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

Melatonin's actions in organisms are more widespread than originally envisaged. Over three decades ago, the changing pattern of nocturnal melatonin production was found to be the signal for the annual cycle of reproduction in photoperiodic species. Since then, melatonin's actions also have been linked to circadian rhythms, immune function, sleep, retinal physiology and endocrine functions in general. In recent years, however, the sphere of influence of melatonin was further expanded when the indole was found to be an effective free radical scavenger and antioxidant. Free radicals are toxic molecules, many being derived from oxygen, which are persistently produced and incessantly attack and damage molecules within cells; most frequently this damage is measured as peroxidized lipid products, carbonyl proteins, and DNA breakage or fragmentation. Collectively, the process of free radical damage to molecules is referred to as oxidative stress. Melatonin reduces oxidative stress by several means. Thus, the indole is an effective scavenger of both the highly toxic hydroxyl radical, produced by the 3 electron reduction of oxygen, and the peroxyl radical, which is generated during the oxidation of unsaturated lipids and which is sufficiently toxic to propagate lipid peroxidation. Additionally, melatonin may stimulate some important antioxidative enzymes, i.e., superoxide dismutase, glutathione peroxidase and glutathione reductase. In in vivo tests, melatonin in pharmacological doses has been found effective in reducing macromolecular damage that is a consequence of a variety of toxic agents, xenobiotics and experimental paradigms which induce free radical generation. In these studies, melatonin was found to significantly inhibit oxidative damage that is a consequence of paraquat toxicity, potassium cyanide administration, lipopolysaccharide treatment, kainic acid injection, carcinogen administration, carbon tetrachloride poisoning, etc., as well as reducing the oxidation of macromolecules that occurs during strenuous exercise or ischemia-reperfusion. In experimental models which are used to study neurodegenerative changes associated with Alzheimer's and Parkinson disease, melatonin was found to be effective in reducing neuronal damage. Its lack of toxicity and the ease with which melatonin crosses morphophysiological barriers and enters subcellular compartments are essential features of this antioxidant. Thus far, most frequently pharmacological levels of melatonin have been used to combat oxygen toxicity. The role of physiological levels of melatonin, which are known to decrease with age, is being investigated as to their importance in the total antioxidative defense capacity of the organism.
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PMID:Melatonin in relation to cellular antioxidative defense mechanisms. 928 72

This study was designed to clarify the effects of pentoxifylline (PTX) and N-acetylcysteine (NAC) on hepatic reperfusion injury in rats. Rats were pretreated with NAC, or PTX, or combination of the drugs. In each rat, liver was isolated after twenty minutes reperfusion following thirty minutes ischemia. Plasma alanine amino transferase (ALT) activity, liver tissue glutathione (GSH) and malondialdehyde (MDA) levels, glutathione peroxidase (GPx), glutathione reductase (GSSGR), superoxide dismutase (SOD) and catalase (CAT) activities were determined. Plasma ALT activity was higher in ischemia/reperfusion groups than in control. It was decreased in the groups given NAC. Administration of NAC maintained tissue GSH levels, whereas the levels were decreased in both the ischemia/reperfusion groups treated (P < 0.05) and untreated with PTX (P < 0.01). Increases in liver MDA concentration in ischemia/reperfusion (P < 0.01) and PTX-treated groups (P < 0.05) were mitigated by administration of NAC. GPx and CAT activities were increased in the ischemia/reperfusion (P < 0.01, P < 0.05) and PTX-treated groups (P < 0.05, P < 0.001). GSSGR activities were increased in the NAC (P < 0.001) and NAC-PTX-treated groups (P < 0.01). SOD activities were higher in the ischemia/reperfusion (P < 0.01) and the PTX-treated (P < 0.01) and the NAC-PTX-treated groups (P < 0.01 ). In conclusion, short-term liver ischemia/reperfusion diminished GSH, increased MDA and induced some antioxidant enzymes. While we could not find any useful effects with PTX as we expected, our findings indicate that NAC might be useful to prevent tissue damage in hepatic ischemia/reperfusion injury.
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PMID:Pentoxifylline and N-acetylcysteine in hepatic ischemia/reperfusion injury. 972 Oct 71

