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

We assessed the effects of melatonin, a powerful scavenger of oxygen free radicals, on ischemia/reperfusion-induced oxidative damage to mitochondria in the rat placenta. In Wistar rats at day 19 of pregnancy, feto-placental ischemia was induced by occluding both utero-ovarian arteries for 20 min. Reperfusion was achieved by releasing the occlusion and restoring circulation for 30 min. Melatonin solution or the vehicle alone was injected intraperitoneally at dose of 10 mg/kg 1 hr before occlusion. Sham-ischemic animals were treated with vehicle. Each group consisted of 10 pregnant rats. We measured placental mitochondrial respiratory control index (RCI; a marker of mitochondrial respiratory activity), the ratio of the added adenosine 5-diphosphate (ADP) concentration to consumption of oxygen during state 3 respiration (ADP/O), and the concentration of thiobarbituric acid reactive substances (TBARS) in each group. RCI and ADP/O were significantly decreased by ischemia/reperfusion, while TBARS were increased. Melatonin prevented these changes. These results indicate that exogenous melatonin protects against ischemia/reperfusion-induced oxidative damage to mitochondria in rat placenta. Melatonin could be useful in treating preeclampsia and possibly other clinical states involving excess free radical production, such as fetal growth restriction and fetal hypoxia.
J Pineal Res 2001 Sep
PMID:Melatonin protects against oxidative mitochondrial damage induced in rat placenta by ischemia and reperfusion. 1155 74

Oxygen free radicals are considered to be important components involved in the pathophysiological tissue alterations observed during ischemia-reperfusion (I/R). In this study, we investigated the putative protective effects of melatonin treatment on renal I/R injury. Wistar albino rats were unilaterally nephrectomized and subjected to 45 min of renal pedicle occlusion followed by 1, 3, 6, 24, 48 hr or 1 wk of reperfusion. Melatonin (10 mg/kg, s.c.) or vehicle was administered twice, 15 min prior to ischemia and immediately before the reperfusion period. At the end of the reperfusion periods, rats were decapitated. Kidney samples were taken for histological examination or the determination of renal malondialdehyde (MDA) and glutathione (GSH) levels, myeloperoxidase (MPO) activity and protein oxidation (PO). Serum creatinine and blood urea nitrogen (BUN) concentrations were measured for the evaluation of renal function. The results revealed that I/R induced nephrotoxicity, as evidenced by increases in BUN and creatinine levels at each time point, was reversed by melatonin treatment. The decrease in GSH and increases in MDA, MPO and PO induced by I/R indicated that renal injury involves free radical formation. As melatonin administration reversed these oxidant responses, improved renal function and microscopic damage, it seems likely that melatonin protects kidney tissue against oxidative damage.
J Pineal Res 2002 Mar
PMID:The protective effect of melatonin on renal ischemia-reperfusion injury in the rat. 1207 69

Cardiac arrhythmias during ischemia-reperfusion (I/R) are believed to be related to free radicals generated in the heart especially during the period of reperfusion. The pineal secretory product, melatonin, is known to be a potent free radical scavenger and its pharmacological concentrations have been shown to reduce the I/R-induced arrhythmias in isolated rat hearts. However, the physiological role of melatonin in the prevention of these arrhythmias is unknown. Rats were pinealectomized (Px) or sham-operated (non-Px) (control) 2 months before the I/R studies. To produce arrhythmias, left main coronary artery was occluded for 7 min, followed by 7 min reperfusion, in anesthetized rats. The incidence of mortality resulted from irreversible ventricular fibrillation (VF) was found significantly higher in the Px rats (63%) than in the control group (25%). Melatonin administration (0.4 mg/kg, either before ischemia or reperfusion) to Px rats significantly reduced the incidence of total (irreversible plus reversible) and irreversible VF and returned them to control values. On the other hand, melatonin administration (0.4 and 4 mg/kg) to non-Px rats failed to attenuate the I/R arrhythmias, significantly. These results suggest that physiological melatonin concentrations are important to reduce the I/R-induced VF and mortality, while pharmacological concentrations of melatonin did not increase its beneficial effect on these arrhythmias. As melatonin levels have been reported to decrease with age, melatonin replacement therapy may attenuate the incidence of sudden cardiac death especially in older patients.
J Pineal Res 2002 Apr
PMID:Effects of physiological and pharmacological concentrations of melatonin on ischemia-reperfusion arrhythmias in rats: can the incidence of sudden cardiac death be reduced? 1207 4

