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)

The aim of the present study was to investigate the protective effect of the pineal secretary product melatonin in a model of splanchnic artery occlusion shock (SAO). SAO shock was induced in rats by clamping both the superior mesenteric artery and the celiac trunk for 45 min, followed thereafter by release of the clamp (reperfusion). At 60 min after reperfusion, animals were sacrificed for tissue histological examination and biochemical studies. There was a marked increase in the oxidation of dihydrorhodamine 123 to rhodamine (a marker of peroxynitrite-induced oxidative processes) in the plasma of the SAO-shocked rats after reperfusion, but not during ischemia alone. Immunohistochemical examination demonstrated a marked increase in the immunoreactivity to nitrotyrosine, an index of nitrogen species such as peroxynitrite, in the necrotic ileum in shocked rats. SAO-shocked rats developed a significant increase of tissue myeloperoxidase and malondialdehyde activity, and marked histological injury to the distal ileum. SAO shock was also associated with a significant mortality (0% survival at 2 hr after reperfusion). Reperfused ileum tissue sections from SAO-shocked rats showed positive staining for P-selectin, which was mainly localized in the vascular endothelial cells. Ileum tissue sections obtained from SAO-shocked rats with anti-intercellular adhesion molecule (ICAM-1) antibody showed a diffuse staining. Melatonin (applied at 3 mg/kg, 5 min prior to reperfusion, followed by an infusion of 3 mg/kg per hr), significantly reduced ischemia reperfusion injury in the bowel as evaluated by histological examination. This prevented the infiltration of neutrophils into the reperfused intestine, is evidenced by reduced myeloperoxidase activity and reduced lipid peroxidation. This was evaluated by malondialdehyde activity which reduced the production of peroxynitrite during reperfusion, markedly reduced the intensity and degree of P-selectin and ICAM-1 in tissue section from SAO-shocked rats and improved their survival. Taken together, our results clearly demonstrate that melatonin treatment exerts a protective effect and part of this effect may be due to inhibition of the expression of adhesion molecule and peroxynitrite-related pathways and subsequent reduction of neutrophil-mediated cellular injury.
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PMID:Beneficial effects of melatonin in a rat model of splanchnic artery occlusion and reperfusion. 1062 2

BACKGROUND: Melatonin, a hormone, has gained popularity and is being used by millions for a variety of indications. There are few data on its safety or its effects on hemodynamics and coronary blood flow. Also, studies have confirmed that melatonin is a potent antioxidant. Therefore, it may be capable of scavenging free radicals during the reperfusion phase after a heart attack. This study evaluates the safety of melatonin with regard to its cardiovascular effects and tests the hypothesis that melatonin might be protective in the setting of ischemia-reperfusion and reduce myocardial infarct size. METHODS AND RESULTS: Anesthetized rabbits were treated with melatonin (n = 8, 10 mg/kg, intravenously) 10 minutes before coronary artery occlusion (CAO) and again 15 minutes before reperfusion. Control rabbits received vehicle (n = 8). All rabbits underwent 30 minutes of occlusion and 3 hour reperfusion. Both before and during CAO, melatonin did not alter heart rate compared with control (185 +/- 7 beats/min v 181 +/- 7 before; and 179 +/- 5 v 181 +/- 9 during, respectively, P = NS) or blood pressure (70 +/- 4 mmHg v 66 +/- 6 before and 59 +/- 4 v 58 +/- 5 during, respectively, P = NS). Regional myocardial blood flow (RMBF) was similar before CAO in the melatonin group (1.18 +/- 0.17 mL/min/g) versus the control group (1.15 +/- 0.10 mL/min/g). Infarct size, expressed as a fraction of ischemic risk zone, was similar in the melatonin (0.29 +/- 0.03) and control groups (0.29 +/- 0.06, P = NS). At a higher dose of 50 mg/kg in treated (n = 7) versus control (n = 7) rabbits, melatonin treatment did not alter heart rate (204 +/- 14 in melatonin group v 181 +/- 5 in controls, P = NS) or blood pressure (80 +/- 11 in melatonin v 66 +/- 7 in controls, P = NS) when compared with control. Melatonin at this dose also did not affect infarct size, 0.38 +/- 0.06, when compared with control, 0.34 +/- 0.07, P = NS. CONCLUSION: Melatonin's effects on hemodynamics and coronary blood flow were neutral, and it did not exacerbate myocardial ischemia or necrosis in this model. Melatonin appears to be a safe drug with no apparent effects on the cardiovascular system in this model.
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PMID:The Effect of Melatonin on Hemodynamics, Blood Flow, and Myocardial Infarct Size in a Rabbit Model of Ischemia-Reperfusion. 1068 93