This study evaluated changes in the antioxidant defences of mitochondria induced by 30 min of forebrain ischemia and recirculation up to 24 h in rats. Following treatment, mitochondria were isolated from two brain subregions: the dorsolateral striatum, an area in which there is loss of most neurons, and the paramedian cortex in which most neurons are resistant to damage. During ischemia and the first few hours of recirculation, the mitochondrial defences were largely preserved based on measurements of the activities of the enzymes, superoxide dismutase, glutathione peroxidase and glutathione reductase, as well as the response of the mitochondria to a subsequent exposure to H2O2 in vitro. However, some moderate changes were detected, particularly in the mitochondria from the dorsolateral striatum. A decrease of 30% in the activity of superoxide dismutase was seen at the conclusion of the ischemic period and a small increase in susceptibility to changes induced by H2O2 was detected during early recirculation. This latter change preceded and possibly contributed to the development of an impairment of respiratory function detected in mitochondria from the dorsolateral striatum at 3 h of recirculation. At 24 h of recirculation, larger changes were seen in the activities of all three of the enzymes in mitochondria from the dorsolateral striatum but not the paramedian cortex that was associated with progression to advanced neuronal damage in the former subregion.
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PMID:The antioxidant defences of brain mitochondria during short-term forebrain ischemia and recirculation in the rat. 975 20

Melatonin was recently reported to be an effective free radical scavenger and antioxidant. Melatonin is believed to scavenge the highly toxic hydroxyl radical, the peroxynitrite anion, and possibly the peroxyl radical. Also, secondarily, it reportedly scavenges the superoxide anion radical and it quenches singlet oxygen. Additionally, it stimulates mRNA levels for superoxide dismutase and the activities of glutathione peroxidase, glutathione reductase and glucose-6-phosphate dehydrogenase (all of which are antioxidative enzymes), thereby increasing its antioxidative capacity. Also, melatonin, at least at some sites, inhibits nitric oxide synthase, a pro-oxidative enzyme. In both in vivo and in vitro experiments melatonin has been shown to reduce lipid peroxidation and oxidative damage to nuclear DNA. While these effects have been observed primarily using pharmacological doses of melatonin, in a small number of experiments melatonin has been found to be physiologically relevant as an antioxidant as well. The efficacy of melatonin in inhibiting oxidative damage has been tested in a variety of neurological disease models where free radicals have been implicated as being in part causative of the condition. Thus, melatonin has been shown prophylactically to reduce amyloid beta protein toxicity of Alzheimer's disease, to reduce oxidative damage in several models of Parkinson's disease (dopamine auto-oxidation, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and 6-hydroxydopamine), to protect against glutamate excitotoxicity, to reduce ischemia-reperfusion injury, to lower neural damage due to gamma-aminolevulinic acid (phorphyria), hyperbaric hyperoxia and a variety of neural toxins. Since endogenous melatonin levels fal 1 markedly in advanced age, the implication of these findings is that the loss of this antioxidant may contribute to the incidence or severity of some age-associated neurodegenerative diseases.
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PMID:Oxidative damage in the central nervous system: protection by melatonin. 977 Feb 44

Melatonin, the chief secretory product of the pineal gland, is a direct free radical scavenger and indirect antioxidant. In terms of its scavenging activity, melatonin has been shown to quench the hydroxyl radical, superoxide anion radical, singlet oxygen, peroxyl radical, and the peroxynitrite anion. Additionally, melatonin's antioxidant actions probably derive from its stimulatory effect on superoxide dismutase, glutathione peroxidase, glutathione reductase, and glucose-6-phosphate dehydrogenase and its inhibitory action on nitric oxide synthase. Finally, melatonin acts to stabilize cell membranes, thereby making them more resistant to oxidative attack. Melatonin is devoid of prooxidant actions. In models of oxidative stress, melatonin has been shown to resist lipid peroxidation induced by paraquat, lipopolysaccharide, ischemia-reperfusion, L-cysteine, potassium cyanide, cadmium chloride, glutathione depletion, alloxan, and alcohol ingestion. Likewise, free radical damage to DNA induced by ionizing radiation, the chemical carcinogen safrole, lipopolysaccharide, and kainic acid are inhibited by melatonin. These findings illustrate that melatonin, due to its high lipid solubility and modest aqueous solubility, is able to protect macromolecules in all parts of the cell from oxidative damage. Melatonin also prevents the inhibitory action of ruthenium red at the level of the mitochondria, thereby promoting ATP production. In humans, the total antioxidative capacity of serum is related to melatonin levels. Thus, the reduction in melatonin with age may be a factor in increased oxidative damage in the elderly.
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PMID:Reactive oxygen intermediates, molecular damage, and aging. Relation to melatonin. 992 48