In the present study, double fluorescence staining combined with confocal laser scanning microscopy analysis were used to examine the effects of melatonin on ischemia-induced neuronal DNA strand breaks and its possible mechanisms in a transient middle cerebral artery (MCA) occlusion model. Results showed that melatonin dose-dependently reduced infarct areas and decreased both DNA double and single strand breaks (DSB and SSB) and enhanced cell viability in the peri-ischemic brain regions. Furthermore, Bcl-2 induction in the ischemic brain was further enhanced by melatonin treatment. Double staining analysis indicated that the cells costained for Bcl-2 and TdT-mediated-deoxyuridine triphosphate (dUTP) nick-end labeling (TUNEL), a DSB marker, displayed a relative regular morphology compared with the cells only stained with TUNEL. Transient ischemia induced an expression of excision repair cross-complementing factor 6 (ERCC6) mRNA, a gene essential for the preferential repair of nuclear excision repair, in the injured neurons. Double labeling showed that ERCC6 only co-localized with proliferating cell nuclear antigen (PCNA), a member of the nuclear excision repair complex, but not with TUNEL. Melatonin further and statistical significantly up-regulated ERCC6 mRNA expression in the peri-ischemic region of rat brains. The results suggest that neuroprotection by melatonin against ischemic injury may be related to modulation of apoptosis and DNA repair capacity.
J Pineal Res 2002 Aug
PMID:Neuroprotection by melatonin against ischemic neuronal injury associated with modulation of DNA damage and repair in the rat following a transient cerebral ischemia. 1212 85

The production of oxygen free radicals has been strongly implicated as an important pathophysiological mechanism mediating myocardial ischemia/reperfusion (I/R) injury. Various antioxidants have cardioprotective effects. Melatonin, an indoleamine synthesized by the pineal gland, is a potent antioxidant and a direct free radical scavenger. This is the first in vivo study to evaluate the effect of melatonin (0.5, 1.0, and 5.0 mg/kg, i.v. bolus) on myocardial I/R injury in anesthetized Sprague-Dawley rats. Results demonstrate that pretreatment with intermediate or high doses of melatonin (1.0 and 5.0 mg/kg) at 10 min before left coronary artery occlusion markedly suppressed ventricular tachycardia (VT) and ventricular fibrillation (VF), while reducing the total number of premature ventricular contractions and total duration of VT and VF that occurred during the 45-min ischemic period. Pretreatment with melatonin dramatically improved survival rate of rats when compared with the I/R-only group. After 1-hr reperfusion, melatonin caused a significant reduction in infarct size when compared with I/R-only group. Meanwhile, pretreatment with melatonin (1.0 mg/kg) significantly reduced superoxide anion production and myeloperoxidase activity; the latter is an index of neutrophil infiltration in the ischemic myocardium. Additionally, pretreatment with melatonin (1.0 and 5.0 mg/kg) significantly attenuated ventricular arrhythmias and mortality elicited by reperfusion following 5-min ischemia. In conclusion, melatonin suppresses ischemia- and reperfusion-induced ventricular arrhythmias and reduces infarct size resulting from I/R injury. The pronounced cardioprotective activity of melatonin may be mediated by its antioxidant activity and by its capacity for neutrophil inhibition in myocardial I/R.
J Pineal Res 2002 Sep
PMID:Protective effects of melatonin on myocardial ischemia/reperfusion injury in vivo. 1215 40

