A role for inflammatory metabolites as modulators of the glutamate N-methyl-d-aspartate receptor in depression and suicidality

Bay-Richter, Cecilie; Linderholm, Klas R.; Lim, Chai K.; Samuelsson, Martin; Träskman‐Bendz, Lil; Guillemin, Gilles J.; Erhardt, Sophie; Brundin, Lena

doi:10.1016/j.bbi.2014.07.012

Cited by 260 publications

(192 citation statements)

References 76 publications

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“…KYN is further metabolized to, among others, 3-hydroxykynurenine (3-HK), quinolinic acid (QUIN) and kynurenic acid (KYNA), catabolites that can contribute to oxidative stress, excitotoxicity, and neuroprotection (for review: (Chiarugi et al, 2001;Haroon et al, 2012;Schwarcz et al, 2012). There is growing evidence for kynureninepathway hyperfunction in stress-related disorders, particularly for MDD (Bay-Richter et al, 2015;Kim et al, 2012;Reus et al, 2015;Savitz et al, 2015;Steiner et al, 2011;Sublette et al, 2011) (for review: (Maes et al, 2011)). …”

Section: Introductionmentioning

confidence: 99%

Mouse chronic social stress increases blood and brain kynurenine pathway activity and fear behaviour: Both effects are reversed by inhibition of indoleamine 2,3-dioxygenase

Fuertig

Azzinnari

Bergamini

et al. 2016

Brain, Behavior, and Immunity

118

125

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Psychosocial stress is a major risk factor for mood and anxiety disorders, in which excessive reactivity to aversive events/stimuli is a major psychopathology. In terms of pathophysiology, immuneinflammation is an important candidate, including high blood and brain levels of metabolites belonging to the kynurenine pathway. Animal models are needed to study causality between psychosocial stress, immune-inflammation and hyper-reactivity to aversive stimuli. The present mouse study investigated effects of psychosocial stress as chronic social defeat (CSD) versus control-handling (CON) on: Pavlovian tone-shock fear conditioning, activation of the kynurenine pathway, and efficacy of a specific inhibitor (IDOInh) of the tryptophan-kynurenine catabolizing enzyme indoleamine 2,3-dioxygenase (IDO1), in reversing CSD effects on the kynurenine pathway and fear. CSD led to excessive fear learning and memory, whilst repeated oral escitalopram (antidepressant and anxiolytic) reversed excessive fear memory, indicating predictive validity of the model. CSD led to higher blood levels of TNF-, IFN-, kynurenine (KYN), 3-hydroxykynurenine (3-HK) and kynurenic acid, higher KYN and 3-HK in amygdala and hippocampus. However, CSD was without effect on IDO1 gene or protein expression in spleen, ileum and liver, whilst increasing liver TDO2 gene expression. Nonetheless, oral IDOInh reduced blood and brain levels of KYN and 3-HK in CSD mice to CON levels, and we therefore infer that CSD increases IDO1 activity by increasing its post-translational activation. Furthermore, repeated oral IDOInh reversed excessive fear memory in CSD mice to CON levels. IDOInh reversal of CSD-induced hyper-activity in the kynurenine pathway and fear system contributes significantly to the evidence for a causal pathway between psychosocial stress, immune-inflammation and the excessive fearfulness that is a major psychopathology in stress-related neuropsychiatric disorders. ABSTRACTPsychosocial stress is a major risk factor for mood and anxiety disorders, in which excessive reactivity to aversive events/stimuli is a major psychopathology. In terms of pathophysiology, immune-inflammation is an important candidate, including high blood and brain levels of metabolites belonging to the kynurenine pathway. Animal models are needed to study causality between psychosocial stress, immune-inflammation and hyper-reactivity 3-HK in CSD mice to CON levels, and we therefore infer that CSD increases IDO1 activity by increasing its post-translational activation. Furthermore, repeated oral IDOInh reversed excessive fear memory in CSD mice to CON levels. IDOInh reversal of CSD-induced hyperactivity in the kynurenine pathway and fear system contributes significantly to the evidence for a causal pathway between psychosocial stress, immune-inflammation and the excessive fearfulness that is a major psychopathology in stress-related neuropsychiatric disorders.3

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Section: Introductionmentioning

confidence: 99%

Mouse chronic social stress increases blood and brain kynurenine pathway activity and fear behaviour: Both effects are reversed by inhibition of indoleamine 2,3-dioxygenase

Fuertig

Azzinnari

Bergamini

et al. 2016

Brain, Behavior, and Immunity

118

125

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“…Depression is believed to arise from the excessive production of the neurotoxic quinolinic acid together with a reduction in kynurenic acid [54]. 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].…”

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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“…Whereas several studies that were performed using specimens from blood or cerebrospinal fluid (CSF) have reported a positive as sociation between various components of the KP and depres sion or suicide, [21][22][23][24] others failed to do so 25,26 or have revealed qualitatively different changes for various analytes. 27 Moreover, evidence for abnormal brain tissue levels of KP metabolites in depressed individuals and individuals who died by suicide is limited or indirect. [28][29][30] The possible role of the KP in the patho physiology of depression therefore requires further clarification.…”

Section: Introductionmentioning

confidence: 99%

Reduced kynurenine pathway metabolism and cytokine expression in the prefrontal cortex of depressed individuals

Clark

Pocivavsek

Nicholson

et al. 2016

jpn

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A role for inflammatory metabolites as modulators of the glutamate N-methyl-d-aspartate receptor in depression and suicidality

Cited by 260 publications

References 76 publications

Mouse chronic social stress increases blood and brain kynurenine pathway activity and fear behaviour: Both effects are reversed by inhibition of indoleamine 2,3-dioxygenase

Mouse chronic social stress increases blood and brain kynurenine pathway activity and fear behaviour: Both effects are reversed by inhibition of indoleamine 2,3-dioxygenase

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

Reduced kynurenine pathway metabolism and cytokine expression in the prefrontal cortex of depressed individuals

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