We evaluated melatonin's antioxidative effect on the free radical-induced impairment of nitric oxide production in the human umbilical artery, which may play an important role in fetal hypoxia and ischemia during preeclampsia. Umbilical artery sections with intact endothelium were obtained from healthy pregnant women who were delivered between 37 and 40 wk of gestation. The production of nitric oxide in the umbilical arteries was stimulated by adding L-arginine followed by incubation for 60 min. Nitric oxide concentrations were estimated by measuring nitrite ions (NO2), using high-performance liquid chromatography. Prior to the addition of L-arginine, the segments were treated with hydrogen peroxide (H2O2) alone (1, 10, 100 microM), or were pretreated with either 50 mM mannitol or melatonin (20, 100, 500 microM) before adding H2O2. Changes in L-arginine-induced NO2 production were expressed as a percentage of NO2 production at the end of preincubation. NO2 production was significantly increased by incubating the umbilical artery sections with L-arginine (P<0.01). Treatment with H2O2 significantly reduced L-arginine-induced NO2-production in a concentration-dependent manner (P<0.01). Pretreatment with melatonin significantly increased NO2 production that had been decreased by H2O2 in a concentration-dependent manner (P<0.01). Similarly, pretreatment with mannitol reversed the H2O2-induced reduction in NO2- production (P<0.001). These results indicate that H2O2 may impair nitric oxide synthesis in the endothelium of human umbilical arteries. Melatonin significantly suppresses the H2O2-induced inhibition effect of nitric oxide production, most likely through its ability to scavenge hydroxyl radicals.
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PMID:Melatonin protects against the free radical-induced impairment of nitric oxide production in the human umbilical artery. 1073 4

There has been increased interest in melatonin recently, since it was shown to be a potent scavenger of toxic free radicals. Melatonin has been found to be effective in protecting against pathological states due to reactive oxygen species release. The present study was performed in order to determine whether melatonin or 5-methoxy-carbonylamino-N-acetyl-tryptamine (5-MCA-NAT), a structurally related indole compound, protect against ischemia-reperfusion injury in the isolated rat heart. Wistar rats were treated in vivo with either melatonin (1 or 10 mg/kg, i.p.) or 5-MCA-NAT (10 mg/kg, i.p.) or their vehicle, 30 min before their hearts were excised and perfused according to the Langendorff technique. Two different protocols were then applied. In the first one, a regional ischemia (5 min)-reperfusion (30 min) sequence was performed in order to record incidence and duration of reperfusion arrhythmias. In the second one, infarct size was assessed after a regional ischemia (30 min)-reperfusion (120 min) sequence. Results show a spectacular protection against ischemia-reperfusion injuries (on arrhythmias as well as on infarct size) in rats pre-treated with 10 mg/kg of melatonin or 5-MCA-NAT. In conclusion, both melatonin and its structural analog, 5-MCA-NAT, appear to confer protection against ischemia-reperfusion injury in the isolated rat heart. This observation suggests that melatonin could have a potential clinical application in the treatment of myocardial ischemia, even if the mechanisms underlying this protection remain to be determined.
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PMID:Protective effects of melatonin against ischemia-reperfusion injury in the isolated rat heart. 1079 67

