In vitro evidence for an antioxidant role of 3-hydroxykynurenine and 3-hydroxyanthranilic acid in the brain

Leipnitz, Guilhian; Schumacher, Cristiana; Dalcin, Karina Borges; Scussiato, Karina; Solano, Alexandre Francisco; Funchal, Cláudia; Dutra-Filho, Carlos Severo; Wyse, Ângela T. S.; Wannmacher, Clóvis Milton Duval; Latini, Alexandra; Wajner, Moaçir

doi:10.1016/j.neuint.2006.04.017

Cited by 77 publications

(60 citation statements)

References 55 publications

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“…TNF-a, IFN-c and also mitochondrial potential, which might be due to the actions of KYNA, a KYN metabolite. Our results are also in consistence with KYN actions in vitro, where, it was shown that 3-hydroxykynurenine significantly reduced thiobarbituric acid reactive substances in cerebral cortex, indicating a direct antioxidant role [21]. However, at high concentrations, KYNA has been shown to be a broad-spectrum endogenous antagonist of ionotropic EAA receptors of both AMPA and NMDA types [3].…”

Section: Discussionsupporting

confidence: 81%

In Vivo Neuroprotective Effects of Peripheral Kynurenine on Acute Neurotoxicity Induced by Glutamate in Rat Cerebral Cortex

Kumar

Babu

2009

Neurochem Res

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N-methyl-D-aspartate (NMDA) receptors play a crucial role in Glutamate (L-Glu) neurotoxicity. To evaluate the effects of astrocyte-derived tryptophan metabolite kynurenic acid (KYNA), on L-Glu neurotoxicity, adult male rats were pretreated with Kynurenine (KYN) which is a precursor of KYNA, at a dose of 30 mg or 300 mg/kg bw i.p., 2 h before stereotactic L-Glu bolus (1 micromole/1 microl) administration in cerebral cortex. Results showed that acute L-Glu increased reactive oxygen species, rate of lipid peroxidation, calcium, nitric oxide and neuroinflammatory markers viz. TNF-alpha, IFN-gamma levels and decreased key antioxidant parameters such as SOD, catalase, total glutathione and glutathione reductase along with mitochondrial membrane potential. While peripheral loading of 30 mg/kg dose of KYN had no protective effects on L-Glu induced neurotoxicity, 300 mg/kg dose prevented the above toxic effects following intracortical L-Glu. KYN apparently crossed blood brain barrier to elevate astrocytic-KYNA level, which seems to protect neurons through several interactive mechanisms.

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Section: Discussionsupporting

confidence: 81%

In Vivo Neuroprotective Effects of Peripheral Kynurenine on Acute Neurotoxicity Induced by Glutamate in Rat Cerebral Cortex

Kumar

Babu

2009

Neurochem Res

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“…These data suggest that 3-HK and 3-HANA mediated neurotoxicity is caused by ROS, which can be specifically counteracted by catalase activity. It has also been reported, however, that both 3-HK and 3-HANA are also capable of antioxidant activity [27] [28]. Notably, 3-HK dependent toxicity is observed in neuronal cell cultures [22] [23], but not in cultured glioma cells [28].…”

Section: Neuroactive Kynurenine Metabolitesmentioning

confidence: 99%

“…It has also been reported, however, that both 3-HK and 3-HANA are also capable of antioxidant activity [27] [28]. Notably, 3-HK dependent toxicity is observed in neuronal cell cultures [22] [23], but not in cultured glioma cells [28]. As the KP takes place predominantly in microglia and astrocytes in the central nervous system (CNS), these data may indicate that glial cells are more likely to tolerate the presence of 3-HK than neurons, where 3-HK is not endogenously produced [29].…”

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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“…The explanation of this dual behavior of 3-HK could be related to its redox properties and the balance between its reductive and oxidative precursor features. In this regard, the reductive, scavenging and antioxidant properties of this metabolite have been described at concentrations ranging those used by us in this study (Christen et al, 1990;Leipnitz et al, 2007; reviewed by Colín-González et al, 2013). However, if under certain conditions 3-HK preferentially undergoes auto-oxidation to form highly oxidant quinones, then its reductive properties could be surpassed by its nature as a precursor of free radicals and quinones.…”

Section: Discussionmentioning

confidence: 82%

“…This behavior of 3-HK, which is opposite to its toxic character, has been described in several reports, some of which discuss a scavenging activity for this molecule, showing that 3-HK is able to scavenge O 2 · À , · OH, peroxyl radicals, and · NO, also acting as an endogenous natural antioxidant (Goshima et al, 1986;Christen et al, 1990;Goda et al, 1999;Leipnitz et al, 2007;Backhaus et al, 2008). Still, its precise role in the CNS remains uncertain.…”

Section: Introductionmentioning

confidence: 87%

The Janus faces of 3-hydroxykynurenine: Dual redox modulatory activity and lack of neurotoxicity in the rat striatum

et al. 2014

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In vitro evidence for an antioxidant role of 3-hydroxykynurenine and 3-hydroxyanthranilic acid in the brain

Cited by 77 publications

References 55 publications

In Vivo Neuroprotective Effects of Peripheral Kynurenine on Acute Neurotoxicity Induced by Glutamate in Rat Cerebral Cortex

In Vivo Neuroprotective Effects of Peripheral Kynurenine on Acute Neurotoxicity Induced by Glutamate in Rat Cerebral Cortex

The kynurenine pathway and neurodegenerative disease

The Janus faces of 3-hydroxykynurenine: Dual redox modulatory activity and lack of neurotoxicity in the rat striatum

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