Evidence that quinolinic acid severely impairs energy metabolism through activation of NMDA receptors in striatum from developing rats

Abstract

In the present study we investigated the effect of intrastriatal administration of 150 nmol quinolinic acid to young rats on critical enzyme activities of energy production and transfer, as well as on 14 CO 2 production from [1-14 C]acetate at distinct periods after quinolinic acid injection. We observed that quinolinic acid injection significantly inhibited complexes II (50%), III (46%) and II-III (35%), as well as creatine kinase (27%), but not the activities of complexes I and IV and citrate synthase in striatum prepared 12 h after treatment. In contrast, no alterations of these enzyme activities were observed 3 or 6 h after quinolinic acid administration. 14 CO 2 production from [1-14 C]acetate was also significantly inhibited (27%) by quinolinic acid in rat striatum prepared 12 h after injection. However, no alterations of these activities were observed in striatum homogenates incubated in the presence of 100 lM quinolinic acid . Pretreatment with the NMDA receptor antagonist MK-801 and with creatine totally prevented all inhibitory effects elicited by quinolinic acid administration. In addition, a-tocopherol plus ascorbate and the nitric oxide synthase inhibitor L-NAME completely abolished the inhibitions provoked by quinolinic acid on creatine kinase and complex III. Furthermore, pyruvate pretreatment totally blocked the inhibitory effects of quinolinic acid injection on complex II activity and partially prevented quinolinic acidinduced creatine kinase inhibition. These observations strongly indicate that oxidative phosphorylation, the citric acid cycle and cellular energy transfer are compromised by high concentrations of quinolinic acid in the striatum of young rats and that these inhibitory effects were probably mediated by NMDA stimulation.

The Endogenous Tryptophan Metabolite and NAD+ Precursor Quinolinic Acid Confers Resistance of Gliomas to Oxidative Stress

“…Here, we explored the relevance of trp catabolism in malignant gliomas beyond immunoactive metabolites and addressed the relevance of quinolinic acid for stress resistance. Quinolinic acid has previously mainly been studied as a neurotoxin accumulating in the CNS of patients with neurodegenerative diseases where it causes excitotoxicity by binding and activating the NMDA receptor (44)(45)(46)(47). Its physiologic relevance as a NAD þ precursor has received much less attention possibly because it has been viewed as a less relevant NAD þ synthesis pathway compared with the de novo NAD þ synthesis pathway through NAMPT or the NAD þ -recycling pathway through NAPRT.…”

An exploration of the associations of pregnancy and perinatal features with cytokines and tryptophan/kynurenine metabolism in children with attention-deficit hyperactivity disorder (ADHD)

“…Levels of all cytokines in pregnant women (Tsunoda et al 2003) or, generalising, at least the inflammatory cytokines (Zhang et al 2008) may 1 The potential toxicity may result from the agonism of the 3HK metabolite quinolinic acid at NMDA receptors (Ribeiro et al 2006). But, it may be noted that further metabolism to NAD(?)…”

Suppressing inflammatory cascade by cyclo-oxygenase inhibitors attenuates quinolinic acid induced Huntington's disease-like alterations in rats

“…Supporting the previous studies, intrastriatal QA injection significantly impaired mitochondrial enzyme activities in the striatum (Ribeiro et al, 2006). Further, report indicated that mitochondrial complex inhibitors preferentially damage substantia nigra dopamine neurons in rat brain slices (Bywood and Johnson, 2003).…”