Prevention of iron- and copper-mediated DNA damage by catecholamine and amino acid neurotransmitters, L-DOPA, and curcumin: metal binding as a general antioxidant mechanism.

Concentrations of labile iron and copper are elevated in patients with neurological disorders, causing interest in metal-neurotransmitter interactions. Catecholamine (dopamine, epinephrine, and norepinephrine) and amino acid (glycine, glutamate, and 4-aminobutyrate) neurotransmitters are antioxidants also known to bind metal ions. To investigate the role of metal binding as an antioxidant mechanism for these neurotransmitters, L-dihydroxyphenylalanine (L-DOPA), and curcumin, their abilities to prevent iron- and copper-mediated DNA damage were quantified, cyclic voltammetry was used to determine the relationship between their redox potentials and DNA damage prevention, and UV-vis studies were conducted to determine iron and copper binding as well as iron oxidation rates. In contrast to amino acid neurotransmitters, catecholamine neurotransmitters, L-DOPA, and curcumin prevent significant iron-mediated DNA damage (IC(50) values of 3.2 to 18 µM) and are electrochemically active. However, glycine and glutamate are more effective at preventing copper-mediated DNA damage (IC(50) values of 35 and 12.9 µM, respectively) than L-DOPA, the only catecholamine to prevent this damage (IC(50) = 73 µM). This metal-mediated DNA damage prevention is directly related to the metal-binding behaviour of these compounds. When bound to iron or copper, the catecholamines, amino acids, and curcumin significantly shift iron oxidation potentials and stabilize Fe(3+) over Fe(2+) and Cu(2+) over Cu(+), a factor that may prevent metal redox cycling in vivo. These results highlight the disparate antioxidant activities of neurotransmitters, drugs, and supplements and highlight the importance of considering metal binding when identifying antioxidants to treat and prevent neurodegenerative disorders.

Iron binding of 3-hydroxychromone, 5-hydroxychromone, and sulfonated morin: Implications for the antioxidant activity of flavonols with competing metal binding sites.

The iron binding properties and antioxidant activities of compounds with hydroxy-keto binding sites, 3-hydroxychromone, 5-hydroxychromone, and sulfonated morin were investigated. For these compounds, prevention of iron-mediated DNA damage and kinetics of Fe(II) oxidation were studied in aqueous solutions close to physiological pH (pH 6). 3-Hydroxychromone and sulfonated morin inhibit iron-mediated DNA damage at lower concentrations than 5-hydroxychromone. All three compounds bind iron, but 3-hydroxychromone and sulfonated morin promote Fe(II) oxidation much faster than 5-hydroxychromone. These results indicate that DNA damage inhibition by flavonols with competing hydroxy-keto binding sites is primarily due to iron binding at the 3-hydroxy-keto site. Iron oxidation rate also plays a significant role in antioxidant activity. In addition to iron binding and oxidation, reactive oxygen species scavenging occurs at high concentrations for the hydroxychromones. This study emphasizes the importance of iron binding in polyphenol antioxidant behavior and provides insights into the iron binding antioxidant activity of similar flavonols such as quercetin and myricetin.

Antioxidant and prooxidant effects of polyphenol compounds on copper-mediated DNA damage.

Inhibition of copper-mediated DNA damage has been determined for several polyphenol compounds. The 50% inhibition concentration values (IC(50)) for most of the tested polyphenols are between 8 and 480 µM for copper-mediated DNA damage prevention. Although most tested polyphenols were antioxidants under these conditions, they generally inhibited Cu(I)-mediated DNA damage less effectively than Fe(II)-mediated damage, and some polyphenols also displayed prooxidant activity. Because semiquinone radicals and hydroxyl radical adducts were detected by EPR spectroscopy in solutions of polyphenols, Cu(I), and H(2)O(2), it is likely that weak polyphenol-Cu(I) interactions permit a redox-cycling mechanism, whereby the necessary reactants to cause DNA damage (Cu(I), H(2)O(2), and reducing agents) are regenerated. The polyphenol compounds that prevent copper-mediated DNA damage likely follow a radical scavenging pathway as determined by EPR spectroscopy.

LICAVAL: combination therapy in acute and maintenance treatment of bipolar disorder.

BACKGROUND: The challenge of Bipolar Disorder (BD) treatment is due to the complexity of the disease. Current guidelines represent an effort to help clinicians in their everyday practice but still have limitations, specially concerning to long term treatment. LICAVAL (efficacy and tolerability of the combination of LIthium and CArbamazepine compared to lithium and VALproic acid in the treatment of young bipolar patients) study aim to evaluate acute and maintenance phase of BD treatment with two combined drugs. METHODS: LICAVAL is a single site, parallel group, randomized, outcome assessor blinded trial. BD I patients according to the DSM-IV-TR, in depressive, manic,/hypomanic or mixed episode, aged 18 to 35 years are eligible. After the diagnostic assessments, the patients are allocated for one of the groups of treatment (lithium + valproic acid or lithium + carbamazepine). Patients will be followed up for 8 weeks in phase I (acute treatment), 6 months in phase II (continuation treatment) and 12 months in phase III (maintenance treatment). Outcome assessors are blind to the treatment. The main outcome is the evaluation of changes in mean scores on CGI-BP-M between baseline and endpoint at the end of each phase of the study. RESULTS: LICAVAL is currently in progress, with patients in phase I, II or III. It will extended until august 2012. CONCLUSIONS: Trials comparing specific treatments efficacy in BD (head to head) can show relevant information in clinical practice. Long term treatment is an issue of great important and should be evaluated carefully in more studies as long as BD is a chronic disease. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00976794.