The role of glial cells in neuronal death has become a major research interest. Glial cell activation has been demonstrated to accompany cerebral ischemia. However, there is disagreement whether such gliosis is a cell death or a neuroprotective response. In the present study, we examined alterations in glial cell responses to the reported neuroprotective action of the free radical scavenger, melatonin, against cerebral ischemia. Adult male Wistar rats were given oral injections of either melatonin (26 micromol/rat) or saline just prior to 1 h occlusion of the middle cerebral artery (MCA), then once daily for 11 or 19 consecutive days. At 11 and 19 days after reperfusion of the MCA, randomly selected animals were killed and their brains removed for immunohistochemical assays. Melatonin significantly enhanced survival of glial cells (as revealed by glial cell specific markers, glial fibrillary acidic protein and aquaporin-4 immunostaining) at both time periods postischemia, and the preservation of these glial cells in the ischemic penumbra corresponded with a markedly reduced area of infarction (detected by immunoglobulin G and hematoxylin-eosin staining), as well as increased neuronal survival. The ischemia-induced locomotor deficits were partially ameliorated in melatonin-treated animals. In vitro replications of ischemia by serum deprivation or by exposure to free radical-producing toxins (sodium nitroprusside and 3-nitropropionic acid) revealed that melatonin (10 microg/ml or 100 microM) treatment of pure astrocytic cultures significantly reduced astrocytic cell death. These results suggest a potential strategy directed at enhancing glial cell survival as an alternative protective approach against ischemic damage.
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PMID:Glial cell survival is enhanced during melatonin-induced neuroprotection against cerebral ischemia. 1087 23

Recent studies have demonstrated that melatonin is a scavenger of oxyradicals and peroxynitrite and an inhibitor of nitric oxide (NO) production. NO, peroxynitrite (formed from NO and superoxide anion), and poly (ADP-Ribose) synthetase (PARS) have been implicated as mediators of neuronal damage following focal ischemia. In the present study, we have investigated the effects of melatonin treatment in Mongolian gerbils subjected to cerebral ischemia. Treatment of gerbils with melatonin (10 mg kg(-1), 30 min before reperfusion and 1, 2, and 6 hr after reperfusion) reduced the formation of post-ischemic brain edema, evaluated by water content. Melatonin also attenuated the increase in the brain levels malondialdehyde (MDA) and the increase in the hippocampus of myeloperoxidase (MPO) caused by cerebral ischemia. Positive staining for nitrotyrosine was found in the hippocampus of Mongolian gerbils subjected to cerebral ischemia. Hippocampus tissue sections, from Mongolian gerbils subjected to cerebral ischemia, also showed positive staining for PARS. The degrees of staining for nitrotyrosine and for PARS were markedly reduced in tissue sections obtained from animals that received melatonin. Melatonin treatment increased survival and reduced hyperactivity linked to neurodegeneration induced by cerebral ischemia and reperfusion. Histological observations of the pyramidal layer of CA-1 showed a reduction of neuronal loss in animals that received melatonin. These results show that melatonin improves brain injury induced by transient cerebral ischemia.
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PMID:Protective effects of melatonin in ischemic brain injury. 1106 44

Oxidative stress, favoring disease progression by a rapid degeneration of endothelial cell function is deeply involved in Systemic Sclerosis (SSc) pathogenesis. Raynaud's phenomenon (RP), present in 90% of patients with SSc, provoking frequent daily episodes of hypoxia-reperfusion injury, produces several episodes of free radicals-mediated endothelial derangement. These events results in a positive feedback effect of luminal narrowing and ischemia and therefore to the birth of a vicious cycle of oxygen free radicals (OFR) generation, leading to endothelial damage, intimal thickening and fibrosis. Thus ischemia and reperfusion are two criticals events that may induce oxidative stress and inactivation of antioxidant enzymes. In RP and SSc, a reduced concentration of ascorbic acid, alpha-tocopherol and beta-carotene as well as low values of Selenium have been reported. This antioxidative potential deficiency increases the propensity to oxidative stress. favoring the development of injury mediated by OFR. We reviewed several antioxidant compounds, aiming at their capacity of reverting endothelial dysfunction and damage, scavenging lipid peroxidation and reducing multiple episodes of hypoxia-reperfusion injury. In order to interrupt SSc vicious cycle, we propose a main strategy for SSc treatment by a supplementation of antioxidants and different kind of drugs with antioxidant property, such as Lazaroids, Resveratrol, Melatonin and Probucol.
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PMID:Emerging potentials for an antioxidant therapy as a new approach to the treatment of systemic sclerosis. 1115 92

