only group, the number of TUNEL-positive, myeloperoxidase-positive, or OX42-positive cells was decreased in the periphery of hematoma and brain prostaglandin E2 level was reduced in the celecoxib-treated group. Celecoxib-treated rats recovered better by the behavioral tests at 7 days after ICH throughout the 28-day period, and the earlier the drug was administered, the better the functional recovery. Evidence of similar effects in an autologous blood-injected model showed that direct collagenase toxicity was not the major cause of inflammation or cell death. These data suggest that celecoxib treatment after ICH reduces prostaglandin E2 production, brain edema, inflammation, and perihematomal cell death in the perihematomal zone and induces better functional recovery.
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PMID:Celecoxib induces functional recovery after intracerebral hemorrhage with reduction of brain edema and perihematomal cell death. 1536 23

Limitation of the stomach damage by its earlier brief ischemia and reperfusion before prolonged ischemia is defined as gastric ischemic preconditioning but whether such brief ischemia of remote organs like heart or liver can also attenuate the gastric damage caused by longer and severe ischemia-reperfusion remains unknown. The cardiac, hepatic and gastric preconditioning were induced by brief ischemia (occlusion of coronary, hepatic and celiac arteries twice for 5 min) applied 30 min before 3 h of ischemia/reperfusion. Standard 3 h ischemia-reperfusion of the stomach produced numerous gastric lesions, decreased gastric blood flow and mucosal prostaglandin E2 generation and increased expression and plasma release of interleukin-1beta and tumor necrosis factor-alpha (TNF-alpha). These effects were significantly attenuated by brief cardiac, hepatic and gastric preconditioning which upregulated cyclooxygenase-2 mRNA but not cyclooxygenase-1 mRNA. The protective effects of brief gastric, cardiac and hepatic preconditioning were attenuated by selective cyclooxygenase-1 and cyclooxygenase-2 inhibitors and capsaicin denervation. We conclude that brief ischemia of remote preconditioning such as heart or liver protects gastric mucosa against severe ischemia-reperfusion-induced gastric lesions as effectively as local preconditioning of the stomach itself via the mechanism involving prostaglandin derived from cyclooxygenase-1 and cyclooxygenase-2 and the activation of sensory nerves releasing calcitonin gene-related peptide (CGRP) combined with the suppression of interleukin-1beta and TNF-alpha expression and release.
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PMID:Ischemic preconditioning of remote organs attenuates gastric ischemia-reperfusion injury through involvement of prostaglandins and sensory nerves. 1536 68

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