Quinolinic acid reduces the antioxidant defenses in cerebral cortex of young rats

Abstract

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.

Atorvastatin Prevents Hippocampal Cell Death due to Quinolinic Acid-Induced Seizures in Mice by Increasing Akt Phosphorylation and Glutamate Uptake

“…We have reported that QA-induced seizures are also related to an unbalance on the clearance of glutamate from the synaptic cleft causing an exacerbation of glutamatergic system (Tavares et al 2000(Tavares et al , 2002(Tavares et al , 2008. Moreover, excitotoxicity induced by QA has been related to its ability to increase free radical content and, consequently, induce oxidative stress (Leipnitz et al 2005;Ganzella et al 2006). Therefore, the mechanisms involved in the neuroprotective effect of atorvastatin against QA-induced hippocampal cell death in mice may be directly related to a reduction in glutamate toxicity, since increased cell viability, phospho-Akt levels and glutamate uptake were observed in hippocampal slices obtained from convulsed or non-convulsed animals.…”

Effect of caffeic acid and rofecoxib and their combination against intrastriatal quinolinic acid induced oxidative damage, mitochondrial and histological alterations in rats

“…Increased concentrations of QA is found in brain of patient's with neurodegenerative diseases, including Huntington's disease and Alzheimer's disease, whose pathophysiology has been recently associated with oxidative stress (Rossato et al 2002;Leipnitz et al 2005). QA is an endogenous glutamate agonist with a relative selectivity toward N-methyl-D-aspartate (NMDA) receptor, causing neuronal death in vitro and in vivo (Santamaría and Ríos 1993).…”

Quinolinic Acid: An Endogenous Neurotoxin with Multiple Targets

“…Furthermore, it has been shown the QUIN capacity to modify the profiles of some endogenous antioxidants in rat brain such as the content of reduced glutathione and copper and zinc-dependent superoxide dismutase activity (Cu, Zn-SOD) [108] and its ability to generate during early stages of toxicity • OH radical [109] and peroxynitrite [86] and to increase lipid peroxidation [108, 110]. In rat brain, intracerebral injection of QUIN resulted in significant neuronal loss and a markedly increased level of SOD1 expression in a time-dependent manner [111]; this increase in SOD1 expression was thought to be a neuroprotective response to limit the oxidative damage caused by QUIN.…”