Ascorbic acid reduces the dopamine depletion induced by MPTP

The administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to mice was found to cause a long-lasting depletion of striatal dopamine concentrations, but did not alter striatal serotonin concentrations. The concomitant administration of ascorbic acid attenuated this MPTP-induced dopamine depletion. These observations are discussed in reference to the possible mechanisms through which MPTP exerts its neurotoxic actions on dopaminergic neurons.     

Ascorbic acid reduces the dopamine depletion induced by methamphetamine and the 1-methyl-4-phenyl pyridinium ion

The neurotoxic actions of methamphetamine and the 1-methyl-4-phenyl pyridinium ion (MPP+) have been ascribed, at least in part, to the generation of free radicals. This hypothesis was evaluated by attempting to reduce the toxic actions of these compounds by pretreatment with an antioxidant, ascorbic acid. The intrastriatal administration of methamphetamine caused a 37% depletion of dopamine. Treatment with 100 or 1000 mg/kg of ascorbic acid significantly reduced the methamphetamine-induced dopamine depletion (by 21 and 27%, respectively). The intrastriatal administration of MPP+ caused an 88% depletion of dopamine. Treatment with 100 or 1000 mg/kg of ascorbic acid significantly reduced the MPP+-induced dopamine depletion (by 22 and 45%, respectively). Thus, free radicals may mediate the toxic actions of these compounds.     

Ascorbic acid and alcohol oxidation

Methanol and ethanol were rapidly metabolized to formaldehyde and acetaldehyde in the presence of ascorbate, 1,10-phenanthroline and either guinea pig hepatic 100,000 g supernatant or 12,000 g pellet fractions. The specific activity of methanol oxidation was 1720 nmoles formaldehyde formed/min/mg protein in the 100,000 g fraction and 790 in the 12,000 g pellet fraction. The specific activity of ethanol oxidation was 1590 nmoles acetaldehyde formed/min/mg protein in the 100,000 g fraction and 820 in the 12,000 g pellet fraction. The activity was enzymatic in that it was linear with time, proportional to protein concentration, and sensitive to temperature. Catalase appeared to be the enzymatic component responsible for the oxidation. In this ascorbate-dependent alcohol oxidation system, oxygen was consumed and H2O2 was formed. When purified catalase and ascorbate were used, complex I was detected and methanol was oxidized.     

Kinetics of paraquat in the isolated rat lung: Influence of sodium depletion

Paraquat accumulates in the lung through a characteristic polyamine uptake system. It has been previously shown that paraquat uptake can be significantly prevented if extracellular sodium (Na+) is reduced, although the available data correspond to experiments performed using tissue slices or incubated cells. This type of in vitro study fails to give information on the actual behaviour occurring in vivo since the anatomy and physiology of the studied tissue is disrupted. Accordingly, the aim of the present study was to explore the usefulness of the isolated rat lung model when applied to characterize the kinetic behaviour of paraquat in this tissue after bolus injection under standard experimental conditions as well as to evaluate the influence of iso-osmotic replacement of Na+ by lithium (Li+) in the perfusion medium. The obtained results show that the present isolated rat lung model is useful for the analysis of paraquat toxicokinetics, which is reported herein for the first time. It was also observed that Na+ depletion in the perfusion medium leads to a decreased uptake of paraquat in the isolated rat lung, although it seems that this condition does not contribute to improve the elimination of paraquat once the herbicide reaches the extravascular structures of the tissue, since the paraquat tissue wash-out phase is similar under both experimental conditions assayed.     

Ascorbic acid inhibits ROS production, NF-kappa B activation and prevents ethanol-induced growth retardation and microencephaly

In this study, we established an embryo model to study the effects of ethanol on fetal development. When embryos of Xenopus laevis (the African clawed frog) were exposed to ethanol, the resultant tadpoles had significantly reduced brain sizes (microencephaly) and retarded growth rates. These effects, similar to those observed in human fetal alcohol syndrome (FAS), were dose- and time-dependent. We further showed that the antioxidant ascorbic acid (vitamin C) could inhibit the ethanol-induced reactive oxygen species (ROS) production and NF-kappaB activation and protect the ethanol-treated embryos against microencephaly and growth retardation. These results suggest the involvement of NF-kappaB and oxidative stress in ethanol-mediated developmental defects, and the potential use of ascorbic acid as a new and effective protective agent for FAS.     

Ascorbic acid and performance in man

Effects on performance of 1,2 and 4g ascorbic acid were studied from 0.5–5.5 h after ingestion in six healthy females. Diazepam (5 mg) was included as an active control, and it impaired digit symbol substitution, visuomotor coordination and complex reaction time. There were no effects of any dose of ascorbic acid on performance.     

