title: Mitochondrial dysfunction related to cell damage induced by 3-hydroxykynurenine and 3-hydroxyanthranilic acid: Non-dependent-effect of early reactive oxygen species production.
abstract: The kynurenines 3-hydroxyanthranilic acid (3-HANA) and its precursor 3-hydroxykynurenine (3-HK) are metabolites derived from tryptophan degradation. 3-HK, has been related to diverse neurodegenerative diseases including Huntington's, Alzheimer's and Parkinson's diseases that share mitochondrial metabolic dysregulation. Nevertheless, the direct effect of these kynurenines on mitochondrial function has not been investigated despite it could be regulated by their redox properties that are controversial. A body of literature has suggested a ROS mediated cell death induced by 3-HK and 3-HANA. On the other hand, some works have supported that both kynurenines have antioxidant effects. Therefore, the aim of this study was to investigate 3-HK and 3-HANA effects on mitochondrial and cellular function in rat cultured cortical astrocytes (rCCA) and in animals intrastriatally injected with these kynurenines as well as to determinate the ROS role on these effects. First, we evaluated 3-HK and 3-HANA effect on cellular function, ROS production and mitochondrial membrane potential in vivo and in vitro in rCCA. Our results show that both kynurenines decreased MTT reduction in a concentration-dependent manner together with mitochondrial membrane potential. These observations were accompanied with increased cell death in rCCA and in circling behavior and morphological changes of injected animals. Interestingly, we found that ROS production was not increased in both in vitro and in vivo experiments, and accordingly lipid peroxidation (LP) was neither increased in striatal tissue of animals injected with both kynurenines. The lack of effect on these oxidative markers is in agreement with the ·OH and ONOO(-) scavenging capacity of both kynurenines detected by chemical combinatorial assays. Altogether, these data indicate that both kynurenines exert toxic effects through mechanisms that include impairment of cellular energy metabolism which are not related to early ROS production.
authors.affiliation: Departamento de Neuroquímica, Instituto Nacional de Neurología y Neurocirugía Manuel Velasco Suárez, Insurgentes Sur 3877, México D.F. 14269, Mexico; Área de Neurociencias, Departamento de Biología de la Reproducción, Universidad Autónoma Metropolitana-Iztapalapa, 09340 México, DF, Mexico.
authors.forename: J
authors.initials: J
authors.lastname: Reyes-Ocampo
authors.affiliation: Departamento de Neuroquímica, Instituto Nacional de Neurología y Neurocirugía Manuel Velasco Suárez, Insurgentes Sur 3877, México D.F. 14269, Mexico.
authors.forename: D
authors.initials: D
authors.lastname: Ramírez-Ortega
authors.affiliation: Departamento de Neuroquímica, Instituto Nacional de Neurología y Neurocirugía Manuel Velasco Suárez, Insurgentes Sur 3877, México D.F. 14269, Mexico.
authors.forename: G I Vázquez
authors.initials: GI
authors.lastname: Cervantes
authors.affiliation: Laboratorio de Neuroinmunología, Instituto Nacional de Neurología y Neurocirugía Manuel Velasco Suárez, S.S.A., México D.F. 14269, Mexico.
authors.forename: B
authors.initials: B
authors.lastname: Pineda
authors.affiliation: Unidad de Neurobiología Dinámica, Departamento de Neuroquímica, Instituto Nacional de Neurología y Neurocirugía Manuel Velasco Suárez, S.S.A., México D.F. 14269, Mexico.
authors.forename: Pavel Montes de Oca
authors.initials: PM
authors.lastname: Balderas
authors.affiliation: Departamento de Neuroquímica, Instituto Nacional de Neurología y Neurocirugía Manuel Velasco Suárez, Insurgentes Sur 3877, México D.F. 14269, Mexico.
authors.forename: D
authors.initials: D
authors.lastname: González-Esquivel
authors.affiliation: Laboratorio de Bioquímica Muscular, Instituto Nacional de Rehabilitación S.S.A., México D.F. 14389, Mexico.
authors.forename: L
authors.initials: L
authors.lastname: Sánchez-Chapul
authors.affiliation: Departamento de Neuroquímica, Instituto Nacional de Neurología y Neurocirugía Manuel Velasco Suárez, Insurgentes Sur 3877, México D.F. 14269, Mexico.
authors.forename: R
authors.initials: R
authors.lastname: Lugo-Huitrón
authors.affiliation: Laboratorio Experimental de Enfermedades Neurodegenerativas. Instituto Nacional de Neurología y Neurocirugía Manuel Velasco Suárez, S.S.A., México D.F. 14269, Mexico.
authors.forename: D
authors.initials: D
authors.lastname: Silva-Adaya
authors.affiliation: Departamento de Neuroquímica, Instituto Nacional de Neurología y Neurocirugía Manuel Velasco Suárez, Insurgentes Sur 3877, México D.F. 14269, Mexico.
authors.forename: C
authors.initials: C
authors.lastname: Ríos
authors.affiliation: Área de Neurociencias, Departamento de Biología de la Reproducción, Universidad Autónoma Metropolitana-Iztapalapa, 09340 México, DF, Mexico.
authors.forename: A
authors.initials: A
authors.lastname: Jiménez-Anguiano
authors.affiliation: Departamento de Neuroquímica, Instituto Nacional de Neurología y Neurocirugía Manuel Velasco Suárez, Insurgentes Sur 3877, México D.F. 14269, Mexico. Electronic address: veped@yahoo.com.mx.
authors.forename: V
authors.initials: V
authors.lastname: Pérez-de la Cruz
mesh_terms: D015095:3-Hydroxyanthranilic Acid / Q000633:toxicity*; D000818:Animals; D001253:Astrocytes / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D004195:Disease Models, Animal; D004734:Energy Metabolism / Q000187:drug effects; D016166:Free Radical Scavengers / Q000494:pharmacology*; D007737:Kynurenine / Q000031:analogs & derivatives* / Q000633:toxicity; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D028361:Mitochondrial Diseases / Q000139:chemically induced*; D010084:Oxidation-Reduction / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013239:Stereotyped Behavior / Q000187:drug effects; D013385:Succinate Dehydrogenase / Q000378:metabolism
chemical_list: D016166:Free Radical Scavengers; D017382:Reactive Oxygen Species; D015095:3-Hydroxyanthranilic Acid; C005045:3-hydroxykynurenine; D007737:Kynurenine; D013385:Succinate Dehydrogenase
keywords: 3-Hydroxyanthranilic acid; 3-Hydroxykynurenine; Kynurenines; Mitochondria dysfunction; Oxidative damage