Biomedical subjects

W Ed Smith

Publications and source records attributed to W Ed Smith.

7 recordsLinked to original sources

PubMed2006

Apolipoprotein E exerts selective and differential control over vitamin E concentrations in different areas of mammalian brain.

Apolipoprotein E (apoE) is known to be a risk factor for the incidence of Alzheimer's disease (AD). In addition, vitamin E has been reported to have a role in the treatment of AD. We examined the potential interrelationship between vitamin E and apoE in brain. As the first step, we determined the concentrations of alpha-tocopherol in selected brain regions of apoE-deficient mice at different ages. The mice were fed normal rodent chow. All regions of the brain in apoE-deficient mice contained less alpha-tocopherol than control samples at 2.5 months of age, the initial time of study. This trend continued for 9.5 months for most regions except the spinal cord and cerebellum. Tocopherol levels in these latter regions of apoE-deficient animals increased to control levels during the study. Serum alpha-tocopherol and cholesterol levels were high in the apoE-deficient animals; however, the CNS cholesterol levels were the same in apoE-deficient and control mice. This suggests that 1) the decline in brain alpha-tocopherol in apoE deficiency is not due to overall alterations in lipid metabolism; and 2) the processing of alpha-tocopherol in brain follows a separate pathway than that of cholesterol. Subcellular concentrations of alpha-tocopherol were unaltered by apoE deficiency indicating that intracellular handling of tocopherol is not affected by apoE. ApoE may be an important protein controlling vitamin E levels in specific brain regions. Further understanding of the interactions between apoE and vitamin E could be important in the appropriate use of vitamin E in AD.

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PubMed2006

Effect of oxidative stress induced by L-dopa on endogenous antioxidants in PC-12 cells.

The mechanism of action of many drugs of abuse involves the dopaminergic pathway. One method of increasing dopamine in brain is by ingestion of L-dopa (3,4-dihydroxy-L-phenylalanine). Interestingly, both dopamine and L-dopa cause oxidative stress which is also a factor in drug-induced damage. Oxidative stress can be reduced by the antioxidant activities of vitamins C (ascorbate) and E (tocopherols). However, the interactions between L-dopa and tocopherols and ascorbate are not well understood. In this article, PC-12 cells (as models of neurons) were cultured for 21 hours with ascorbate (400 microM) and/or alpha tocopherol (25 microM) and in the presence or absence of L-dopa (250 microM). After incubation, cells were harvested and analyzed for the various biochemical components by HPLC. As expected, the addition of L-dopa resulted in an almost threefold increase in cellular dopamine content. Addition of alpha tocopherol resulted in marked increase in cellular tocopherol. Similarly, addition of ascorbate substantially increased its cellular concentration. These increases were strongly attenuated by the presence of L-dopa in the medium. The data indicate that: (a) the uptake systems for ascorbate and tocopherols in these cells are inhibited by L-dopa and/or (b) L-dopa treatment causes an increase in the rate of utilization of the two nutrients. Thus L-dopa modulates the cellular dynamics of ascorbate and tocopherol altering cellular antioxidant protection.

Animals↗

PubMed2005

Moderate hyperoxia (40%) increases antioxidant levels in mouse tissue.

BACKGROUND: Oxygen is routinely administered to patients to improve clinical outcome. Since studies have shown that administering 100% oxygen can cause unwanted side effects, intermediate concentrations of 40% oxygen are used in clinical practice. In this study, we examined whether the breathing of 40% oxygen causes beneficial effects upon tissue levels of antioxidants such as vitamin E, vitamin C, and glutathione. METHODS: Four-month-old mice were separated into two groups: control (n = 11) and experimental (n = 11). The treatment group was administered 40% oxygen for 10 days. Brain, heart, lung, liver, testes, and skeletal muscle were harvested and tissue antioxidant levels were determined by HPLC. RESULTS: Vitamin E concentrations were higher in brain, heart, lung, liver, and testes of the treatment group (P < 0.05). Glutathione concentrations were higher in the lung tissue only (P < 0.05). No differences were found in vitamin C levels. CONCLUSIONS: The data suggest that mice respond to oxidative stress by increasing tissue vitamin E incorporation and cellular synthesis of glutathione in the lung when exposed to moderate levels (40%) of hyperoxia.

Animals↗

PubMed2004

Iron uncouples oxidative phosphorylation in brain mitochondria isolated from vitamin E-deficient rats.

Few, if any, studies have examined the effect of vitamin E deficiency on brain mitochondrial oxidative phosphorylation. The latter was studied using brain mitochondria isolated from control and vitamin E-deficient rats (13 months of deficiency) after exposure to iron, an inducer of oxidative stress. Mitochondria were treated with iron (2 to 50 microM) added as ferrous ammonium sulfate. Rates of state 3 and state 4 respiration, respiratory control ratios, and ADP/O ratios were not affected by vitamin E deficiency alone. However, iron uncoupled oxidative phosphorylation in vitamin E-deficient mitochondria, but not in controls. In vitamin E-deficient mitochondria, iron decreased ADP/O ratios and markedly stimulated state 4 respiration; iron had only a modest effect on these parameters in control mitochondria. Thus, vitamin E may have an important role in sustaining oxidative phosphorylation. Low concentrations of iron (2 to 5 microM) oxidized mitochondrial tocopherol that exists in two pools. The release of iron in brain may impair oxidative phosphorylation, which would be exacerbated by vitamin E deficiency. The results are important for understanding the pathogenesis of human brain disorders known to be associated with abnormalities in mitochondrial function as well as iron homeostasis (e.g., Parkinson's disease).

