Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:1.13.11.12 (lipoxygenase)
 8,696 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To determine whether ischemia followed by subsequent reperfusion can induce fetal cerebral oxidative damage, we created a model of fetal ischemia/reperfusion using rats at day 19 of pregnancy. Fetal ischemia was induced by unilateral occlusion of the utero-ovarian artery for 20 min. Reperfusion was achieved by releasing the occlusion and restoring the circulation for 30 min. The opposite uterine horn was used as control. We measured brain mitochondrial respiratory control index (RCI) and the concentration of thiobarbituric acid-reactive substances (TBARS) in each group. Arachidonic acid (AA) peroxidation induced by the incubation of brain microvessel fraction and AA was measured. AA peroxidation was also evaluated with and without aspirin, an inhibitor of cyclooxygenase and phenidone, which inhibits both of cyclooxygenase and lipoxygenase. The RCI significantly decreased by the occlusion with (p < 0.01) or without reperfusion (p < 0.05). The TBARS level significantly increased with occlusion plus reperfusion (p < 0.01). AA peroxidation was significantly greater in the occlusion and occlusion plus reperfusion groups than in the control groups (p < 0. 01). Aspirin did not affect peroxidation, while phenidone significantly inhibited it in a concentration-dependent manner (p < 0.001). Accordingly, ischemia followed by reperfusion is likely to induce fetal cerebral lipid peroxidation, which may inhibit mitochondrial respiratory activity. The phenidone-inhibited enzyme lipoxygenase may participate importantly in this peroxidation.
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PMID:Oxidative damage in fetal rat brain induced by ischemia and subsequent reperfusion. Relation to arachidonic acid peroxidation. 1039 92

The abrupt elevation in the levels of cyclooxygenase or lipoxygenase metabolites of arachidonic acid during cerebral ischemia contributes to neuronal injury. Recently, evidence has accumulated that both excitotoxic and apoptotic features can coexist in ischemia models in vitro and in vivo. In this study, we evaluated whether phenidone, an inhibitor of both cyclooxygenase and lipoxygenase, can provide protection against excitotoxin- or ischemia-induced neurotoxicity, including the staurosporine apoptosis model, in mouse cortical cultures. We examined the protective effect of phenidone against free radical injuries induced by arachidonic acid, hydrogen peroxide, xanthine/xanthine oxidase, Fe2+/ascorbic acid. Pre- and post-treatment with phenidone (300 microM for 24 h) moderately attenuated the neuronal injury induced by 50 microM kainate and oxygen/glucose deprivation (45 min) by 33% and 50%, respectively. It had no effect on NMDA induced injury (150 microM for 5 min). The maximum dose of phenidone (300 microM) reduced the oxidative injury induced by arachidonic acid (71% inhibition), hydrogen peroxide (95% inhibition), xanthine/xanthine oxidase (57% inhibition), and Fe2+/ascorbic acid (99% inhibition) neurotoxicity. Phenidone (300 microM) decreased staurosporine (100 nM)-induced apoptosis to 30%. These results suggest that phenidone may contribute to neuronal survival by modulating oxidative stress, which is involved in the excitotoxic and apoptotic processes occurring under ischemic conditions.
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PMID:Phenidone attenuates oxygen/glucose deprivation-induced neurotoxicity by antioxidant and antiapoptotic action in mouse cortical cultures. 1050 49

Since ebselen is known to have glutathione peroxidase-like activity and inhibitory effects on lipoxygenase and cyclo-oxygenase, we investigated its protective effects against cerebral ischemia in the rat using microdialysis. Ebselen was given through a gastric tube 30 min before occlusion in the experimental groups. Ischemia was induced using 4-vessel occlusion either transiently (20-min occlusion of the arteries followed by reperfusion), or over a prolonged period (120-min occlusion). Extracellular lactate, pyruvate and purine catabolites were sampled using microdialysis and measured by high performance liquid chromatography. During ischemia, the level of lactate, adenosine, inosine and hypoxanthine in the control group increased markedly. The lactate: pyruvate ratio increased during ischemia and decreased after reperfusion. Although the level of lactate and adenosine decreased immediately after reperfusion, those of inosine and hypoxanthine showed delayed decrease. Ebselen reduced the maximum values of lactate and purine catabolites significantly and markedly in transient ischemia. Although it reduced the values significantly in prolonged ischemia, the decrements were less marked than those in transient ischemia. Based on these results we consider ebselen to protect against ischemic metabolic changes and to accelerate the recovery during reperfusion.
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PMID:Effects of ebselen on cerebral ischemia and reperfusion evaluated by microdialysis. 1055 92

