Perinatal kynurenine 3‐hydroxylase inhibition in rodents: Pathophysiological implications

Ceresoli-Borroni, Gianpiera; Guidetti, Paolo; Amori, Laura; Pellicciari, Roberto; Schwarcz, Robert

doi:10.1002/jnr.21183

Cited by 28 publications

(18 citation statements)

References 63 publications

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“…Of potential relevance in this context is the fact that basal brain concentrations of several KP metabolites, including KYNA, are substantially higher prenatally than postnatally [23]. Cause(s) and physiological ramifications of these elevated metabolite levels, as well as possible implications for pathological events during the perinatal period [61], await further clarification.…”

Section: Discussionmentioning

confidence: 99%

Restraint Stress during Pregnancy Rapidly Raises Kynurenic Acid Levels in Mouse Placenta and Fetal Brain

Notarangelo

Schwarcz²

2016

Dev Neurosci

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Stressful events during pregnancy adversely affect brain development and may increase the risk of psychiatric disorders later in life. Early changes in the kynurenine (KYN) pathway (KP) of tryptophan (TRP) degradation, which contains several neuroactive metabolites, including kynurenic acid (KYNA), 3-hydroxykynurenine (3-HK), and quinolinic acid (QUIN), may constitute a molecular link between prenatal stress and delayed pathological consequences. To begin testing this hypothesis experimentally, we examined the effects of a 2-h restraint stress on KP metabolism in pregnant FVB/N mice on gestational day 17. TRP, KYN, KYNA, 3-HK, and QUIN levels were measured in maternal and fetal plasma and brain, as well as in the placenta, immediately after stress termination and 2 h later. In the same animals, we determined the activity of TRP 2,3-dioxygenase (TDO) in the maternal liver and in the placenta. Compared to unstressed controls, mostly transient changes in KP metabolism were observed in all of the tissues examined. Specifically, stress caused significant elevations of KYNA levels in the maternal plasma, placenta, and fetal brain, and also resulted in increased levels of TRP and KYN in the placenta, fetal plasma, and fetal brain. In contrast, 3-HK and QUIN levels remained unchanged from control values in all tissues at any time point. In the maternal liver, TDO activity was increased 2 h after stress cessation. Taken together, these findings indicate that an acute stress during the late gestational period preferentially affects the KYNA branch of KP metabolism in the fetal brain. Possible long-term consequences for postnatal brain development and pathology remain to be examined.

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Section: Discussionmentioning

confidence: 99%

Restraint Stress during Pregnancy Rapidly Raises Kynurenic Acid Levels in Mouse Placenta and Fetal Brain

Notarangelo

Schwarcz²

2016

Dev Neurosci

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“…Increasing 3HK levels were also associated with a shorter pregnancy, lower birth weight and APGAR levels. As, at the time of sampling, the levels of the potentially toxic 3HK were on average lower in children with ADHD than in controls, any trend towards an increase may be viewed as a risk factor for the later development of the CNS through adolescence, as shown in several species of mammal (Cerresoli-Borroni et al 2007). …”

Section: Tryptophan Metabolismmentioning

confidence: 97%

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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“…Another promising line of investigation, which has been only sparingly pursued so far 125, 184–185 , will explore the possibility that the role of brain kynurenines changes over the course of the life span. Do kynurenines derived from the mother shape metabolism along the kynurenine pathway, and the function of pathway metabolites, in the fetal brain?…”

Section: Challenges For Future Researchmentioning

confidence: 99%

Kynurenines in the mammalian brain: when physiology meets pathology

et al. 2012

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The essential amino acid tryptophan is not only a precursor of serotonin but is also degraded to several other neuroactive compounds, including kynurenic acid, 3-hydroxykynurenine and quinolinic acid. The synthesis of these metabolites is regulated by an enzymatic cascade, known as the kynurenine pathway, that is tightly controlled by the immune system. Dysregulations of the pathway, causing hyper- or hypofunction of active metabolites, are associated with neurodegenerative and other neurological disorders, as well as psychiatric diseases such as depression and schizophrenia. With recently developed pharmacological agents, it is now possible to restore metabolic equilibrium and envisage novel therapeutic interventions.

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Perinatal kynurenine 3‐hydroxylase inhibition in rodents: Pathophysiological implications

Cited by 28 publications

References 63 publications

Restraint Stress during Pregnancy Rapidly Raises Kynurenic Acid Levels in Mouse Placenta and Fetal Brain

Restraint Stress during Pregnancy Rapidly Raises Kynurenic Acid Levels in Mouse Placenta and Fetal Brain

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

Kynurenines in the mammalian brain: when physiology meets pathology

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