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

Oxidative damage by free radicals has been proposed as a mechanism of cerebral injury due to ischemia and reperfusion. Hypothermia protects against ischemic necrosis; however, its effect on oxidative stress has not been investigated. In this study, the effects of hypothermia on oxidative stress were studied by determining consumption of endogenous antioxidants after temporary focal ischemia in rats. Thirty-two Sprague-Dawley rats anesthetized with 1.5% isoflurane underwent 3 h of middle cerebral artery occlusion under hypothermic (33 degrees C) or normothermic (37 degrees C) conditions followed by 3 h of normothermic reperfusion. In the first study (n = 8 per group), intraischemic hypothermia suppressed the reduction of tissue concentrations of endogenous antioxidants, ascorbate (P < or = 0.05), and glutathione (P < or = 0.05) in ischemic cortex but not in caudoputamen. In a parallel study (n = 8 per group), hypothermia reduced tissue damage in ischemic frontoparietal cortex (P < or = 0.05), but not in caudoputamen. Laser-Doppler estimates of cortical blood flow showed that intraischemic hypothermia significantly attenuated early postischemic hyperperfusion (P < or = 0.01) and delayed postischemic hypoperfusion (P < or = 0.01). These results demonstrate that intraischemic mild hypothermia reduces oxidative stress and cell injury after prolonged focal ischemia followed by reperfusion. The reduction of oxidative stress by hypothermia may be related indirectly to attenuation of postischemic blood flow changes.
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PMID:Mild intraischemic hypothermia suppresses consumption of endogenous antioxidants after temporary focal ischemia in rats. 795 23

The study was carried out to evaluate the effect of different degrees of hypothermia on nerve conduction and the possible beneficial effect of vitamin C in the amelioration of the impairment in nerve conduction due to hypothermia. Sixty male Wistar rats, 225-250 g, were randomly divided into two equal groups of untreated controls and vitamin C treated experimental groups. Sciatic nerve conduction and nerve temperature (Tn) were recorded at different degrees of hypothermia by step-wise lowering of rectal temperature (Tr) from 38 to 20 degrees C. A regression analysis showed a positive linear relationship of Tr with nerve conduction velocity (NCV) and with Tn in both groups (p < 0.001). There was also a positive linear relationship between Tn and NCV in both groups: control, p < 0.001; experimental, p < 0.05. Comparisons between the regression equations of Tr with NCV, Tr with Tn, and Tn with NCV showed significant differences between the two groups (p < 0.001). There was no significant relationship between Tr and the amplitude of the action potential. Vitamin C may have a protective effect against the impairment of NCV due to hypothermia.
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PMID:Effect of vitamin C in modulating the hypothermic influence on nerve conduction. 904 18

Accumulation of products of lipid peroxidation (malondialdehyde, conjugated dienes, lipid peroxides, and Schiff bases) was evaluated in rabbit kidney cortex slices made ischemic for 60 min followed by 18 h storage at 5 degrees C in UW Na gluconate solution and 210 min normothermic reoxygenated incubation. In addition, the effect of adding Trolox (1 mM), deferoxamine (1 mM), and ascorbate (1 mM) as supplemental antioxidants to the UW gluconate solution was evaluated. Lipid peroxidation was slightly increased after hypothermic storage compared to slices subjected to ischemia alone but was not significantly different than ischemic slices during subsequent incubation at normothermia. The addition of either deferoxamine or Trolox to the storage solution substantially reduced lipid peroxidation both during hypothermic storage and subsequent to normothermic incubation. Ascorbate had a mild prooxidant effect as a sole additive to the UW gluconate solution but was clearly prooxidant when combined with either deferoxamine or Trolox. These results suggest that supplemental antioxidants added to the UW gluconate solution under conditions analogous to machine perfusion preservation have a potential role in reducing oxidative stress in kidney tissues harvested after warm ischemia and that hypothermia may be a valuable adjunct to resuscitative therapeutic regimens developed for salvage of ischemic kidneys for transplantation.
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PMID:The efficacy of antioxidants administered during low temperature storage of warm ischemic kidney tissue slices. 920 Aug 25

Our group recently observed that manganese prevents oxidative brain injury in the iron-induced parkinsonian animal model. It has also been suggested that manganese retards while copper promotes the development of atherosclerosis. In this report, we provide further evidence to support a controversial notion that manganese is an atypical antioxidant. Among transition metals, Cu2+ and Fe2+ (0.1 to 125 microM), but not Mn2+, converted hydrogen peroxide to reactive hydroxyl radicals via the Fenton reaction at pH 7.4. Iron's pro-oxidative rate is relatively slow, but it is accelerated further by ascorbate (50 microM) in 37 degrees C Dulbecco's phosphate buffered saline. Moreover, Mn2+ (0-80 microM) concentration dependently retarded diene conjugation of human low density lipoproteins stimulated by 5 microM Cu2+. This new result is consistent with our recent finding that Mn2+ (0 to 20 microM) does not initiate brain lipid peroxidation while it inhibits iron-induced peroxidation of polyunsaturated fatty acids. These unexpected manganese results are somewhat at odds with a prominent theory that manganese is a prooxidative transition metal. Furthermore, iron and copper induced free radical generation and lipid peroxidation are suppressed by lowering the incubation temperature; this suggests that hypothermia may decrease the oxidative stress and damage in vivo. In conclusion, normal dietary intake of manganese may protect cells and neurons from oxidant stress through the inhibition of propagation of lipid peroxidation caused by hydroxyl radicals generated by pro-oxidative transition metals such as iron and copper. Potential therapeutical uses of manganese, manganese SOD mimetics and hypothermia for protecting brain neurons and vascular endothelial cells against oxidative stress and damage have been successfully demonstrated in both animal models and clinical trials.
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PMID:Implications for atypical antioxidative properties of manganese in iron-induced brain lipid peroxidation and copper-dependent low density lipoprotein conjugation. 1038 4