1. Unlike some interfaces between the blood and the nervous system (e.g., nerve perineurium), the brain endothelium forming the blood-brain barrier can be modulated by a range of inflammatory mediators. The mechanisms underlying this modulation are reviewed, and the implications for therapy of the brain discussed. 2. Methods for measuring blood-brain barrier permeability in situ include the use of radiolabeled tracers in parenchymal vessels and measurements of transendothelial resistance and rate of loss of fluorescent dye in single pial microvessels. In vitro studies on culture models provide details of the signal transduction mechanisms involved. 3. Routes for penetration of polar solutes across the brain endothelium include the paracellular tight junctional pathway (usually very tight) and vesicular mechanisms. Inflammatory mediators have been reported to influence both pathways, but the clearest evidence is for modulation of tight junctions. 4. In addition to the brain endothelium, cell types involved in inflammatory reactions include several closely associated cells including pericytes, astrocytes, smooth muscle, microglia, mast cells, and neurons. In situ it is often difficult to identify the site of action of a vasoactive agent. In vitro models of brain endothelium are experimentally simpler but may also lack important features generated in situ by cell:cell interaction (e.g. induction, signaling). 5. Many inflammatory agents increase both endothelial permeability and vessel diameter, together contributing to significant leak across the blood-brain barrier and cerebral edema. This review concentrates on changes in endothelial permeability by focusing on studies in which changes in vessel diameter are minimized. 6. Bradykinin (Bk) increases blood-brain barrier permeability by acting on B2 receptors. The downstream events reported include elevation of [Ca2+]i, activation of phospholipase A2, release of arachidonic acid, and production of free radicals, with evidence that IL-1 beta potentiates the actions of Bk in ischemia. 7. Serotonin (5HT) has been reported to increase blood-brain barrier permeability in some but not all studies. Where barrier opening was seen, there was evidence for activation of 5-HT2 receptors and a calcium-dependent permeability increase. 8. Histamine is one of the few central nervous system neurotransmitters found to cause consistent blood-brain barrier opening. The earlier literature was unclear, but studies of pial vessels and cultured endothelium reveal increased permeability mediated by H2 receptors and elevation of [Ca2+]i and an H1 receptor-mediated reduction in permeability coupled to an elevation of cAMP. 9. Brain endothelial cells express nucleotide receptors for ATP, UTP, and ADP, with activation causing increased blood-brain barrier permeability. The effects are mediated predominantly via a P2U (P2Y2) G-protein-coupled receptor causing an elevation of [Ca2+]i; a P2Y1 receptor acting via inhibition of adenyl cyclase has been reported in some in vitro preparations. 10. Arachidonic acid is elevated in some neural pathologies and causes gross opening of the blood-brain barrier to large molecules including proteins. There is evidence that arachidonic acid acts via generation of free radicals in the course of its metabolism by cyclooxygenase and lipoxygenase pathways. 11. The mechanisms described reveal a range of interrelated pathways by which influences from the brain side or the blood side can modulate blood-brain barrier permeability. Knowledge of the mechanisms is already being exploited for deliberate opening of the blood-brain barrier for drug delivery to the brain, and the pathways capable of reducing permeability hold promise for therapeutic treatment of inflammation and cerebral edema.
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PMID:Inflammatory mediators and modulation of blood-brain barrier permeability. 1069 6

The lipoxygenase inhibitor FLM 5011 was used for protection of the coronary microcirculation against ischemia/ reperfusion injury after ligation of the left coronary artery in dogs. Epimyocardial biopsies from ischemic and non-ischemic areas of protected and unprotected areas taken before and after ischemia of 90 min duration and after 180 min reperfusion were analysed by means of electron microscopic morphometry. The ischemic injury consisted in endothelial swelling, luminal blebbing, and formation of irregular protrusions, partly occurrence of pericapillary edema and cellular debris. Plasmalemmal vesicles seemed to decrease in frequency, mitochondria showed focal or generalized degeneration of cristae and matrix. Reperfusion partly deteriorated the damage, partly restoration of ultrastructural parameters was to be observed. There were no significant differences between the infarcted and not infarcted areas. FLM 5011 treatment reduced the endothelial edema, blebbing and occurrence of pericapillary debris and stabilized the number of vesicles. The protection of the mitochondrial cristae and matrix was statistically significant. The results indicate that FLM 5011, under the condition of the experiment, effectively protects the ultrastructure of essential endothelial structures of myocardial microcirculation, explained by the blocking of the noxious leucotrienes and peptidoleucotrienes liberated by the 5-lipoxygenase pathway of the free arachidonic acid and by scavenging of oxygen free radicals. The results must be confirmed by further experiments including biochemical and functional parameters.
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PMID:Lipoxygenase inhibitor FLM 5011, an effective protectant of myocardial microvessels against ischemia-reperfusion injury? An ultrastructural-morphometric study. 1077 50