Ascorbic acid deficiency and hepatic UDP-glucuronyltransferase

The effect of dietary ascorbic acid on hepatic microsomal UDP-glucuronyltransferase (UDPGT) activity towards p-aminophenol, bilirubin, and acetaminophen was investigated. Ascorbate deficiency produced a 33% reduction in the specific activity of UDPGT towards p-aminophenol, whereas there was no difference between microsomes from ascorbate-deficient and supplemented guinea pigs in the activity towards bilirubin and acetaminophen. This suggests that the effect of the vitamin is on a specific isozyme. This reduction was correlated with the reduced quantity of hepatic microsomal cytochrome P-450, which has been previously reported for ascorbate-deficient guinea pigs. No difference was found in the apparent affinity for the substrate, p-aminophenol, or the cofactor, UDP-glucuronic acid. Differences in microsomal UDPGT activity towards p-aminophenol occurred between the two groups with membrane-perturbing processes such as sonication and Triton X-100. Sonication and magnesium chloride were found to increase activity 329% in ascorbate-supplemented animals and 138% in the ascorbate-deficient group. The addition of ascorbate acid in vitro, or its analog d-isoascorbic acid, could protect against the detrimental effects of excess substrate by maintaining a linear enzymatic rate over a 30-min time period; there was no significant effect on the initial rate of hepatic microsomal UDPGT activity in the ascorbate-supplemented animals whereas there was a significant increase in the ascorbate-deficient group. Glutathione was as effective as ascorbic acid in protecting against the detrimental effects of excess substrate whereas cysteine and dimethyltetrapteridine were only partially effective. Ascorbyl-2-sulfate and alpha-tocopherol had no significant effect.(ABSTRACT TRUNCATED AT 250 WORDS)     

Ascorbic acid and chemically induced methemoglobinemias

Sodium nitrite was added to suspensions of washed guinea pig red cells in concentrations which converted about a third of the total blood pigment to methemoglobin. Various aliquots also contained added ascorbic acid in concentrations of 0.05, 0.5, or 5.0 mm (“physiological” levels are between 0.05 and 0.1 mm). Methemoglobin levels were followed for 2 hr at 37°C. None of the tested concentrations of ascorbate significantly attenuated methemoglobin formation. On the contrary, significantly higher methemoglobin levels were sometimes found with 5.0 mm ascorbate. Guinea pigs were maintained several weeks on a scorbutogenic diet with or without ascorbate supplementation in their water. When blood ascorbate levels were significantly different, both groups were given intraarterial sodium nitrite, 40 mg/kg, and methemoglobin levels were followed with time as above. At none of the sampling times was there a significant difference in the methemoglobin levels between the 2 groups. As judged by the appearance of radioactivity in blood at various times after sc injection, the two groups also showed no difference in the rates at which they absorbed KS¹⁴CN. In human red cell suspensions 5.0 mm ascorbate significantly attenuated the methemoglobinemic response to tested concentrations of sodium nitrite, hydroxylamine and phenylhydroxylamine at 1 hr, but lower concentrations of ascorbate were without effect. When human red cells were first exposed to nitrite, then washed and ascorbate added, significant acceleration of methemoglobin reduction was observed with 5.0 mm ascorbate at 12, 24, and 36 hr, and with 0.5 mm ascorbate at 12 and 24 hr. In contrast, the oxygen capacities of suspensions with 5.0 mm ascorbate were significantly higher than control only at 12 and 24 hr, whereas with 0.5 mm ascorbate they were significantly higher at 12, 24, and 36 hr. In plain buffer, 5.0 mm ascorbate produced a small but significant loss of the tested concentration of sodium nitrite within 2 hr, but not at shorter intervals or at lower ascorbate concentrations.     

Ascorbic acid: a scavenger of superoxide radical

The second order rate constant for the reaction between ascorbic acid and superoxide at pH 7.4 using the xanthine-xanthine oxidase system was estimated to be 5.4 x 10(6) M-1 sec-1. The results indicate that the efficacies of superoxide dismutase and ascorbic acid for catalyzing the decay of superoxide radical in animal tissues are similar. The significance of ascorbic acid as a scavenger of superoxide is discussed from the point of view of evolution of ascorbic acid synthesizing capacity in the terrestrial vertebrates.     

