Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: DrugBank:EXPT00568 (ascorbate)
 23,072 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Oxygen-derived free radicals have been implicated in the pathogenesis of vasogenic edema and infarction caused by ischemia and reperfusion injury. In earlier studies, exogenously supplied liposome-entrapped CuZn superoxide dismutase (CuZn-SOD) ameliorated ischemic brain edema and infarction in rats following focal cerebral ischemia. To ascertain directly the role of SOD in the protection against superoxide radical-induced injury, we measured infarct size and water content 24 hr following focal cerebral ischemia in nontransgenic mice and in transgenic mice bearing the human SOD1 gene. These transgenic mice have 3.1-fold higher cellular CuZn-SOD activity in the brain than do their nontransgenic littermates. We also measured antioxidant levels (reduced glutathione and reduced ascorbate) of contralateral cortex, infarct cortex, surrounding cortex, and striatum. Infarct size and brain edema were significantly decreased in transgenic mice compared with nontransgenic mice. Reduced glutathione and reduced ascorbate levels decreased in the ischemic hemisphere, but levels in surrounding cortex and striatum were significantly higher in transgenic mice than in nontransgenic mice. These results indicate that increased endogenous SOD activity in brain reduces the level of ischemic damage and support the concept that superoxide radicals play an important role in the pathogenesis of infarction and edema following focal cerebral ischemia.
 ...
PMID:Attenuation of focal cerebral ischemic injury in transgenic mice overexpressing CuZn superoxide dismutase. 176 30

It has been proposed that free radical reactions are involved in ischemic brain damage. Since irreversible pathological changes occurs very early phase of the focal ischemia and the ischemic brain edema reaches its peak at about 2 days of ischemia, the free radical reactions must take place before these changes. Superoxide dismutase is a famous enzyme that dismutase superoxide anion, which is believed to be one of the initiator of the free radical reactions. If superoxide anion plays a pivotal role in the genesis of pathological ischemic brain damage and edema, the activity of the enzyme may decrease in the early phase of ischemia. Ascorbic acid is also known to be a scavenger of superoxide anion, and brain tissue contains it in a high concentration. We investigated the changes in superoxide dismutase activity and concentration of reduced ascorbate in focal ischemia. Focal ischemia was produced in rats by permanent occlusion of the left middle cerebral artery. The animals were decapitated 30 minutes, 4, 24, and 48 hours after the operation. Middle cerebral artery territory of each cerebral hemisphere was homogenized and centrifuged with phosphate buffer. The supernatant was divided into two aliquots; one was dialyzed to remove ascorbate and the other was not. The SOD activity was measured by electron-spin-resonance (ESR) spin trapping method, and the ascorbic acid concentration was measured by high performance liquid chromatography with electrochemical detection (HPLC-ECD). Protein concentration was measured by Lowry's method. The enzyme activity was expressed as unit/mg protein, and the ascorbic acid concentration was expressed as microgram/g tissue. The SOD activity decreased markedly by dialysis.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:[Temporal profile of the superoxide dismutase and the ascorbic acid in focal cerebral ischemia]. 179 14

Trolox, a hydrophilic analog of vitamin E, was reported to scavenge peroxyl radicals from artificial systems better than its parent compound. Here we examined the possible cytoprotective effect of Trolox in cultured hepatocytes and in the rat liver. In cultured rat hepatocytes, 0.5 to 16 mmol/L Trolox (with optimum between 1 to 2 mmol/L) was observed to prolong the survival of cells exposed to oxyradicals generated with xanthine oxidase-hypoxanthine. The protection by 1 mmol/L Trolox surpassed that provided by either ascorbate, mannitol, superoxide dismutase and/or catalase--each at a level giving its maximal protection in the same system. In both a global and partial model of hepatic ischemia-reperfusion in rats, infusion of Trolox (7.5 to 10 mumol/kg body weight) just before reflow reduced by greater than 80% the liver necrosis sustained in untreated (no Trolox) control rats. Such organ salvage was apparently accompanied by approximately 50% reduction in the amount of hepatic conjugated dienes, which were quantified by a highly specific radiochemical assay. Since conjugated dienes are presumed to be good "markers" of oxyradical damage, our data may have provided a semiquantitative link between free radical-induced necrosis and its chemical imprint in vivo. The data also indicated a relatively rapid and potent antioxidant-like action by Trolox on rat hepatocytes and on the postischemic reperfused rat liver.
 ...
PMID:Trolox protects rat hepatocytes against oxyradical damage and the ischemic rat liver from reperfusion injury. 199 27

