title: Early modulation of the transcription factor Nrf2 in rodent striatal slices by quinolinic acid, a toxic metabolite of the kynurenine pathway.
abstract: Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is a transcription factor involved in the orchestration of antioxidant responses. Although its pharmacological activation has been largely hypothesized as a promising tool to ameliorate the progression of neurodegenerative events, the actual knowledge about its modulation in neurotoxic paradigms remains scarce. In this study, we investigated the early profile of Nrf2 modulation in striatal slices of rodents incubated in the presence of the toxic kynurenine pathway metabolite, quinolinic acid (QUIN). Tissue slices from rats and mice were obtained and used throughout the experiments in order to compare inter-species responses. Nuclear Nrf2 protein levels and oxidative damage to lipids were compared. Time- and concentration-response curves of all markers were explored. Nrf2 nuclear activation was corroborated through phase 2 antioxidant protein expression. The effects of QUIN on Nrf2 modulation and oxidative stress were also compared between slices of wild-type (Nrf2(+/+)) and Nrf2 knock-out (Nrf2(-/-)) mice. The possible involvement of the N-methyl-d-aspartate receptor (NMDAr) in the Nrf2 modulation and lipid peroxidation was further explored in mice striatal slices. In rat striatal slices, QUIN stimulated the Nrf2 nuclear translocation. This effect was accompanied by augmented lipid peroxidation. In the mouse striatum, QUIN per se exerted an induction of Nrf2 factor only at 1h of incubation, and a concentration-response effect on lipid peroxidation after 3h of incubation. QUIN stimulated the striatal content of phase 2 enzymes. Nrf2(-/-) mice were slightly more responsive than Nrf2(+/+) mice to the QUIN-induced oxidative damage, and completely unresponsive to the NMDAr antagonist MK-801 when tested against QUIN. Findings of this study indicate that: (1) Nrf2 is modulated in rodent striatal tissue in response to QUIN; (2) Nrf2(-/-) striatal tissue was moderately more vulnerable to oxidative damage than the Wt condition; and (3) early Nrf2 up-regulation reflects a compensatory response to the QUIN-induced oxidative stress in course as part of a general defense system, whereas Nrf2 down-regulation might contribute to more intense oxidative cell damage.
authors.affiliation: Laboratorio de Aminoácidos Excitadores, Instituto Nacional de Neurología y Neurocirugía, S.S.A., Mexico City, Mexico.
authors.forename: A L
authors.initials: AL
authors.lastname: Colín-González
authors.affiliation: Instituto Nacional de Geriatría, S.S.A., Mexico City, Mexico.
authors.forename: A
authors.initials: A
authors.lastname: Luna-López
authors.affiliation: Departamento de Ciencias de la Salud, DCBS, Universidad Autónoma Metropolitana Iztapalapa, Mexico City, Mexico.
authors.forename: M
authors.initials: M
authors.lastname: Königsberg
authors.affiliation: Division of Neurotoxicology, National Center for Toxicological Research, FDA, Jefferson, AR, USA.
authors.forename: S F
authors.initials: SF
authors.lastname: Ali
authors.affiliation: Departamento de Biología, Facultad de Química, Universidad Nacional Autónoma de México, Mexico City, Mexico.
authors.forename: J
authors.initials: J
authors.lastname: Pedraza-Chaverrí
authors.affiliation: Laboratorio de Aminoácidos Excitadores, Instituto Nacional de Neurología y Neurocirugía, S.S.A., Mexico City, Mexico. Electronic address: absada@yahoo.com.
authors.forename: A
authors.initials: A
authors.lastname: Santamaría
mesh_terms: D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism*; D005260:Female; D006801:Humans; D007737:Kynurenine / Q000378:metabolism; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D018384:Oxidative Stress / Q000502:physiology*; D017378:Quinolinic Acid / Q000633:toxicity*; D051381:Rats; D017208:Rats, Wistar
chemical_list: D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; C495637:Nfe2l2 protein, rat; D007737:Kynurenine; D017378:Quinolinic Acid
keywords: ARE; DMF; EDTA; EGTA; HD; HEPES; HO-1; Huntington’s disease; KP; Kynurenine pathway; MDA; MK-801; N-methyl-d-aspartate receptor; NAD(P)H; NMDAr; Nrf2; Nuclear factor (erythroid-derived 2)-like 2; QUIN; ROS; S-allyl cysteine; SAC; SOD; TBARS; antioxidant defense; antioxidant response element; dimethylfumarate; dizocilpine; ethylene glycol tetraacetic acid; ethylenediaminetetraacetic acid; excitotoxicity; gamma-glutamylcysteine ligase-C; heme oxygenase-1; hydroxyethyl piperazineethanesulfonic acid; kynurenine pathway; malondialdehyde; nicotinamide adenine dinucleotide phosphate-oxidase; oxidative stress; quinolinic acid; reactive oxygen species; superoxide dismutase; tBHQ; tert-butylhydroquinone; thiobarbituric acid reactive substances; γ-GCL-C