Systemic administration of melatonin (5 to 20 mg/kg) has been reported to inhibit the induction of acute gastric mucosal lesions by stress or ischemia-reperfusion in rats. We recently demonstrated that intracisternal (i.c.) melatonin at low doses (1 to 100 ng) dose-dependently decreased acid and pepsin outputs in rats. The aim of the present study was to further investigate the peripheral and central roles of melatonin in gastric mucosal defense. Using a radioimmunoassay, we measured melatonin concentrations in the plasma and cerebrospinal fluid (CSF) of the cisterna magna in rats subjected to water immersion restraint stress and given intraperitoneal (i.p.) or i.c. injection of melatonin. Water immersion restraint stress was followed by a significant duration-related increase in peripheral plasma melatonin levels; the stress similarly produced a time-dependent increase in the extent of gastric mucosal lesions. Administration of melatonin (1 or 10 mg/kg, i.p., or 100 ng/10 microl, i.c.) significantly reduced the extent of stress-induced gastric damage, by 46%, 67%, and 54%, respectively. The effective i.c. dose of melatonin was at least 10,000-fold smaller than the effective i.p. dose. Melatonin levels in plasma and CSF after the i.p. injection of melatonin at 10 mg/kg were dramatically higher than those after the i.c. injection of vehicle or 100 ng of melatonin. Our results suggest that the peripheral gastroprotective action of melatonin should be investigated with due regard to these central effects.
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PMID:Melatonin's gastroprotective and antistress roles involve both central and peripheral effects. 1122 76

Melatonin has been shown to act as a radical scavenger in various chemical and biological model systems in vitro. Kinetic evidence is now provided showing that melatonin inhibits the irreversible degradation of hemoglobin (Hb), when incubated with red blood cells exposed to the oxidant activity of cumene hydroperoxide (cumOOH). A decrease of heme loss and accumulation of soluble methemoglobin (met-Hb) are explained in terms of the interaction of the indoleamine with perferryl Hb (Hb[Fe(IV)=O]), a highly reactive Hb-derived radical species responsible for the irreversible Hb degradation. A kinetic study, in pure chemical solution, showed that melatonin can effectively reduce the oxoferryl heme group of perferryl-Hb, thus forming met-Hb. The reducing activity of melatonin is of the same order as that of Trolox, the water-soluble vitamin E analog. This novel radical-scavenging activity of melatonin may contribute to the previously observed protective effects of melatonin in ischemia-reperfusion injury.
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PMID:Reaction of melatonin with hemoglobin-derived oxoferryl radicals and inhibition of the hydroperoxide-induced hemoglobin denaturation in red blood cells. 1155 66

We investigated the effects of melatonin on ischemia/reperfusion-induced oxidative damage to mitochondria in fetal rat brain. The utero-ovarian arteries were occluded bilaterally for 20 min in female Wistar rats on day 19 of pregnancy to induce fetal ischemia. Reperfusion was achieved by releasing the occlusion and restoring circulation for 30 min. A sham operation was performed in control rats. Melatonin (10 mg/kg) or vehicle was injected intraperitoneally 60 min prior to occlusion. We measured the respiratory control index (RCI) and the adenosine 5-diphosphate (ADP)/oxygen ratio as indicators of mitochondrial respiratory activity, as well as the concentration of thiobarbituric acid-reactive substances (TBARS) in the mitochondria of fetal brain. Ischemia/reperfusion significantly elevated the concentration of TBARS and significantly reduced the RCI as well as the ADP/oxygen ratio. Melatonin treatment reversed the ischemia/reperfusion-induced reductions in the RCI (2.29 +/- 0.06-2.64 +/- 0.09, P < 0.05) and in the ADP/oxygen ratio (1.48 +/- 0.03-1.57 +/- 0.02, P < 0.05), and also reduced the elevation in concentration of TBARS (11.00 +/- 0.34-7.57 +/- 0.74 nM/mg protein, P < 0.01), resulting in values similar to those in untreated, sham-ischemic animals. The results indicate that administration of melatonin to pregnant rats may prevent ischemia/reperfusion-induced oxidative mitochondrial damage in fetal rat brain.
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PMID:Melatonin protects against ischemia/reperfusion-induced oxidative damage to mitochondria in fetal rat brain. 1155 73


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