Induction of indolamine 2,3-dioxygenase and kynurenine 3-monooxygenase in rat brain following a systemic inflammatory challenge: A role for IFN-γ?

Connor, Thomas J.; Starr, Neasa; O'Sullivan, Jeff; Harkin, Andrew

doi:10.1016/j.neulet.2008.06.007

Cited by 194 publications

(154 citation statements)

References 34 publications

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“…Notably, activation of IDO1 increases the L-KYN/TRP ratio [40] [41]. In addition, KMO activity can also be influenced by proinflammatory stimuli; systemic administration of LPS in rats increases levels of KMO in the hippocampus [42] [43] and whole brain extracts [44], while in human hippocampal progenitor cells IL-1ß treatment induces transcription of the genes encoding both KMO and KYNU [41]. Immune response can also cause activation of microglia, as well as influx of proinflammatory cytokines and macrophages into the brain.…”

Section: Regulation Of the Kynurenine Pathway In The Cns And Peripherymentioning

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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Section: Regulation Of the Kynurenine Pathway In The Cns And Peripherymentioning

confidence: 99%

The kynurenine pathway and neurodegenerative disease

Maddison

Giorgini

2015

Seminars in Cell & Developmental Biology

243

223

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“…Reduced levels of kynurenic acid have been correlated with severe depressive and suicidal symptoms [55,56], and decreased blood levels of this molecule has been detected in the patients with major depressive disorder [57]. Quinolinic acid is a neurotoxic agent, and its production is significantly enhanced by proinflammatory cytokines through their stimulation of the rate limiting step enzyme in the quinolinic acid pathway, kynurenine-3-monooxygenase (KMO) enzyme [58,59]. For instance, levels of quinolinic acid in the cerebrospinal fluids of suicide attempters showed around 300 % increase compared to healthy controls [60].…”

Section: Gastrointestinal Inflammation and Depressionmentioning

confidence: 99%

Role of Microbiota and Tryptophan Metabolites in the Remote Effect of Intestinal Inflammation on Brain and Depression

Waclawiková¹,

Aidy²

2018

Preprint

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The human gastrointestinal tract is inhabited by trillions of commensal bacteria collectively known as the gut microbiota. Our recognition of the significance of the complex interaction between the microbiota, and its host has grown dramatically over the past years. A balanced microbial community is a key regulator of the immune response, and metabolism of dietary components, which in turn, modulates several brain processes impacting mood and behavior. Consequently, it is likely that disruptions within the composition of the microbiota would remotely affect the mental state of the host. Here, we discuss how intestinal bacteria and their metabolites can orchestrate gut-associated neuroimmune mechanisms that influence mood and behavior leading to depression. In particular, we focus on microbiota-triggered gut inflammation and its implications in shifting the tryptophan metabolism towards kynurenine biosynthesis while disrupting the serotonergic signaling. We further investigate the gaps to be bridged in this exciting field of research in order to clarify our understanding of the multifaceted crosstalk in the microbiota-gut-brain interphase, bringing about a novel microbiota-targeted therapeutics for mental illnesses.

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“…But the present results suggest that this cholinergic aspect was not pertinent for ADHD families. Instead, there are modest signs of increasingly toxic metabolism in the ADHD offspring with increasing levels of 3HK (Connor et al 2008, dioxygenase induction after inflammatory challenge), S100B (Himeda et al 2006 with MPTP-treated mice) and the pro-inflammatory IL-6 (Harding et al 2005 on premature children).…”

Section: Smokingmentioning

confidence: 99%

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

Oades

2011

ADHD Atten Def Hyp Disord

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Intra-individual variability of the characteristics of children with attention-deficit hyperactivity (ADHD) may reflect compromised glial energy supply in the synapse. We reported recently that while serum levels of a glial marker, the cytokine S100B, were not seriously altered, levels of other cytokines and tryptophan metabolites were related to symptoms, attention and variability. Here, we explore with a regression analysis whether levels of these substances were associated with features of the index pregnancy of potential aetiological significance. Serum was taken from 35 children with DSM-IV ADHD (14 on medication) and 21 typically developing controls to measure 8 cytokines (S100B, IL-2, IL-6, IL-10, IL-13, IL-16, TNF-α and IFN-γ) and 5 metabolites (Tryptophan, Kynurenine, Kynurenate [KA], 3-hydroxy-kynurenine [3HK] and 5-hydroxyindole acetic acid [5-HIAA]). The mothers received a 124-item questionnaire on features surrounding the pregnancy. (1) For children with ADHD, a shorter pregnancy and smaller birth weight were associated statistically with increased 3HK and IFN-γ and for obstetric problems with decreased TNF-α levels. (2) Maternal smoking related to decreasing kynurenine and increasing 3HK and S100B levels in ADHD children. Paternal smoking was associated with increased tryptophan in the controls and increased IL-6 levels in ADHD children. (3) The taking of supplements often related to decreasing TNF-α, increasing IL-10 and lower 5-HIAA levels in the ADHD children. Less 5-HIAA but more tryptophan was associated with earlier and later life events, respectively. (4) Increased IL-16 and 5-HIAA levels in the ADHD group related to reports of poorer infant health. Unexpectedly, more child care (seafood and time together) in ADHD than healthy families was implicated by lower tryptophan levels and an altered balance of pro-inflammatory cytokines. Across measures control families generally showed either non-significant associations or the opposite to those of the ADHD group. In ADHD children more than controls, the balance of potentially toxic or protective kynurenine metabolites and of pro- over anti-inflammatory cytokines may reflect the perinatal experience associated with stress, but not with maternal illness.

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Induction of indolamine 2,3-dioxygenase and kynurenine 3-monooxygenase in rat brain following a systemic inflammatory challenge: A role for IFN-γ?

Cited by 194 publications

References 34 publications

The kynurenine pathway and neurodegenerative disease

The kynurenine pathway and neurodegenerative disease

Role of Microbiota and Tryptophan Metabolites in the Remote Effect of Intestinal Inflammation on Brain and Depression

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

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