Arachidonic acid (AA) is metabolized via cyclooxygenase (COX), lipoxygenase (LOX), and cytochrome P-450 (CP450) pathways to a variety of bioactive products. The sensitivity of cardiac afferent endings to AA and its metabolites, especially those derived from LOX and CP450 pathways, is currently unclear. We examined AA-induced activation of cardiac vagal chemosensitive afferents in non- and postischemic hearts in rats and evaluated the relative contributions of the three metabolic pathways to the effects. Epicardial application of AA activated the cardiac afferents dose dependently in both nonischemic and postischemic hearts, with afferent responses greater in the latter condition. In nonischemic hearts, the afferent response to AA was abolished only after simultaneous administration of indomethacin and 17-octadecynoic acid (COX and CP450 inhibitors, respectively). Nordihydroguaiaretic acid (a LOX inhibitor) had no effect on the afferent response to AA. In postischemic hearts, abolition of the afferent response to AA required simultaneous blockade of all three pathways. None of the AA metabolic inhibitors affected resting activity of cardiac afferents in nonischemic hearts, but each suppressed afferent activity during ischemia-reperfusion. Most COX metabolites, CP450 metabolites, and 5-LOX metabolites tested were capable of activating cardiac afferents. The 12-LOX metabolites and 15-LOX metabolites had no effect on afferent activity. These data indicate that in the nonischemic heart, basal AA metabolism does not contribute to resting afferent activity, but AA is capable of activating cardiac afferents via COX and CP450 but not LOX pathways. During ischemia-reperfusion, all three metabolic pathways contribute to activation of cardiac vagal afferents with an enhanced responsiveness to AA. Our results suggest that induction of the 5-LOX pathway contributes to the enhanced sensitivity of cardiac vagal afferents to AA in the ischemic condition.
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PMID:Activation of cardiac afferents by arachidonic acid: relative contributions of metabolic pathways. 1140 73

Intracellular recordings were made from hippocampal CA1 neurons in rat slice preparations. Superfusion with oxygen- and glucose-deprived medium (in vitro ischemia) produced a rapid depolarization approximately 5 min after the onset of the superfusion. Even when oxygen and glucose were reintroduced immediately after rapid depolarization, the membrane depolarized further (persistent depolarization) and reached 0 mV (irreversible depolarization) after 5 min from the reintroduction. The pretreatment of the slice preparation with a phospholipase A2 (PLA2) inhibitor, para-bromophenacyl bromide, or a cytochrome p-450 inhibitor, 17-octadecynoic acid, significantly restored the membrane to the preexposure potential level after the reintroduction of oxygen and glucose. The administration of 14,15-epoxyeicosatrienoic acid or 20-hydroxyeicosatetraenoic acid did not change the latency of the rapid depolarization and did not allow the membrane potential to recover after the ischemic exposure. In contrast, after pretreatment with cyclooxygenase or lipoxygenase inhibitors, such as indomethacin, resveratrol, Dup-697, nordihydroguaiaretic acid, and 3,4-dihydrophenyl ethanol, a minority of neurons tested showed postischemic recovery from the persistent depolarization. Improved recovery was also seen after treatment with the free radical scavengers, edaravone and alpha-tocopherol. These results suggest that the activation of the arachidonic acid cascade via PLA2 and the free radicals produced by arachidonic acid metabolism contribute to the irreversible depolarization produced by in vitro ischemia.
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PMID:Arachidonic acid metabolites contribute to the irreversible depolarization induced by in vitro ischemia. 1291 87

