ascorbic-acid and fisetin

Many of the physiological benefits attributed to flavonoids are thought to stem from their potent antioxidant and free radical scavenging properties. Recently, it was shown that flavonoids protect nerve cells from oxidative stress by multiple mechanisms, only one of which is directly related to their antioxidant activity, suggesting that specific flavonoids may have other properties that could make them useful in the treatment of conditions that lead to nerve cell death. In particular, it was asked if any flavonoid could mimic neurotrophic proteins. To examine this possibility, we looked at the ability of flavonoids to induce nerve cell differentiation using PC12 cells. PC12 cells were treated with a variety of flavonoids to determine if there was a correlation between their neuroprotective activity and their neurite outgrowth-promoting activity. In addition, the signaling pathways required for flavonoid-induced differentiation were examined. We found that only a small subset of the flavonoids that were neuroprotective could induce neurite outgrowth by an extracellular signal-regulated kinase-dependent process. There was a strong correlation between the concentrations of the flavonoids that were neuroprotective and the concentrations that induced differentiation. These results suggest that the consumption of specific flavonoids could have further beneficial effects on nerve cells following injury, in pathological conditions or in normal aging.

Topics: Acetylcysteine; Animals; Ascorbic Acid; Blotting, Western; Cell Differentiation; Dose-Response Relationship, Drug; Drug Interactions; Enzyme Activation; Enzyme Inhibitors; Flavonoids; Flavonols; Free Radical Scavengers; GTP Phosphohydrolases; Mitogen-Activated Protein Kinases; Nerve Growth Factor; PC12 Cells; Phosphorylation; ras Proteins; Rats; Time Factors

Concurrent pulse-radiolytic generation of flavonoid aroxyl radicals and ascorbyl radicals causes a complex kinetic interplay of competing and parallel reactions. Evaluation by "kinetic modelling," that is, taking into account all possible reactions by a set of differential equations, allowed us to determine equilibria constants for the univalent steps by a novel method. From these kinetic data we were able to calculate the redox potentials for dihydroquercetin, quercetin, rutin (a quercetin 3-glycoside), kaempferol, fisetin, and luteolin. Despite the limited number of substances, two structural criteria became apparent: all substances containing the B-ring catechol group and the 2,3-double bond have a higher redox potential than ascorbate and are consequently able to oxidize it to the ascorbyl radical. With fisetin and kaempferol having values very similar to ascorbate, only the flavanone dihydro-quercetin was capable of reducing the ascorbyl radical, thus fulfilling the so-called "ascorbate-protective" function, originally proposed by Szent-Györgyi. While flavonoids are effective radical scavengers, these rather high redox potentials for most flavonols may explain their occasional prooxidative behavior.

Topics: Ascorbic Acid; Flavonoids; Flavonols; Hydrogen-Ion Concentration; Kaempferols; Kinetics; Luteolin; Molecular Structure; Oxidation-Reduction; Pulse Radiolysis; Quercetin; Rutin

We investigated the ability of various plant flavonoids (a) to inhibit 5-lipoxygenase and cyclooxygenase activities in rat peritoneal leukocytes, (b) to inhibit lipid peroxidation in rat liver microsomes, and (c) to stimulate DNA degradation caused by the antibiotic bleomycin in the presence of ferric ions. These compounds were compared with a range of synthetic phenolic substances including carnosol, vanillin, vitamin E and its analogue trolox c. The flavonoids were potent inhibitors of non-enzymatic peroxidation in membranes but this was not significantly correlated with their ability to inhibit either pathway of eicosanoid synthesis, suggesting that their mode of inhibition of 5-lipoxygenase/cyclooxygenase is not simply due to interception of peroxyl radicals generated at the active site of the enzymes. Many of the flavonoids and other compounds (including carnosol, vitamin E and trolox c) stimulated Fe3+/bleomycin-dependent DNA degradation. Those flavonoids which stimulated DNA degradation at low concentrations but which inhibited it at higher concentrations ("biphasic" effect, possibly caused by changing relative contributions of ability to reduce ferric-bleomycin or to chelate iron ions from the bleomycin) were selective inhibitors of 5-lipoxygenase compared to cyclo-oxygenase. In contrast, those flavonoids that did not stimulate DNA degradation at all proved to be cyclo-oxygenase selective inhibitors. Compounds that increased Fe3+/bleomycin-dependent DNA damage up to a maintained plateau were non-selective inhibitors of both 5-lipoxygenase and cyclo-oxygenase. Thus, a combination of iron-chelating and iron ion-reducing properties appears to be required for selective 5-lipoxygenase inhibition by phenolic compounds. Carnosol, vitamin E and trolox c were also found to be 5-lipoxygenase inhibitors of varying potency, and all were less active as cyclo-oxygenase inhibitors.

Topics: Abietanes; Animals; Antioxidants; Ascorbic Acid; Chromans; Cytochrome c Group; Diet; DNA Damage; Female; Ferric Compounds; Flavonoids; Flavonols; Leukocytes; Lipid Peroxidation; Lipoxygenase Inhibitors; Microsomes, Liver; Oxidation-Reduction; Oxygenases; Phenanthrenes; Phenols; Plant Extracts; Quercetin; Rats; Rats, Inbred Strains; Vitamin E