The effect of quinolinate on rat brain lipid peroxidation is dependent on iron

Stípek, S; Šťastný, F; Plátenı́k, Jan; Crkovská, J; Zima, Tomáš

doi:10.1016/s0197-0186(97)90002-4

Cited by 81 publications

(28 citation statements)

References 25 publications

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“…The results presented in this paper are in accordance with a previous study (36) where QA at high concentrations was able to abolish iron-induced TBARS production. In support, our data showed that DFO, a classical chelating of Fe 3+ , completely abolished QA pro-oxidant activity, demonstrating iron ions involvement on QA-induced TBARS production.…”

Section: Discussionsupporting

confidence: 93%

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Krebs Cycle Intermediates Modulate Thiobarbituric Acid Reactive Species (TBARS) Production in Rat Brain In Vitro

2005

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The aim of this study was to investigate the effect of Krebs cycle intermediates on basal and quinolinic acid (QA)- or iron-induced TBARS production in brain membranes. Oxaloacetate, citrate, succinate and malate reduced significantly the basal and QA-induced TBARS production. The potency for basal TBARS inhibition was in the order (IC50 is given in parenthesis as mM) citrate (0.37) > oxaloacetate (1.33) = succinate (1.91) > > malate (12.74). alpha-Ketoglutarate caused an increase in TBARS production without modifying the QA-induced TBARS production. Cyanide (CN-) did not modify the basal or QA-induced TBARS production; however, CN- abolished the antioxidant effects of succinate. QA-induced TBARS production was enhanced by iron ions, and abolished by desferrioxamine (DFO). The intermediates used in this study, except for alpha-ketoglutarate, prevented iron-induced TBARS production. Oxaloacetate, citrate, alpha-ketoglutarate and malate, but no succinate and QA, exhibited significantly iron-chelating properties. Only alpha-ketoglutarate and oxaloacetate protected against hydrogen peroxide-induced deoxyribose degradation, while succinate and malate showed a modest effect against Fe2+/H2O2-induced deoxyribose degradation. Using heat-treated preparations citrate, malate and oxaloacetate protected against basal or QA-induced TBARS production, whereas alpha-ketoglutarate induced TBARS production. Succinate did not offer protection against basal or QA-induced TBARS production. These results suggest that oxaloacetate, malate, succinate, and citrate are effective antioxidants against basal and iron or QA-induced TBARS production, while alpha-ketoglutarate stimulates TBARS production. The mechanism through which Krebs cycle intermediates offer protection against TBARS production is distinct depending on the intermediate used. Thus, under pathological conditions such as ischemia, where citrate concentrations vary it can assume an important role as a modulator of oxidative stress associated with such situations.

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Section: Discussionsupporting

confidence: 93%

“…In addition, it has been reported that QA was able to stimulate lipid peroxidation in rat brain homogenates and its pro-oxidant effect is blocked by MK 801 and a variety of antioxidants (25,(32)(33)(34)(35). Of particular importance, the in vitro pro-oxidant activity of QA is dependent on iron ions [36,37].…”

Section: Introductionmentioning

confidence: 99%

Krebs Cycle Intermediates Modulate Thiobarbituric Acid Reactive Species (TBARS) Production in Rat Brain In Vitro

2005

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“…QUIN promotes lipid peroxidation [11] in an NMDA receptor [12] and iron (II) [13] dependent manner. Furthermore, QUIN-iron complexes produce reactive oxygen species (ROS) upon auto-oxidation [14].…”