The myocardium, like other tissues, has enzyme and non-enzyme systems to neutralize free radicals. The enzymes superoxide dismutase, catalase and glutathione peroxidase and glutathione reductase as well as the non-enzyme antioxidants vitamin E and ascorbic acid are the main antioxidants. Oxidants are produced by the mitochondria under normal conditions and by other sources under pathologic conditions. The quantity of antioxidants present in the myocardium is matched to the production of oxygen free radicals that may be produced under basal physiological conditions. However, the myocardium can be exposed to increased levels of oxygen free radicals under conditions in which myocardial metabolism, i.e. mitochondrial oxidative phosphorylation, is accelerated to match the adenosine triphosphate utilized to support the increased work load on the heart or can be exposed to oxygen free radicals under pathologic conditions such as ischemia and reperfusion, inflammation, and cardiotoxic drugs such as anti-cancer agents. Under such circumstances the normal heart has been shown to increase its antioxidant production and to be, with time, protected from further sources of oxygen free radicals. In particular, hearts previously exposed to a stimulus to produce greater antioxidant levels show less damage during ischemia reperfusion injury presumably because of neutralization of oxygen free radicals. This review will present several situations in which the myocardium increases its tolerance to ischemia reperfusion injury as a result of an initial oxidative stress.
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PMID:The role of alcohol in the oxidant antioxidant balance in heart. 1041 58

Aldose reductase has been implicated in the etiology of diabetic complications, atherosclerosis, and ischemia-reperfusion injury. Aldose reductase inhibitors are known to have species-dependent differences in biotransformation enzyme induction. Whether aldose reductase inhibitors, which have antioxidant potential, alter the oxidative stress pathway is unknown. This study has determined whether four daily ip treatments of either low (10 mg/kg) or high (50 mg/kg) doses of AL-1576 or AL-4114 alter the activities of the antioxidant defense enzymes catalase, glutathione reductase, glutathione peroxidase, superoxide dismutase, and the concentrations of reduced and oxidized glutathione in livers of normal rats and rabbits. There was no change in the concentration of thiobarbituric acid reactive substances in either rat or rabbit livers, indicating that lipid peroxidation was not increased by any treatment. Hepatic catalase, superoxide dismutase, and glutathione peroxidase activities and concentrations of reduced and oxidized glutathione were not significantly altered in rat, though glutathione reductase activity was increased after high doses of both drugs. However, in rabbit liver, glutathione reductase activity decreased in a dose-dependent manner after AL-4114 treatment, while superoxide dismutase and glutathione peroxidase activities decreased only after the low dose of AL-4114. Although AL-4114 and AL-1576 did not directly generate increased lipid peroxidation within normal rat and rabbit livers, some of the enzymes responsible for oxidative defense were altered, particularly in rabbit livers.
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PMID:Effects of aldose reductase inhibitors on antioxidant defense in rat and rabbit liver. 1065 32

BACKGROUND: The metabolic and hemodynamic effects of nisoldipine supplementation in cardioplegia after ischemic injury were investigated in 13 isolated rabbit hearts. Group 1 consisted of 6 hearts, which received St. Thomas II cardioplegic solution. In group 2, nisoldipine was added to the cardioplegic solution at a concentration of 0.1 mg/kg in 7 hearts. METHODS: The explanted hearts were suspended from Langendorff apparatus and were perfused with Krebs-Henseleit solution. Left ventricular pressure, heart rate, malondialdehyde, glutathione peroxidase, glutathione reductase, reduced glutathione, oxidized glutathione, creatine kinase MB, (CK-MB), aspartate transaminase, and lactate dehydrogenase (LDH) were measured before and after 60 minutes of ischemia. Peak generated pressure after ischemia was significantly higher in group 2 versus group 1 while end-diastolic pressure was significantly lower in group 2 after ischemic arrest (P <.05). RESULTS: Malondialdehyde levels were lower in group 2 (P <.05). Glutathione peroxidase and glutathione reductase levels were significantly higher in group 2 (P <.05). The only enzymatic significant difference was observed between the preischemic and postischemic levels of aspartate transaminase in group 2 (P <.05). CONCLUSIONS: These findings show beneficial effects of nisoldipine cardioplegia, although its use as a cardioplegic additive is not yet possible. We believe, however, the effects of oral nisoldipine before cardiac surgery can be studied in a clinical setting.
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PMID:Nisoldipine Cardioplegia in the Isolated Rabbit Heart. 1068 69