Hallervorden-Spatz syndrome is an autosomal-recessive brain disorder with signs of extrapyramidal dysfunction and mental deterioration, which associate with iron accumulation in globus pallidus and substantia nigra pars reticulata. Studies of oxidant stress in parkinsonian animal models suggest a linkage of iron overload to axonal dystrophy. Redox cycling of iron complexes (i.e., ferrous citrate and hemoglobin) increases hydroxyl radicals, lipid peroxidation, axonal dystrophy, and necrotic or apoptotic cell death. An increase of oxidative stress in the basal ganglia because of redox cycling of iron complexes leads to dopamine overflow and psychomotor dysfunction. Iron overload-induced axonal dystrophy has been demonstrated consistently using in vitro and in vivo models with a prominent feature of lipid peroxidation. This iron-induced oxidative stress is often accentuated by ascorbate and oxidized glutathione, although it is suppressed by the following antioxidants: S-nitrosoglutathione or nitric oxide, MnSOD mimics, manganese, U-78517F, Trolox, and deferoxamine. Preconditioning induction of stress proteins (i.e., hemeoxygenase-1 and neuronal nitric oxide synthase) and hypothermia therapy suppress the generation of toxic reactive oxygen, lipid, and thiol species evoked by bioactive iron complexes in the brain. Finally, combined antioxidative therapeutics and gene induction procedures may prove to be useful for slowing progressive neurodegeneration caused by iron overload in the brain.
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PMID:Iron overload, oxidative stress, and axonal dystrophy in brain disorders. 1155 44

The authors are systematically exploring pharmacologic preservation for temporarily unresuscitable exsanguination cardiac arrest in dogs. They hypothesized that the antioxidant Tempol improves cerebral outcome when added to aortic saline flush at the start of cardiac arrest. In study A, no drug (n = 8), Tempol 150 mg/kg (n = 4), or Tempol 300 mg/kg (n = 4) was added to 25 mL/kg saline flush at 24 degrees C (achieving mild cerebral hypothermia) at the start of 20-minute cardiac arrest. In study B, no drug (n = 8) or Tempol 300 mg/kg (n = 7) was added to 50 mL/kg saline flush at 2 degrees C (achieving moderate cerebral hypothermia) at the start of 40-minute cardiac arrest. Cardiac arrest was reversed with cardiopulmonary bypass. Mild hypothermia lasted for 12 hours, controlled ventilation was sustained to 24 hours, and intensive care was provided for up to 72 hours. In study A, overall performance category 1 or 2 (good outcome) was achieved in all eight dogs treated with Tempol compared with three of eight dogs in the control group ( P = 0.03). In study B, good outcome was achieved in all seven dogs treated with Tempol versus only two of 8 dogs in the control group ( P = 0.007). In both studies, neurologic deficit scores were significantly better in the Tempol group, but not total histologic damage scores. At 72 hours, electron paramagnetic resonance spectroscopy of Tempol revealed direct evidence for its presence in the brain. Single- and double-strand DNA damage, nitrotyrosine immunostaining, total antioxidant reserve, and ascorbate acid levels were similar between groups, and thiol levels were decreased after Tempol in study B. The authors conclude that when added to aortic saline flush at the start of prolonged cardiac arrest, the antioxidant Tempol can enhance mild or moderate hypothermic cerebral preservation in terms of improved functional outcome. The mechanisms involved in this beneficial effect need further clarification.
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PMID:Antioxidant Tempol enhances hypothermic cerebral preservation during prolonged cardiac arrest in dogs. 1180

Exposure to an extremely cold environment without proper protection leading to hypothermia is an emergency, one of the several complications of which is impairment in nerve conduction. Our previous work in the rat model has shown the beneficial effect of vitamin C in modulating the effect of hypothermia on nerve conduction. The present study aimed to evaluate the effect of vitamins C and E, administered alone or in combination, in modulating the effect of mild hypothermia on human ulnar nerve conduction. The study was carried out on 26 volunteers divided into three groups: group I received vitamin C supplementation (2000 mg/day in a single dose and 1,000 mg/day for the next 6 days), group II received vitamins C and E in combination (1,000 mg and 800 mg respectively in a single dose and 500 mg and 400 mg respectively for the next 6 days) and group III received vitamin E (800 mg in a single dose and the same for the next 6 days). The recordings were carried out before and after single and weekly supplementation in each group. There was a fall in ulnar nerve conduction velocity with a reduction in the oral temperature of 2-2.5 degrees C. Vitamin C administered alone and in combination with vitamin E reduced the fall in ulnar nerve conduction velocity. Prior supplementation with vitamin C and E could help ameliorate the impairment in human ulnar nerve conduction due to hypothermia.
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PMID:Effect of vitamin C and E supplementation in modulating the peripheral nerve conduction following cold exposure in humans. 1282 84