Animals↗

PubMed2004

Oxidation of vitamin E and vitamin C and inhibition of brain mitochondrial oxidative phosphorylation by peroxynitrite.

The effects of peroxynitrite (PN; product of the reaction between nitric oxide and superoxide) on mitochondrial respiration as well as oxidation of alpha-tocopherol and ascorbic acid were studied. Mitochondria were isolated from brain hemispheres of 4-month-old male Fisher rats by standard centrifugation procedures utilizing Ficoll gradients. Treatment of brain mitochondria with PN caused a concentration-dependent impairment of oxidative phosphorylation and depletion of the endogenous antioxidants alpha-tocopherol and ascorbic acid. PN-induced mitochondrial dysfunction was characterized by 1) decreases in state 3 respiration and oxidative phosphorylation, 2) loss of respiratory control [ratio of ADP-stimulated (state 3) to basal (state 4) respiration], and 3) uncoupling of oxidative phosphorylation. PN did not function as a pure uncoupler, insofar as the increase in state 4 respiration was accompanied by a larger decrease in state 3 respiration. This contrasts with the uncoupling action of the protonophore carbonyl cyanide m-chlorophenylhydrozone, which increases both state 3 and state 4 respiration. PN-induced reduction in respiratory control and oxidative phosphorylation closely paralleled the oxidation of membrane tocopherol and were preceded by loss of ascorbate. alpha-Tocopherol (the most potent biological lipid antioxidant) may have a unique role in protecting mitochondrial membranes from oxidative stress. The two antioxidant nutrients alpha-tocopherol and ascorbate (which interact with each other and glutathione) may be intimately involved in protecting mitochondria in situations in which excessive release of superoxide and nitric oxide occurs under normal and/or pathological conditions.

Animals↗

PubMed2004

Oxidative stress and inhibition of oxidative phosphorylation induced by peroxynitrite and nitrite in rat brain subcellular fractions.

Nitrite and nitrate, two endogenous oxides of nitrogen, are toxic in vivo. Furthermore, the reaction of superoxide (produced by all aerobic cells) with nitric oxide (NO) generates peroxynitrite, a potent oxidizing agent, that can cause biological oxidative stress. Using subcellular fractions from rat brain hemispheres we studied oxidative stress induced by these nitrogen compounds with special emphasis on nitrite. The consumption of Vitamin C (ascorbate) and Vitamin E (alpha tocopherol), two of the important nutritional antioxidants, was followed in synaptosomes (nerve-ending particles) and mitochondria along with changes in parameters of mitochondrial oxidative phosphorylation. Nitrite, but not nitrate, oxidized ascorbate without oxidizing alpha tocopherol in both synaptosomes and mitochondria whereas peroxynitrite oxidized both ascorbate and alpha tocopherol. Functionally, both nitrite and peroxynitrite inhibited mitochondrial oxidative phosphorylation. Nitrite was less potent than peroxynitrite when the effects of equal concentrations of the two were compared. However, since nitrite is much more stable than peroxynitrite the impact of nitrite as an oxidant in vivo could be as much or even more significant than peroxynitrite. Nitrate would not have similar action unless it is reduced to nitrite. It is possible that nitrite may impair oxidative phosphorylation through modulating levels of nitric oxide, changing the activity of heme proteins or a mild uncoupling of mitochondria.

Animals↗

PubMed2004

Alpha and gamma tocopherols in cerebrospinal fluid and serum from older, male, human subjects.

OBJECTIVE: The major forms of vitamin E in human physiological fluids are alpha and gamma tocopherols which exhibit different biological activities under a variety of assay conditions. The goal of this study was to obtain indirect information about the transport of tocopherols across the blood/spinal fluid barrier by comparing the concentrations of alpha and gamma tocopherols in serum and cerebrospinal fluid (CSF). METHODS: CSF and serum samples were obtained simultaneously from 28 human, male subjects excluding those with known pathology during the performance of spinal anesthesia procedures. The samples were centrifuged and frozen, and analyzed for tocopherols by HPLC with electrochemical detection. RESULTS: The concentrations of alpha and gamma tocopherols in CSF correlated significantly with their respective concentrations in serum. This would be expected since these nutrients have to be supplied by diet to serum followed by transport to the brain. The ratios of alpha to gamma tocopherols in the CSF and serum were highly correlated. High concentrations of alpha in serum tended to suppress gamma in both serum and CSF. CONCLUSIONS: These data suggest that the processes involved in the entry of tocopherol from blood to the CSF do not discriminate between the alpha and gamma tocopherols. In contrast, alpha tocopherol is highly preferred during the packaging of plasma lipoproteins by the liver. Our data also suggest that alpha and gamma tocopherols will be available to the human brain via transport from blood.

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