In this study we addressed the function of the Krebs cycle to determine which enzyme(s) limits the availability of reduced nicotinamide adenine dinucleotide (NADH) for the respiratory chain under H(2)O(2)-induced oxidative stress, in intact isolated nerve terminals. The enzyme that was most vulnerable to inhibition by H(2)O(2) proved to be aconitase, being completely blocked at 50 microm H(2)O(2). alpha-Ketoglutarate dehydrogenase (alpha-KGDH) was also inhibited but only at higher H(2)O(2) concentrations (>/=100 microm), and only partial inactivation was achieved. The rotenone-induced increase in reduced nicotinamide adenine dinucleotide (phosphate) [NAD(P)H] fluorescence reflecting the amount of NADH available for the respiratory chain was also diminished by H(2)O(2), and the effect exerted at small concentrations (</=50 microm) of the oxidant was completely prevented by 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), an inhibitor of glutathione reductase. BCNU-insensitive decline by H(2)O(2) in the rotenone-induced NAD(P)H fluorescence correlated with inhibition of alpha-ketoglutarate dehydrogenase. Decrease in the glutamate content of nerve terminals was induced by H(2)O(2) at concentrations inhibiting aconitase. It is concluded that (1) aconitase is the most sensitive enzyme in the Krebs cycle to inhibition by H(2)O(2), (2) at small H(2)O(2) concentrations (</=50 microm) when aconitase is inactivated, glutamate fuels the Krebs cycle and NADH generation is unaltered, (3) at higher H(2)O(2) concentrations (>/=100 microm) inhibition of alpha-ketoglutarate dehydrogenase limits the amount of NADH available for the respiratory chain, and (4) increased consumption of NADPH makes a contribution to the H(2)O(2)-induced decrease in the amount of reduced pyridine nucleotides. These results emphasize the importance of alpha-KGDH in impaired mitochondrial function under oxidative stress, with implications for neurodegenerative diseases and cell damage induced by ischemia/reperfusion.
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PMID:Inhibition of Krebs cycle enzymes by hydrogen peroxide: A key role of [alpha]-ketoglutarate dehydrogenase in limiting NADH production under oxidative stress. 1112 72

The current study tested the hypothesis that ischemia-reperfusion (I-R) can cause more severe myocardial dysfunction and oxidative damage in senescent rats than young adult rats. Male Fischer 344 rats at the age of 6 (adult) and 24 (old) months were subjected to an open-chest heart surgery and randomly assigned to one of the following treatments: ischemia only (I), with the occlusion of the main descending branch of the left coronary artery (LCA) for 30 min; I-R, with the release of LCA occlusion for 20 min; or sham (S) operation. Heart mechanical performance was monitored using a fluid-filled catheter inserted in the right carotid artery and advanced to the left ventricle. Ischemia caused similar reductions of left ventricle systolic pressure (LVSP) and contractility (+/-dP/dt) in adult and aged hearts. After I-R, adult hearts regained 82% (P<0.05) of the pre-ischemic LVSP, whereas the aged hearts regained 91% (P>0.05) of LVSP. There was no significant difference in the reduction of +/-dP/dt with I-R between adult and aged hearts. Old rats had lower pre-ischemic heart rate than adult rats, however, I-R caused no reduction of heart rate, and a smaller reduction of pressure-rate double product in the aged rats (10%, P>0.05) than the adult rats (23%, P<0.01). Aged rats demonstrated greater myocardial and plasma glutathione (GSH) concentrations prior to surgery, and maintained higher GSH levels and GSH:glutathione disulfide (GSSG) ratio with I-R. Aged hearts also had higher GSH peroxidase, GSH reductase and GSH sulfur-transferase activities than adult hearts, while I-R induced lipid peroxidation was similar. It is concluded that senescent hearts with intact circulatory and neural inputs are not more susceptible to I-R injury than adult hearts during myocardial I-R, partly because they have a greater GSH antioxidant protection.
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PMID:Aged rat hearts are not more susceptible to ischemia-reperfusion injury in vivo: role of glutathione. 1129 68


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