The brain normally derives most of its energy from the aerobic oxidation of glucose and therefore it must be nourished with a rich supply of both glucose and oxygen. Interference with the blood supply, such as in ischemia, could shift the brain to search for another source of energy and to spare its own glucose. Ischemia results not only in energy fuel disturbance, but also in free radical formation and Ca(2+) homeostasis disruption. Therefore, our investigations studied the influence of ischemia on energy fuels, on some natural free radical scavengers, and the relationship between the changes of these parameters in brain and blood. Each of these was also studied under the influence of melatonin, a well-known free radical scavenger, and nifedipine, a Ca(2+)-channel blocker and antioxidant, during ischemia followed by reperfusion (I/R). Adult male Wistar rats were subjected to global ischemia by occlusion of the two carotid arteries for 1 hr (group I), followed by reperfusion for another hour in group II. Drugs were injected after ischemia (group I), and before or after reperfusion onset in the second group. Two series of animals were used. In the first series the effect of the two drugs on the activity of superoxide dismutase (SOD), glutathione reductase (GR), and lactate dehydrogenase (LDH) was investigated in the cytosolic fraction of four brain areas, viz., cortex (CC), thalamus/hypothalamus (T/TH), midbrain (MB) and medulla, pons and cerebellum (MPC). Moreover, the level of both SOD and GR in the erythocytes of these rats was also estimated. In the second series, we studied the effect of each drug on the content of glucose and beta-hydroxybutyrate (beta-HB) in whole brain, in addition to the plasma levels of glucose, beta-HB and lactate. The results showed that (i), ischemia elevated the brain levels of LDH and beta-HB, as well as the plasma level of glucose, beta-HB, lactate and erythocytic GR. Conversely, it lowered glucose, SOD and GR levels in the brain; (ii), reperfusion reversed the ischemic effect on all the previously altered parameters except for plasma levels of lactate and glucose; (iii), melatonin (10 mg/kg, i.p) and nifedipine (1.5 mg/kg, i.p), restored the energy fuel levels in the brain of ischemic and I/R rats, as well as the ischemic effect on the erythocyte activities of SOD and GR. Furthermore, both drugs reversed I/R effect on the cytosolic activities of the antioxidant enzymes. We conclude that melatonin and nifedipine are both neuroprotective with improvement in the antioxidant system and energy fuels.
J Pineal Res 2002 Sep
PMID:Effect of melatonin and nifedipine on some antioxidant enzymes and different energy fuels in the blood and brain of global ischemic rats. 1215 42

Myocardial ischemia-reperfusion (I/R) represents a clinically relevant problem associated with thrombolysis, angioplasty and coronary bypass surgery. I/R injury is believed to be a consequence of free radical generation in the heart especially during the period of reperfusion. The pineal secretory product, melatonin, is known to be a potent free radical scavenger and pharmacological concentrations have been shown to reduce the I/R-induced cardiac damage in isolated rat hearts. However, the physiological role of melatonin in the prevention of this damage is unknown. Rats were pinealectomized or sham-operated (control) 2 months before the I/R studies. To produce cardiac damage, the left main coronary artery was occluded for 30 min, followed by 120 min reperfusion, in anesthetized rats. Infarct size, expressed as the percentage of the risk zone, was found significantly higher in pinealectomized rats (49+/-3.4%) than in the control group (34+/-3.6%). Melatonin administration (4 mg/kg, either before ischemia or reperfusion) to pinealectomized rats significantly reduced the infarct size values and returned them to the control values. On the other hand, melatonin administration (4 mg/kg) to sham-operated rats failed to attenuate significantly the I/R-induced infarct size. These results suggest that physiological melatonin concentrations are important in reducing the I/R-induced myocyte damage, while pharmacological concentrations of melatonin did not add to the beneficial effect. As melatonin levels have been reported to decrease with age, melatonin replacement therapy may attenuate I/R-induced myocardial injury, especially in older patients.
J Pineal Res 2002 Nov
PMID:Myocardial ischemia-reperfusion in rats: reduction of infarct size by either supplemental physiological or pharmacological doses of melatonin. 1239 May 6

Melatonin, a pineal secretory product, synthesized from l-tryptophan, has received increased attention because of its antioxidative and immunomodulatory properties. It has been detected in the gut and shown to protect the gastric mucosa, and liver from acute damage, but the role of melatonin in the protection of the pancreas against acute inflammation is not clear. The aim of this study was to investigate the effects of melatonin and its precursor, l-tryptophan, on caerulein-induced pancreatitis (CIP) and on ischemia/reperfusion (I/R)-provoked pancreatitis in rats. CIP was induced by subcutaneous infusion of caerulein to the rats (25 microg/kg). I/R was induced by clamping of the inferior splenic artery for 30 min followed by 2 hr of reperfusion. Melatonin (10, 25 or 50 mg/hr) or l-tryptophan (50, 100 or 250 mg/kg) was given as a bolus intraperitoneal (i.p.) injection 30 min prior to the onset of pancreatitis. CIP and I/R were confirmed by histologic examination and manifested by typical pancreatic edema, by an increase of plasma levels of amylase (by 500% in CIP and by 40% in I/R) and the pro-inflammatory tumor necrosis factor alpha (TNFalpha) (by 500%). Lipid peroxidation products such as malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE), were increased several fold in the pancreas CIP and I/R, whereas pancreatic blood flow (PBF) was significantly reduced in these animals. Pretreatment of rats subjected to CIP or to I/R with melatonin (25 or 50 mg/kg i.p.) or l-tryptophan (100 or 250 mg/kg i.p.) significantly reduced pancreatic edema, plasma levels of amylase and TNFalpha and diminished pancreatic MDA + 4-HNE contents, while enhancing PBF, pancreatic integrity and plasma levels of the anti-inflammatory interleukin 10 (IL-10). This was accompanied by a marked and dose-dependent rise of plasma melatonin immunoreactivity. Gene expression of N-acetyl transferase, an enzyme involved in melatonin biosynthesis, was detected in the pancreas of normal rats and was significantly enhanced in the rats with CIP. We conclude that exogenous melatonin, and that produced from l-tryptophan, attenuates pancreatic damage induced by CIP or by I/R and this effect may be attributable to the reduction in lipid peroxidation and TNFalpha release combined with an increase of plasma anti-inflammatory IL-10 in rats with acute pancreatitis.
J Pineal Res 2003 Jan
PMID:Protective effect of melatonin and its precursor L-tryptophan on acute pancreatitis induced by caerulein overstimulation or ischemia/reperfusion. 1248 71

