Quinolinic acid reduces the antioxidant defenses in cerebral cortex of young rats.
Quinolinic acid (QA), the major metabolite of the kynurenine pathway, is found at increased concentrations in brain of patients affected by various common neurodegenerative diseases, including Huntington's disease and Alzheimer's disease. Recently, a role for QA in the pathophysiology of glutaric acidemia type I (GAI) was postulated. Considering that oxidative stress has been recently involved in the pathophysiology of the brain injury in these neurodegenerative disorders; in the present study, we investigated the in vitro effect of QA on various parameters of oxidative stress, namely total radical-trapping antioxidant potential (TRAP), total antioxidant reactivity (TAR), glutathione (GSH) levels, thiobarbituric acid-reactive substances (TBA-RS) measurement and chemiluminescence in cerebral cortex of 30-day-old rats. QA diminished the brain non-enzymatic antioxidant defenses, as determined by the reduced levels of TRAP, TAR and GSH. We also observed that QA significantly increased TBA-RS and chemiluminescence. Therefore, in vitro QA-treatment of rat cortical supernatants induced oxidative stress by reducing the tissue antioxidant defenses and increasing lipid oxidative damage, probably as a result of free radical generation. In addition, we examined the effect of QA on TBA-RS levels in the presence of glutaric acid (GA) and 3-hydroxyglutaric acid (3HGA), which are accumulated in GAI, as well as in the presence of 3-hydroxykynurenine (3HK), a tryptophan metabolite of the kynurenine pathway with antioxidant properties. It was verified that the single addition of QA or GA plus 3HGA to the incubation medium significantly stimulated in vitro lipid peroxidation. Furthermore, 3HK completely prevented the TBA-RS increase caused by the simultaneous addition of QA, GA and 3HGA. Taken together, it may be presumed that QA induces oxidative stress in the brain, which may be associated, at least in part, with the pathophysiology of central nervous system abnormalities of neurodegenerative diseases in which QA accumulates.
Leipnitz
Guilhian
G
Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal de Rio Grande do Sul, Rua Ramiro Barcelos N 2600 - Anexo, CEP 90035-003, Porto Alegre, RS, Brazil.
Schumacher
Cristiana
C
Scussiato
Karina
K
Dalcin
Karina B
KB
Wannmacher
Clóvis M D
CM
Wyse
Angela T D
AT
Dutra-Filho
Carlos S
CS
Wajner
Moacir
M
Latini
Alexandra
A
D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D000975:Antioxidants / Q000494:pharmacology*; D001923:Brain Chemistry / Q000187:drug effects*; D002540:Cerebral Cortex / Q000187:drug effects* / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005977:Glutarates / Q000494:pharmacology; D005979:Glutathione Peroxidase / Q000378:metabolism; D066298:In Vitro Techniques; D015227:Lipid Peroxidation / Q000187:drug effects; D056913:Mediator Complex Subunit 1; D017378:Quinolinic Acid / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism
C108959:3-hydroxyglutaric acid; D000975:Antioxidants; D005977:Glutarates; C538857:Med1 protein, rat; D056913:Mediator Complex Subunit 1; D017392:Thiobarbituric Acid Reactive Substances; D014157:Transcription Factors; D005979:Glutathione Peroxidase; D017378:Quinolinic Acid