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Neurotoxicology. 2015 Sep;50:81-91. doi: 10.1016/j.neuro.2015.08.003. Epub 2015 Aug 5.

Mitochondrial dysfunction related to cell damage induced by 3-hydroxykynurenine and 3-hydroxyanthranilic acid: Non-dependent-effect of early reactive oxygen species production.

Author information

1
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.
2
Departamento de Neuroquímica, Instituto Nacional de Neurología y Neurocirugía Manuel Velasco Suárez, Insurgentes Sur 3877, México D.F. 14269, Mexico.
3
Laboratorio de Neuroinmunología, Instituto Nacional de Neurología y Neurocirugía Manuel Velasco Suárez, S.S.A., México D.F. 14269, Mexico.
4
Unidad de Neurobiología Dinámica, Departamento de Neuroquímica, Instituto Nacional de Neurología y Neurocirugía Manuel Velasco Suárez, S.S.A., México D.F. 14269, Mexico.
5
Laboratorio de Bioquímica Muscular, Instituto Nacional de Rehabilitación S.S.A., México D.F. 14389, Mexico.
6
Laboratorio Experimental de Enfermedades Neurodegenerativas. Instituto Nacional de Neurología y Neurocirugía Manuel Velasco Suárez, S.S.A., México D.F. 14269, Mexico.
7
Área de Neurociencias, Departamento de Biología de la Reproducción, Universidad Autónoma Metropolitana-Iztapalapa, 09340 México, DF, Mexico.
8
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.

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.

KEYWORDS:

3-Hydroxyanthranilic acid; 3-Hydroxykynurenine; Kynurenines; Mitochondria dysfunction; Oxidative damage

PMID:
26254737
DOI:
10.1016/j.neuro.2015.08.003
[Indexed for MEDLINE]

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