Section: Neuroactive Kynurenine Metabolitesmentioning

confidence: 99%

The kynurenine pathway and neurodegenerative disease

Maddison

Giorgini

2015

Seminars in Cell & Developmental Biology

234

223

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Neuroactive metabolites of the kynurenine pathway (KP) of tryptophan degradation have been closely linked to the pathogenesis of several neurodegenerative diseases. Tryptophan is an essential amino acid required for protein synthesis, and in higher eukaryotes is also converted into the key neurotransmitters serotonin and tryptamine. However, in mammals >95% of tryptophan is metabolized through the KP, ultimately leading to the production of nicotinamide adenosine dinucleotide (NAD + ). A number of the pathway metabolites are neuroactive; e.g. can modulate activity of several glutamate receptors and generate/scavenge free radicals. Imbalances in absolute and relative levels of KP metabolites have been strongly associated with neurodegenerative disorders including Huntington's, Alzheimer's, and Parkinson's diseases. The KP has also been implicated in the pathogenesis of other brain disorders (e.g. schizophrenia, bipolar disorder), as well as several cancers and autoimmune disorders such as HIV. Pharmacological and genetic manipulation of the KP has been shown to ameliorate neurodegenerative phenotypes in a number of model organisms, suggesting that it could prove to be a viable target for the treatment of such diseases. Here, we provide an overview of the KP, its role in neurodegeneration and the current strategies for therapeutic targeting of the pathway.

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“…This activity can produce substantial oxidation of cellular lipids, especially in the presence of transition metal ions [5].…”

Section: Quinolinic Acidmentioning

confidence: 99%

An expanding range of targets for kynurenine metabolites of tryptophan

Stone

Stoy

Darlington

2013

Trends in Pharmacological Sciences

294

207

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The kynurenine pathway of tryptophan metabolism accounts for most of the tryptophan that is not committed to protein synthesis and includes compounds active in the nervous and immune systems. Kynurenine acts on the aryl hydrocarbon receptor, affecting metabolism of xenobiotics and promoting carcinogenesis. Quinolinic acid is an agonist at N-methyl-D-aspartate receptors (NMDAR), but is also pro-oxidant, has immunomodulatory actions and promotes the formation of hyperphosphorylated tau proteins. Kynurenic acid blocks NMDARs and 7-homomeric nicotinic cholinoceptors but is also an agonist at the orphan G-protein-coupled receptor GPR35. 3-hydroxykynurenine and 3-hydroxyanthranilic acid have pronounced redox activity and regulate T cell function. Cinnabarinic acid can activate metabotropic glutamate receptors.The aim of this review is to highlight the increasing range of molecular targets for components of the kynurenine pathway, in both the nervous and immune systems, in relation to their relevance to disease and drug development. 3 The kynurenine pathwayApart from the tryptophan used in protein synthesis, most of this amino acid in mammals is oxidised along the kynurenine pathway. Only around 1% of tryptophan is used for the synthesis of 5-hydroxytrpytamine (5-HT). For many years, most compounds along the pathway ( Figure 1) were thought to have little biological activity until quinolinic acid was shown to be an agonist at glutamate receptors sensitive to NMDA [1] and kynurenic acid was found to be an antagonist at these and other ionotropic glutamate receptors [2]. These two compounds have been the focus of attention on the kynurenine pathway for over 30 years [3,4]. In parallel with work on the central nervous system (CNS), however, there has been growing interest in the role of kynurenines in the immune system, and the last few years have seen the identification of more molecular targets acted on by quinolinic acid, kynurenic acid or other components of the pathway. The key enzymes, indoleamine-2,3-dioxygenase (IDO) and kynurenine-3-monoxygenase (KMO) are also potential drug targets.The aim of this review is to highlight the increasing range of molecular targets now recognised in the nervous and immune systems in relation to their relevance to disease and drug development. Kynurenine metabolites and their receptors in disease Quinolinic acidIn addition to its ability to activate NMDARs selectively, quinolinic acid can generate reactive oxygen species (ROS). This activity can produce substantial oxidation of cellular lipids, especially in the presence of transition metal ions [5]. 4The axon-sparing neuronal loss produced by quinolinic acid in vivo may be due partly to formation of ROS [6] although it certainly also involves activation of NMDARs.Acting on human primary astrocytes, excitotoxic concentrations of quinolinic acid can also promote the expression and secretion of some of the more potent Kynurenic acidTwo early studies of the anti-epileptic actions of kynurenic acid independently reported that i...

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The effect of quinolinate on rat brain lipid peroxidation is dependent on iron

Cited by 81 publications

References 25 publications

Krebs Cycle Intermediates Modulate Thiobarbituric Acid Reactive Species (TBARS) Production in Rat Brain In Vitro

Krebs Cycle Intermediates Modulate Thiobarbituric Acid Reactive Species (TBARS) Production in Rat Brain In Vitro

The kynurenine pathway and neurodegenerative disease

An expanding range of targets for kynurenine metabolites of tryptophan

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