From in vitro studies involving multilamellar liposomes or other artificial systems, several groups of workers have deduced that Trolox (a water-soluble analogue of vitamin E) and ascorbate are synergistic antioxidants. Here, we demonstrate that while Trolox and ascorbate individually protect cultured hepatocytes against oxyradicals generated either with xanthine oxidase plus hypoxanthine or with hydrogen peroxide, the two antioxidants do not appear to be synergistic when used in equimolar combinations. Also, in a rat model of hepatic ischemia-reperfusion, we observed that infusion of Trolox or ascorbate (7.5-10 mumol/kg body weight) into the postischemic liver reduced the reperfusion injury by 76 or 67%, respectively. However, when both compounds were used together (each at the same dose as used separately), the organ salvage amounted to only 79%. Therefore, there is no evidence of synergism between Trolox and ascorbate in our in vitro and especially in vivo systems.
 ...
PMID:Trolox and ascorbate: are they synergistic in protecting liver cells in vitro and in vivo? 203 21

Free radicals have been incriminated in a variety of injurious processes including the toxicity of the herbicide paraquat and the damage following ischemia and reperfusion of different organs. Based on the assumption that iron and copper could serve as mediators for the transformation of relatively low reactive species (such as superoxide radicals, hydrogen peroxide, ascorbate, and others) to the highly reactive species, in the site-specific metal-mediated mechanism, two new modes for intervention have been tried out. The first is the introduction of specific chelators that "pull" out redox-active and available metals, and by this reduce the apparent damage. Desferrioxamine was shown to protect bacterial cells and mammals against the poisonous effects of paraquat. Using the retrogradly perfused isolated rat heart, we have demonstrated that the chelator neocuproine, which effectively binds both iron and copper provides a major protection against hydrogen peroxide-induced cardiac damage and against ischemia/reperfusion-induced arrhythmias. Likewise, TPEN a heavy metal chelator, provides almost total (greater than 90%) protection against ischemia/reperfusion-induced arrhythmias. The other mode of intervention is the use of redox-inactive metal ions that could compete for the binding sites of iron and copper, and by this "push" these metal ions out, lead to their displacement, and divert the site of free radical attack. Applying Zn(II) complexes provided a marked protection against metal mediated free radical-induced damage in the copper-mediated paraquat toxicity to E. coli, and in the arrhythmias induced by ischemia and reperfusion. It is proposed that the complex zinc-desferrioxamine would be the ultimate protector being effective by both the "pull" and "push" mechanisms.
 ...
PMID:Protection against free radical-induced and transition metal-mediated damage: the use of "pull" and "push" mechanisms. 206 Aug 41

Allopurinol and its metabolite oxypurinol inhibited basal oxidation of ascorbate and exerted comparable concentration-dependent inhibitory effects on the oxidation of ascorbate catalysed by cupric ion, but the stimulation produced by ferric ion was affected minimally. UV spectral analysis suggested the formation of an allopurinol-ascorbate-copper ion complex. The oxidation of erythrocyte membrane lipids by ferric ion and cupric ion-t-butylhydroperoxide was also inhibited by allopurinol and oxypurinol, by the metal chelators EDTA and uric acid, and by the antioxidant butylated hydroxytoluene. The metal chelating actions of allopurinol and oxypurinol may be relevant to their protective actions against ischemia/reperfusion injury.
 ...
PMID:Inhibition of transition metal ion-catalysed ascorbate oxidation and lipid peroxidation by allopurinol and oxypurinol. 211 56

The real-time kinetics of the release of ascorbyl free radicals in the coronary perfusate from isolated rat hearts submitted to an ischemia/reperfusion sequence has been achieved by continuous-flow ESR using high-speed acquisition techniques. Enhanced ESR detection of ascorbyl free radicals was obtained by addition of dimethyl sulfoxide (Me2SO), a strong cation chelator and oxidizing agent. A continuous-flow device allowed a direct monitoring of the ascorbyl free radical and/or ascorbate leakage in coronary perfusate by observation of the ascorbyl radical doublet (aH = 0.188 mT and g = 2.0054). 1. The results showed that ascorbyl free radical release occurred mainly during sequences of low-flow ischemia (90 min) coupled or not with 30 min of zero-flow ischemia followed by reperfusion (60 min). The kinetic profiles of ascorbyl-free-radical detection confirm in quantitative terms the expected correlation between the duration of the ischemic insult and the magnitude of ascorbate extracellular release upon reperfusion. There is indication that ascorbyl free radical depletion could be secondary to oxygen-derived-free-radical-induced cellular damage. 2. The amount of residual ascorbic acid was quantitated on myocardial tissue at the end of reperfusion using Me2SO as extracting solvent. Intense oxidation of ascorbate and chemical stabilization of the resulting free radical species provided by Me2SO allowed ESR measurement of a marked tissue ascorbate depletion related to the duration of ischemia. 3. Perfusion of superoxide dismutase during low-flow ischemia and the first 10 min of reperfusion greatly inhibited both extracellular release and endogenous ascorbate depletion. These results suggest that the ascorbate redox system constitutes a major protective mechanism against free-radical-induced myocardial injury. 4. The proposed direct ESR detection of ascorbyl free radicals in the coronary perfusates or in tissue extracts does not require extensive chemical preparation and conditioning of effluent or tissue samples. It provides an interesting straightforward alternative to the evaluation of detrimental free radical processes affecting the myocardium during ischemia and reperfusion.
 ...
PMID:Ascorbyl free radical as a reliable indicator of free-radical-mediated myocardial ischemic and post-ischemic injury. A real-time continuous-flow ESR study. 217 67