Ethyl alcohol (ethanol) is readily absorbed from all parts of the gastrointestinal tract due to its hydrophilic potential. The biological effects in humans refer to practically every organ and system. The basic enzyme involved in its oxidation is alcohol dehydrogenase. Another important metabolic pathway is the Microsomal Ethanol-Oxidizing System (MEOS). Toxic effect on basic cell functions is produced both by ethanol and acetic aldehyde, its oxidation product which accounts for most of the acute and delayed effects of ethanol toxicity. In acute ethanol intoxication's the CNS symptoms are the first to manifest. Ethanol affects the CNS functions mainly through stimulating opiate and benzodiazepine receptors and a number of neurotransmitters. However, the attempts to diminish the toxic effects of ethanol on CNS by blocking the affected receptors have proved to be ineffective. In acute poisoning a basic essential is to sustain vital functions by following the principles of intensive care. Each case of acute ethanol intoxication must be subject to neurological examination for possible cerebro-cranial traumas. The diagnostics and treatment procedures should take account of the possible symptoms: convulsions, respiratory and cardiac failure, hypoglycemia, hypothermia, and severe gastric dysfunction. Vital signs monitoring and control of acid-base and water-electrolyte balance are a must. The toxic properties of ethanol metabolites can be particularly hazardous to patients treated with disulfiram. The patients who develop "antabuse response" should be given immediately iron and vitamin C intravenously.
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PMID:[Biological and toxic effects of ethanol: diagnostics and treatment of acute poisonings]. 1456 85

Ultraprofound hypothermia (< 5 degrees C) induces changes to cell membranes such as liquid-to-gel lipid transitions and oxidative stress that have a negative effect on membrane function and cell survival. We hypothesized that fatty acid substitution of endothelial cell lipids and alterations in their unsaturation would modify cell survival at 0 degrees C, a temperature commonly used during storage and transportation of isolated cells or tissues and organs used in transplantation. Confluent bovine aortic endothelial cells were treated with 18-carbon fatty acids (C18:0, C18:1n-9, C18:2n-6, or C18:3n-3), C20:5n-3 or C22:6n-3 (DHA), and then stored at 0 degrees C without fatty acid supplements. Storage of control cells caused the release of lactate dehydrogenase (LDH) and a threefold increase in lipid peroxidation (LPO) when compared to control cells not exposed to cold. Pre-treating cells with C18:0 decreased the unsaturation of cell lipids and reduced LDH release at 0 degrees C by 50%, but all mono- or poly-unsaturated fatty acids increased injury in a concentration-dependent manner and as the extent of fatty acid unsaturation increased. DHA-treatment increased cell fatty acid unsaturation and caused maximal injury at 0 degrees C, which was prevented by lipophilic antioxidants BHT or vitamin E, the iron chelator deferoxamine, and to a lesser extent by vitamin C. Furthermore, the cold-induced increase in LPO was reduced by C18:0, vitamin E, or DFO but enhanced by DHA. In conclusion, the findings implicate iron catalyzed free radicals and LPO as a predominant mechanism of endothelial cell injury at 0 degrees C, which may be reduced by increasing lipid saturation or treating cells with antioxidants.
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PMID:Endothelial cell fatty acid unsaturation mediates cold-induced oxidative stress. 1667 60

Cardiopulmonary bypass (CPB) is associated with oxidative stress. This study examined antioxidant levels in adults undergoing CPB surgery and their correlation with clinical variables. Arterial blood samples were obtained from 27 patients undergoing CPB. The time-course variation of vitamin C (spectrofluorimetry), alpha-tocopherol and retinol (HPLC) levels were determined. Plasma vitamin C rose initially but gradually decayed during reperfusion until 60% reduction of baseline values post-surgery. alpha-Tocopherol and retinol were reduced along CPB with post-operative values approximately 25% lower than baseline. No significant changes were found for selenium and glutathione peroxidase. PaO(2) values rose steadily throughout CPB. A correlation existed for alpha-tocopherol and retinol depletion vs maximal PaO(2) throughout CPB but no correlation was found for antioxidant consumption vs duration of ischaemia and reperfusion and hypothermia level. In conclusion, consumption of arterial blood antioxidant vitamins occurs with CPB in relation with PaO(2) levels but not for other clinical variables measured in this study.
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PMID:Changes in alpha-tocopherol and retinol levels during cardiopulmonary bypass correlate with maximal arterial partial pressure of oxygen. 1772 25


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