Quinolinic Acid: Neurotoxin or Oxidative Stress Modulator?

Lenka Kubicova,Vladimir Chobot,Franz Hadacek

doi:10.3390/ijms141121328

Lenka Kubicova, Vladimir Chobot + Show 1 more

Open Access

https://doi.org/10.3390/ijms141121328

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Abstract

Quinolinic acid (2,3-pyridinedicarboxylic acid, QUIN) is a well-known neurotoxin. Consequently, QUIN could produce reactive oxygen species (ROS). ROS are generated in reactions catalyzed by transition metals, especially iron (Fe). QUIN can form coordination complexes with iron. A combination of differential pulse voltammetry, deoxyribose degradation and Fe(II) autoxidation assays was used for explorating ROS formation in redox reactions that are catalyzed by iron in QUIN-Fe complexes. Differential pulse voltammetry showed an anodic shift of the iron redox potential if iron was liganded by QUIN. In the H2O2/FeCl3/ascorbic acid variant of the deoxyribose degradation assay, the dose-response curve was U-shaped. In the FeCl3/ascorbic acid variant, QUIN unambiguously showed antioxidant effects. In the Fe(II) autoxidation assay, QUIN decreased the rate of ROS production caused by Fe(II) oxidation. Our study confirms that QUIN toxicity may be caused by ROS generation via the Fenton reaction. This, however, applies only for unnaturally high concentrations that were used in attempts to provide support for the neurotoxic effect. In lower concentrations, we show that by liganding iron, QUIN affects the Fe(II)/Fe(III) ratios that are beneficial to homeostasis. Our results support the notion that redox chemistry can contribute to explaining the hormetic dose-response effects.

Highlights

Quinolinic acid (2,3-pyridinedicarboxylic acid; QUIN) is an intermediate of the kynurenine metabolic pathway of the amino acid, tryptophan
QUIN was identified as an important endogenous neurotoxin that participates in the pathogeneses of various neurodegenerative and psychical diseases, such as Parkinson’s, Alzheimer’s and Huntington’s diseases, schizophrenia and depressions [1,3]
When iron was predominantly liganded by QUIN, Fe(II)/Fe(III) redox cycling was less efficient in the reduction of molecular oxygen (2) compared to the coordination complexes with ascorbic acid, which caused higher thiobarbituric acid reactive species (TBARS) development than the Fe(III)ethylenediaminetetraacetic acid (EDTA) complex

Summary

Introduction

Quinolinic acid (2,3-pyridinedicarboxylic acid; QUIN) is an intermediate of the kynurenine metabolic pathway of the amino acid, tryptophan. Very high QUIN concentrations inhibited lipid peroxidation in an iron-ascorbate system [18], such as the rate of Fe(II) autoxidation, resulting in ROS production decreasing if it was liganded by QUIN [19]. We studied Fe(II)/Fe(III) redox cycling in QUIN and ethylenediaminetetraacetic acid (EDTA) coordination complexes in terms of ROS production in two chemical assays, deoxyribose degradation and Fe(II) autoxidation. Iron ions that are added as chloride salt can form coordination complexes with the test compound; in the case of the addition of iron as a Fe-EDTA complex, this is not possible Further modifications of this assay, when hydrogen peroxide and/or ascorbic acid are omitted, provide more extensive information about the redox chemistry of the test compounds and their complexes with iron [27]. Many complex properties, such as the spin states of the d electrons or steric factors, can influence the redox potential of iron and that of the ligand, both of which determine the redox chemistry of the complex [15,29]

Results and Discussion

Differential Pulse Voltammetry

Deoxyribose Degradation Assay Variants

Conclusions