title: The Janus faces of 3-hydroxykynurenine: dual redox modulatory activity and lack of neurotoxicity in the rat striatum.
abstract: 3-Hydroxykynurenine (3-HK), an intermediate metabolite of the kynurenine pathway, has been largely hypothesized as a neurotoxic molecule contributing to neurodegeneration in several experimental and clinical conditions. Interestingly, the balance in literature points to a dual role of this molecule in the CNS: in vitro studies describe neurotoxic and/or antioxidant properties, whereas in vivo studies suggest a role of this metabolite as a weak neurotoxin. This work was designed to investigate, under different experimental conditions, whether or not 3-HK is toxic to cells, and if the redox activity exerted by this molecule modulates its actions in the rat striatum. In order to evaluate these effects, 3-HK was administered in vitro to isolated striatal slices, and in vivo to the striatum of rats. In striatal slices, 3-HK exerted a concentration- and time-dependent effect on lipid peroxidation, inducing both pro-oxidant actions at low (5-20) micromolar concentrations, and antioxidant activity at a higher concentration (100µM). Interestingly, while 3-HK was unable to induce mitochondrial dysfunction in slices, at the same range of concentrations it prevented the deleterious effects exerted by the neurotoxin and related metabolite quinolinic acid (QUIN), the mitochondrial toxin 3-nitropropionic acid, and the pro-oxidant compound iron sulfate. These protective actions were related to the stimulation of glutathione S-transferase (GST) and superoxide dismutase (SOD) activities. In addition, 3-HK stimulated the protein content of the transcription factor and antioxidant regulator Nrf2, and some of its related proteins. Accordingly, 3-HK, but not QUIN, exhibited reductive properties at high concentrations. The striatal tissue of animals infused with 3-HK exhibited moderate levels of lipid and protein oxidation at short times post-lesion (h), but these endpoints were substantially decreased at longer times (days). These effects were correlated with an early increase in glutathione reductase (GR) and GST activities. However, these changes were likely to be merely compensatory as 3-HK-infused animals did not display behavioral (rotation) alterations or morphological changes in their injected striata. Altogether, these findings suggest that, despite 3-HK might exert pro-oxidant actions under certain conditions, these changes serve to evoke a redox modulatory activity that, in turn, could decrease the risk of cell damage. In light of this evidence, 3-HK seems to be more a redox modulatory molecule than a neurotoxic metabolite.
authors.affiliation: Laboratorio de Aminoácidos Excitadores, Instituto Nacional de Neurología y Neurocirugía, SSA, Mexico City 14269, Mexico.
authors.forename: Ana Laura
authors.initials: AL
authors.lastname: Colín-González
authors.affiliation: Laboratorio de Aminoácidos Excitadores, Instituto Nacional de Neurología y Neurocirugía, SSA, Mexico City 14269, Mexico.
authors.forename: Marisol
authors.initials: M
authors.lastname: Maya-López
authors.affiliation: Departamento de Biología, Facultad de Química, Universidad Nacional Autónoma de México, Mexico City, Mexico.
authors.forename: José
authors.initials: J
authors.lastname: Pedraza-Chaverrí
authors.affiliation: Division of Neurotoxicology, National Center for Toxicological Research, FDA, Jefferson, AR, USA.
authors.forename: Syed F
authors.initials: SF
authors.lastname: Ali
authors.affiliation: Departamento de Medicina Experimental, Facultad de Medicina, Universidad Nacional Autónoma de México, Mexico City, Mexico.
authors.forename: Anahí
authors.initials: A
authors.lastname: Chavarría
authors.affiliation: Laboratorio de Aminoácidos Excitadores, Instituto Nacional de Neurología y Neurocirugía, SSA, Mexico City 14269, Mexico. Electronic address: absada@yahoo.com.
authors.forename: Abel
authors.initials: A
authors.lastname: Santamaría
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D007737:Kynurenine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology / Q000633:toxicity; D008297:Male; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D017072:Neostriatum / Q000187:drug effects / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D010084:Oxidation-Reduction; D051381:Rats; D017208:Rats, Wistar
chemical_list: D000975:Antioxidants; C005045:3-hydroxykynurenine; D007737:Kynurenine
keywords: Antioxidant systems; Cell preservation; Kynurenine pathway; Oxidative stress; Redox activity