Melatonin is a potent antioxidant and free radical scavenger. Previously, we showed that a single injection of melatonin before ischemia significantly reduced the infarct volume in both permanent and 3-hr middle cerebral artery occlusion (MCAO) rat stroke models. Nitric oxide (NO) and other free radicals play an important role in the pathogenesis of cerebral ischemia, and they have been postulated to mediate the breakdown of the blood-brain barrier (BBB) during ischemia. In this study, we evaluated the influence of melatonin, given at 30 min before MCAO, on brain NO concentration and BBB breakdown. Brain NO concentration was measured at 15 min of MCAO using electron paramagnetic resonance spectroscopy. BBB breakdown at 3 hr of reperfusion following 3 hr of MCAO was assessed using Evans blue extravasation. The relative brain NO concentration was increased to 141.69 +/- 9.71% (mean +/- S.E.M.; n = 9) at 15 min of MCAO. Treatment with melatonin at 1.5, 5, or 50 mg/kg significantly reduced the brain NO concentration to 104.20 +/- 11.20% (n = 8), 55.67 +/- 5.58% (n = 11), and 104.86 +/- 12.56% (n = 9), respectively. Melatonin at 5 mg/kg did not affect Evans blue extravasation. Our results suggest that a single injection of melatonin protects against focal cerebral ischemia partly via inhibition of ischemia-induced NO production and that this regimen does not prevent BBB breakdown following ischemia-reperfusion.
J Pineal Res 2003 Mar
PMID:Melatonin reduces nitric oxide level during ischemia but not blood-brain barrier breakdown during reperfusion in a rat middle cerebral artery occlusion stroke model. 1256 2

The brain is highly susceptible to focal or global ischemia. Unless ischemia is promptly reversed, reperfusion produces further cerebral damage. Acute thrombolysis or defibrinogenation is effective only in selective patients with ischemic stroke and carries a significant risk of bleeding complications. Whereas numerous neuroprotectants were shown to be effective in experimental studies, none of them have been shown to work in clinical trials. The major pathogenetic mechanisms of ischemia/reperfusion injury include excitotoxicity, disturbed calcium ion homeostasis, overproduction of nitric oxide and other free radicals, inflammation, and apoptosis. Nitric oxide and other free radicals, the key mediators of excitotoxicity and disturbed calcium ion homeostasis, cause direct injury and also indirectly damage via inflammation and apoptosis. Melatonin is a potent free radical scavenger and an indirect antioxidant. This mini review summarizes the in vivo and in vitro evidence that melatonin protects against ischemia/reperfusion injury. There is convincing evidence from the literature that melatonin treatment is highly effective in different in vivo and in vitro models of excitotoxicity or ischemia/reperfusion in multiple animal species. Melatonin is safe and non-toxic in humans, and its administration via the oral route or intravenous injection is convenient. While more experimental studies should be conducted to further explore the neuroprotective mechanisms and to document any synergistic or additive protection from combining melatonin with thrombolysis, defibrinogenation or other neuroprotectants, interested clinical scientists should consider planning phase II and III studies to confirm the benefit of melatonin as an acute stroke treatment or a preventive measure for stroke patients.
J Pineal Res 2003 Apr
PMID:The utility of melatonin in reducing cerebral damage resulting from ischemia and reperfusion. 1261 73


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