Opiate-receptor antagonists improve behavioral, electrophysiologic and/or histologic outcome in various experimental models of central nervous system ischemia. To address the potential mechanism(s) by which opiate-receptor antagonists may exert their protective actions in cerebral ischemia, metabolic and biochemical changes were measured in brain of rats pretreated with the opiate-receptor antagonist nalmefene or vehicle and subjected to 60 min of global ischemia followed by 2 hr of reperfusion. 31P and 1H magnetic resonance spectroscopy were used to follow the metabolic changes during ischemia and reperfusion, after which brain tissue was frozen in situ. Biochemical assays included free fatty acids, thromboxane B2, ascorbate, vitamin E and amino acids. Nalmefene-treated animals showed more rapid and complete recovery of cellular bioenergetic state (as indicated by the phosphocreatine to inorganic phosphate ratio), tissue acidosis and lactate levels during reperfusion than placebotreated controls. Ischemia/reperfusion caused significant increases of fatty free acids and thromboxane, associated with significant decreases of ascorbate and glutamate; nalmefene pretreatment limited each of these changes. The degree of metabolic improvement as reflected by recovery of high energy phosphates and reduction of lactic acidosis were highly correlated with changes in tissue levels of arachidonate and glutamate. Thus, the beneficial effects of opiate-receptor antagonists in cerebral ischemia may be due, in part, to an ability to enhance metabolic recovery with associated, reduction in phospholipid hydrolysis and excitotoxin release.
 ...
PMID:Opiate-receptor antagonist improves metabolic recovery and limits neurochemical alterations associated with reperfusion after global brain ischemia in rats. 224 36

To verify whether lipid peroxidation is associated with focal cerebral ischemia, a unilateral middle cerebral artery occlusion was carried out in rats. The concentrations of various endogenous antioxidants in the ischemic center were measured, including alpha-tocopherol and ubiquinones as lipid-soluble antioxidants and ascorbate as a water-soluble antioxidant. At 30 minutes after ischemia, alpha-tocopherol decreased to 79% of baseline, reduced ubiquinone-9 to 73%, ubiquinone-10 to 66%, and reduced ascorbate to 76%. Six hours after ischemia, alpha-tocopherol decreased to 63% and reached a plateau, whereas reduced ubiquinones and reduced ascorbate declined further to 16% and 10%, respectively, 12 hours after ischemia and then reached plateau levels. These results suggest functional and durational differences between antioxidants and lipid peroxidation in this ischemic model. Although the reciprocal increase in oxidized ubiquinones during ischemia was not observed, that of oxidized ascorbate was noted. The complementary antioxidant system between cytoplasmic and membranous components, the combination alpha-tocopherol/ascorbate, was estimated from the calculated consumption ratio of these antioxidants on the basis that the loss of these reduced antioxidants is due to neutralization of free radicals. This system is suggested to play an important role in the early ischemic period. Urate also increased during ischemia. The possible involvement of the xanthine-xanthine oxidase system in initiating free radical reactions in cerebral ischemia is also discussed.
 ...
PMID:Lipid peroxidation in focal cerebral ischemia. 276 92

Lipid peroxidation (LPO) was investigated in cortical layer homogenates from 56 rat kidneys, intact or exposed to a 30-minute heat ischemia performed without any protection or after a preliminary administration of prednisolone alone or in combination with methypred. Prednisolone was administered i.m. in a dose of 30 mg/kg 2 hrs before and the same dosage of methypred a day before the onset of the experiment. Homogenates were studied both for the initial levels of malonic dialdehyde (MDA) and for the MDA formation in the presence of LPO which was activated in the phosphate buffer by pH 6.8 ascorbate (5.10(-4) M) 5, 10, 15, 20, 25 and 30 minutes after the incubation. The results obtained demonstrated that versus the intact kidneys, in the kidneys exposed to a 30-minute treatment with heat ischemia there were increased levels of initial MDA in the renal tissue, a dramatic increment of its formation during the incubation of homogenate with ascorbate. Shifts in the kinetic curves in homogenates from ischemic kidneys were noted as well. A more dramatic rise (versus intact kidneys) in the MDA formation levels in the presence of LPO observed at the initial stage of the incubation was suggestive of an exhaustive effect of heat ischemia on the system of endogenous antioxidants. The dramatic increment of MDA levels was recorded during a 30-minute incubation. Administration of prednisolone alone or in combination with methypred resulted in a significant inhibition of LPO in ischemic renal tissue.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:[Lipid peroxidation in a kidney tissue homogenate from rats under heat-induced ischemia with and without glucocorticoid protection]. 280 79


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>