5-Hydroxyanthranilic Acid, a Tryptophan Metabolite, Generates Oxidative Stress and Neuronal Death via p38 Activation in Cultured Cerebellar Granule Neurones

Smith, Alan; Smith, Robert A.; Stone, T.W.

doi:10.1007/s12640-009-9034-0

Cited by 54 publications

(47 citation statements)

References 40 publications

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“…3-Hydroxyanthranilic acid (3-HA) and 3-hydroxykynurenine (3-HK) are metabolized via kynurenine pathway. However, these metabolites have been reported rather cofactors in the oxidative damage (12,13). Another metabolite, 5-hydrotryptamine (5-HT), was reported to be involved in the pathogenesis of inflammation in experimental colitis (14).…”

Section: Discussionmentioning

confidence: 99%

Protective effect of tryptophan against dextran sulfate sodium- induced experimental colitis

Shizuma¹,

Mori²,

Fukuyama³

2009

Turk J Gastroenterol

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Section: Discussionmentioning

confidence: 99%

Protective effect of tryptophan against dextran sulfate sodium- induced experimental colitis

Shizuma¹,

Mori²,

Fukuyama³

2009

Turk J Gastroenterol

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“…The formation of these lesions can be blocked via either NMDA receptor inhibition or scavenging of free radicals using N-tert-butyl-a-(2-sulphophenyl)-nitrone. Synthesized further downstream in the pathway, the metabolite 3-HANA readily auto-oxidizes and consequently generates highly reactive species such as hydrogen peroxide and hydroxyl radicals [25] [26], which is enhanced by SOD but abolished by catalase [26] [23]. These data suggest that 3-HK and 3-HANA mediated neurotoxicity is caused by ROS, which can be specifically counteracted by catalase activity.…”

Section: Neuroactive Kynurenine Metabolitesmentioning

confidence: 95%

“…Indeed, 3-HK treatment of cultured striatal and cortical neurons results in reduced viability, shrunken, irregular somata and reduced neuritic outgrowths, which is prevented by the antioxidant catalase, but not superoxide dismutase (SOD) [21] [22] [23]. Notably, intrastriatal co-injection of 3-HK with QUIN potentiates excitotoxic neuronal lesions [24].…”

Section: Neuroactive Kynurenine Metabolitesmentioning

confidence: 99%

The kynurenine pathway and neurodegenerative disease

Maddison

Giorgini

2015

Seminars in Cell & Developmental Biology

243

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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“…3-Hydroxykynurenine (3HK), 3-hydroxyanthranilic acid (3HAA), and 5-hydroxyanthranilic acid (5HAA) induce cell death which increases with the exposure time and intracellular concentration compounds (Smith et al 2009 ). Actually, the precursor of 3HAA, 3HK, is a potential endogenous neurotoxin.…”

Section: Toxic Versus Protective Effect Of Tryptophan Metabolitesmentioning

confidence: 99%

Tryptophan and Cell Death

Engin¹

2015

Tryptophan Metabolism: Implications for Biological Processes, Health and Disease

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Cell death attributed to the tryptophan (Trp) metabolites is dependent on the exposure time and intracellular concentrations of cytotoxic Trp derivatives such as 3-hydroxykynurenine (3HK), 3-hydroxyanthranilic acid (3HAA), 5-hydroxyanthranilic acid (5HAA), and quinolinic acid (QA). However, 3HAA, 3HK, and QA at low concentrations may also serve as a precursor for nicotinamide adenine dinucleotide [NAD + ] which has vital importance to maintain cell viability. Inhibition of indoleamine 2,3-dioxygenase (IDO) activity results in a dosedependent decrease in intracellular [NAD + ] levels. Mitochondrial permeability transition occurs in several forms of necrotic cell death. Disturbances in the normal function of the mitochondria are associated with the alterations in the balance of Trp metabolism. While kynurenic acid (KA) has proven to be neuroprotective with the potential endogenous antioxidant properties, QA is a specifi c agonist at the N-methyl-d -aspartate (NMDA) receptors and a potent neurotoxin with the marked free radical-producing property. QA-induced cytotoxic effects are mediated by overactivation of NMDA-like receptors and overexpression of inducible nitric oxide synthase (iNOS). l -Kynurenine-derived neurotoxin-induced apoptosis occurs through reactive oxygen species (ROS)-mediated pathways and is blocked by antioxidants. Unlike the kynurenine pathway, the methoxyindole metabolites of Trp metabolism protect cells against oxidative stress-induced apoptosis. Furthermore, deprivation of Trp triggers autophagy in a mammalian target of rapamycin (mTOR)-dependent manner. mTOR inhibition can suppress the activation of cyclin-dependent kinases and then inhibits the cell cycle progress, suppresses cell proliferation, and fi nally results in cell apoptosis.

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5-Hydroxyanthranilic Acid, a Tryptophan Metabolite, Generates Oxidative Stress and Neuronal Death via p38 Activation in Cultured Cerebellar Granule Neurones

Cited by 54 publications

References 40 publications

Protective effect of tryptophan against dextran sulfate sodium- induced experimental colitis

Protective effect of tryptophan against dextran sulfate sodium- induced experimental colitis

The kynurenine pathway and neurodegenerative disease

Tryptophan and Cell Death

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