Free fatty acids (FFAs) are elevated in the brain following both ischemic and traumatic injury. Phospholipase activation, with the subsequent release of FFAs from membrane phospholipids, is the likely mechanism. In addition to phospholipases A1, B, C, and D, there are at least 19 groups of PLA2, including multiple cytosolic, calcium independent, and secretory isoforms. Phospholipase activity can be regulated by calcium, by phosphorylation, and by agonists binding to G-protein-coupled receptors. These enzymes normally function in the physiological remodeling of cellular membranes, whereby FFAs are removed by phospholipase activity and then reacylated with a different FFA. However, reductions in the cell's ability to maintain normal metabolic function and the resultant fall in ATP levels can cause the failure of reacylation of membrane phospholipids. Alterations to membrane phospholipids would be expected to compromise many cellular functions, including the ability to accumulate excitotoxic amino acids. This review presents evidence for a central role of phospholipases and their products in the etiology of damage following injury to the brain. Phospholipase expression and activity is increased in animal models of cerebral ischemia and trauma. FFA release from the in vivo rat brain is reduced following the application of selective phospholipase inhibitors, and this inhibition also decreases the severity of cortical damage following forebrain ischemia, focal (middle cerebral artery occlusion) ischemia, and cerebral trauma. Mice with knockouts of PLA2 have decreased infarct volumes. Human data demonstrate a correlation between the elevation of CSF FFAs and worsened outcome following stroke, traumatic brain injury, and subarachnoid hemorrhage. The released FFAs, especially arachidonic and docosahexaenoic acids, together with the production of lysophospholipids, can initiate a chain of events which may be responsible for the development of neuronal damage. Inhibitors of both cyclooxygenase and lipoxygenase pathways have been shown to reduce cerebral deficits following ischemia and trauma. These results suggest therapeutic strategies to reduce morbidity following cerebral injury using selective inhibitors of phospholipases, cyclooxygenases, and lipoxygenases, underlining the need for further investigation of their role in the development of cerebral damage.
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PMID:The role of phospholipases, cyclooxygenases, and lipoxygenases in cerebral ischemic/traumatic injuries. 1451 63

A single exposure to nitric oxide (NO) donors produces a long-lasting hyporesponsiveness to phenylephrine (HRP) in rat aorta rings. Here the authors investigate the role of the endothelial layer in the development of NO-induced HRP and the putative role of endothelium-derived vasoconstrictors in counteracting it. The NO donor S-nitrosoacetyl-D,L-penicillamine (SNAP) induced a dose-dependent reduction in the maximal effect (Emax) of phenylephrine. In rings without endothelium, Emax dropped to 60%, 25%, and 10% of control values 1 h after a 30-min incubation with SNAP (2, 20, and 200 microM, respectively). In contrast, the presence of endothelium prevented the HRP induced by 2 microM SNAP and significantly reduced the HRP elicited by 20 and 200 microM SNAP (Emax reductions of 50% and 65%, respectively), thereby characterizing the endothelium protective effect. Superoxide dismutase (SOD; 100 IU/mL), MnTBAP (a nonenzymatic SOD mimetic; 100 microM), captopril (10 microM), MK886 (a lipoxygenase inhibitor; 10 microM) and BQ 123 (endothelin receptor A antagonist; 1 microM) did not change the endothelium protective effect. Therefore, increased release of vasoconstrictors that would counteract NO-induced loss in phenylephrine responses cannot account for the protective effect of endothelium. In contrast, oxidation of sulphydryls with DTNB prevented the onset of SNAP-induced HRP. A better understanding of mechanisms by which the endothelial layer (or protein sulphydryl groups present in it) exerts its protective effect towards the NO-induced loss in physiological vasoconstriction is likely to be of value in cardiovascular conditions such as ischemia/reperfusion and septic shock.
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PMID:The presence of the endothelial layer reduces nitric oxide-induced hyporesponsiveness to phenylephrine in rat aorta. 1537 Feb 95

Recent studies of ischemia-reperfusion (I/R) injury have focused on the function of neutrophils as well as the actions of inflammatory cytokines. However, few reports address cyclooxygenases (COXs) and lipoxygenases (LOXs). We researched the expression of COXs (COX-1 and COX-2) and LOXs (5-LOX and 12-LOX) in rat renal I/R injury. The right kidney of male Lewis rats was excised, and the left renal artery and vein clamped for a 90-minute ischemia time. Rats were humanely killed at 0, 1.5, 3, 5, and 12 hours after reperfusion. COX and LOX expressions were studied using immunohistostaining. COX-2 and LOX expressions were observed only on endothelial cells of normal kidney. From 1.5 to 5 hours after reperfusion, COX-2 and LOXs expressions gradually intensified on endothelial cells. COX-2 and LOXs expression were most intense on endothelial cells at 5 hours after reperfusion. Twelve hours after reperfusion, necrosis extended throughout the ischemic kidney and nearly all the tubular epithelial cells were destroyed. Thus, at 12 hours after reperfusion, COX-2 and LOXs expressions on endothelial cells became weaker. However, COX-1 expression was not different at every time after reperfusion. COX-2 and LOXs were expressed in a rat model showing renal I/R injury. Several hours after the maximum of COX-2 and LOXs expressions, the maximal renal I/R injury was observed. These results suggest a relationship between COX-2 and LOXs expressions and renal I/R injury.
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PMID:The expression of cyclooxygenases and lipoxygenases in renal ischemia-reperfusion injury. 1551 5


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