Oxygen therapeutics: oxygen delivery without blood

Nearly 14 million units of packed red blood cells are transfused in the United States each year. According to the U.S. Department of Health and Human Services, in 1999, 6% of hospitals reported a shortage of blood, resulting in the cancellation or postponement of surgical procedures. The many limitations and risks of transfusions of packed red blood cells in critically ill patients have facilitated interest in developing alternative agents for oxygen delivery. Over the past few decades, safe and effective substitutes have been in development. However, no currently approved agent provides both oxygen transport and volume in place of packed red blood cells. Oxygen therapeutic products have several advantages compared with packed red blood cells, including a prolonged shelf-life, lack of a cross-matching requirement, and minimal infectious risks or concerns about immunogenicity. Hemoglobin-based oxygen carriers and perfluorocarbons are being developed. Two products are undergoing clinical trials. Polyheme is undergoing a phase III study in trauma patients, and Hemopure is being evaluated in a phase II study in patients undergoing cardiopulmonary bypass surgery. A third product (Hemolink) was being evaluated in a phase III study in patients undergoing coronary artery bypass grafting surgery; however, the trial was suspended. In addition, several other hemoglobin-based oxygen carriers are in the preclinical stages. Oxygen therapeutics have several potential clinical applications in the management of perioperative blood loss, trauma, acute normovolemic hemodilution, traumatic brain injury, and blood requirements in patients who refuse or have contraindications to transfusions of red blood cells.     

Ascorbic acid and pyridoxine in experimental anaphylaxis

Two vitamins, ascorbic acid (AA) and pyridoxine have been suggested by others as useful drugs for the treatment of bronchial asthma, although the views concerning AA or controversial. We have tested both vitamins in some models of histamine release and experimental anaphylaxis. AA does not inhibit mast cell degranulation induced by phospholipase A and histamine release from isolated rat mast cells induced by compound 48/80 or antigen (egg albumin). On the contrary, in the latter tests pyridoxine exerts inhibition in a range of concentrations from 10(-3)-10(-2) M. We conclude: 1. There is no experimental basis for considering ascorbic acid as a prophylactic antiasthmatic drug as is disodium cromoglycate. 2. Pyridoxine must receive additional basic and clinical investigations in this field.     

Ascorbic acid deficiency and the flavin-containing monooxygenase

Activity of the flavin-containing monooxygenase (FMO) was reduced significantly in ascorbic acid deficient guinea pigs. Reduction in oxidation of dimethylaniline (DMA) and of thiobenzamide was associated with a decrease in the activity of the FMO. In both ascorbate supplemented and deficient guinea pig hepatic 12,000 g supernatant fractions, SKF-525A and n-octylamine did not inhibit DMA N-oxidation. Phenobarbital pretreatment did not increase the rate of N-oxidation of DMA. In addition, hepatic supernatant fractions thermally treated at 50 degree were unable to N-oxidize DMA, but 80% of the cytochrome P-450 activity was retained. Also, N-oxidation of DMA was reduced by 53% at pH 7.0, while oxidation of cytochrome P-450 specific substrates was inhibited by only 19%. Kinetic studies of DMA N-oxidation indicate no significant change in the apparent Km in ascorbate supplemented or deficient animals. The in vitro addition of ascorbic acid had no effect on the activity of the FMO. The toxicological implications of the reduction in FMO activity in ascorbic acid deficiency are discussed.     

Ascorbic acid metabolism and the clinical factors which affect tissue saturation with ascorbic acid

The factors which give rise to tissue desaturation of ascorbic acid are classified and discussed. Nutritional deprivation, normal physiological factors and metabolic factors, and pathophysiological factors may all give rise to acute and continuing ascorbic acid tissue desaturation while the factors continue to operate. Nutritional desaturation can easily be rectified by providing supplementary Vitamin C in adequate dosage. The other factors can only be rectified when the causative mechanism is arrested. Iatrogenic desaturation may be produced by aspirin and several other drugs. While causative factors excluding that of nutrition are operating, it is very difficult if not impossible to restore normal tissue values of ascorbic acid. In consequence side effects which arise from supplementary Vitamin C administration do not arise in these circumstances. The supplementary Vitamin C administration is defined as compensatory administration of Vitamin C. In healthy individuals administration of supplementary Vitamin C can be defined as (large doses). Such large doses may give rise to side effects. The mechanism by which ascorbic acid is involved in the inflammatory response is discussed.     

Ascorbic acid, dehydroascorbic acid and glutathione in liver disease

Controlled studies were conducted to find out the plasma values of ascorbic acid, dehydroascorbic acid (DHA), urinary excretion of ascorbic acid and blood levels of glutathione in patients with viral hepatitis, alcoholic hepatitis, cirrhosis of liver and carcinoma of liver. Leucocyte ascorbic acid and DHA/AA index were also determined in order to assess the ascorbic acid status of these patients. It was observed that the plasma and leucocytes contents of ascorbic acid were significantly subnormal with markedly decreased urinary excretion in these patients. Decreased level of glutathione and significantly higher level of DHA reflect an over all reducing status of the body is markedly deranged in these conditions. Further it was observed that the DHA/AA ratios were significantly altered in these groups of patients.