L-Tryptophan-kynurenine pathway enzymes are therapeutic target for neuropsychiatric diseases: Focus on cell type differences

Fujigaki, Hidetsugu; Yamamoto, Yorimasa; Saito, Kuniaki

doi:10.1016/j.neuropharm.2016.01.011

Cited by 131 publications

(136 citation statements)

References 167 publications

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“…Downstream metabolites of kynurenine responded differently to MF. Plasma kynurenic acid levels were not different, whereas quinolinic acid a compound with neurotoxic effects (24), showed a trend for higher levels with AA-MF compared with GMP-MF (p=0.0604). Moreover, urinary excretion of quinolinic acid was significantly higher with AA-MF compared with GMP-MF (p=0.01).…”

Section: Resultsmentioning

confidence: 89%

Metabolomic changes demonstrate reduced bioavailability of tyrosine and altered metabolism of tryptophan via the kynurenine pathway with ingestion of medical foods in phenylketonuria

Ney

Murali

Stroup

et al. 2017

Molecular Genetics and Metabolism

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Background Deficiencies of the monoamine neurotransmitters, such as dopamine synthesized from Tyr and serotonin synthesized from Trp, are of concern in PKU. Our objective was to utilize metabolomics analysis to assess monoamine metabolites in subjects with PKU consuming amino acid medical foods (AA-MF) and glycomacropeptide medical foods (GMP-MF). Methods Subjects with PKU consumed a low-Phe diet combined with AA-MF and GMP-MF for 3 weeks each in a randomized, controlled, crossover study. Metabolomic analysis was conducted by Metabolon, Inc. on plasma (n=18) and urine (n=9) samples. Catecholamines and 6-sulfatoxymelatonin were measured in 24-hr urine samples. Results Intake of Tyr and Trp was ~50% higher with AA-MF, and AA-MF were consumed in larger quantities, less frequently during the day compared with GMP-MF. Performance on neuropsychological tests and concentrations of neurotransmitters derived from Tyr and Trp were not significantly different with AA- MF or GMP-MF. Plasma serotonin levels of gut origin were higher in subjects with variant compared with classical PKU, and with GMP-MF compared with AA-MF in subjects with variant PKU. Metabolomics analysis identified higher levels of microbiome-derived compounds synthesized from Tyr, such as phenol sulfate, and higher levels of compounds synthesized from Trp in the kynurenine pathway, such as quinolinic acid, with ingestion of AA-MF compared with GMP-MF. Conclusions The Tyr from AA-MF is less bioavailable due, in part, to greater degradation by intestinal microbes compared with the Tyr from prebiotic GMP-MF. Research is needed to understand how metabolism of Trp via the kynurenine pathway and changes in the intestinal microbiota affect health for individuals with PKU.

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Section: Resultsmentioning

confidence: 89%

Metabolomic changes demonstrate reduced bioavailability of tyrosine and altered metabolism of tryptophan via the kynurenine pathway with ingestion of medical foods in phenylketonuria

Ney

Murali

Stroup

et al. 2017

Molecular Genetics and Metabolism

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“…In mammalian cells, Kynurenine pathway (KP) mediates degradation of the majority of cellular tryptophan through different enzyme branches (Fujigaki et al, 2017). The 3-hydroxyanthranilate 3, 4-dioxygenase (KMO) enzyme, which is predominantly expressed in microglia, metabolizes tryptophan to neuroactive 3-hydroxykynurenine (3HK) and quinolinic acid (QUIN) (Heyes et al, 1992).…”

Section: Signaling Pathways Underlying the Microglial Activation In Hdmentioning

confidence: 99%

“…In addition, suppressing the expression of tryptophan-2, 3-dioxygenase (TDO), another rate limiting enzyme in KP, was demonstrated to be neuroprotective in MS (Lanz et al, 2017). Additionally, inhibiting KP is likely to be protective in several neurologic diseases (Fujigaki et al, 2017), probably by modulating microglial activation mediated neurotoxicity.…”

Section: Signaling Pathways Underlying the Microglial Activation In Hdmentioning

confidence: 99%

Microglial Activation in the Pathogenesis of Huntington’s Disease

Yang

Huang

et al. 2017

Front. Aging Neurosci.

106

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Huntington’s disease (HD) is an autosomal dominantly inherited neurodegenerative disorder caused by expanded CAG trinucleotide repeats (>36) in exon 1 of HTT gene that encodes huntingtin protein. Although HD is characterized by a predominant loss of neurons in the striatum and cortex, previous studies point to a critical role of aberrant accumulation of mutant huntingtin in microglia that contributes to the progressive neurodegeneration in HD, through both cell-autonomous and non-cell-autonomous mechanisms. Microglia are resident immune cells in the central nervous system (CNS), which function to surveil the microenvironment at a quiescent state. In response to various pro-inflammatory stimuli, microglia become activated and undergo two separate phases (M1 and M2 phenotype), which release pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α), anti-inflammatory cytokines, and growth factors (TGF-β, CD206, and Arg1), respectively. Immunoregulation by microglial activation could be either neurotoxic or neuroprotective. In this review, we summarized current understanding about microglial activation in the pathogenesis and progression of HD, with a primary focus of M1 and M2 phenotype of activated microglia and their corresponding signaling pathways.

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“…IDO1, which metabolizes tryptophan to kynurenine, and KMO, which metabolizes the latter molecule, 53 were both down-regulated, which could compromise maternal immunosuppression. 54 …”

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confidence: 99%

Preeclampsia: novel insights from global RNA profiling of trophoblast subpopulations

Gormley

Ona

Kapidzic

et al. 2017

American Journal of Obstetrics and Gynecology

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BACKGROUND:The maternal signs of preeclampsia, which include the new onset of high blood pressure, can occur because of faulty placentation. We theorized that transcriptomic analyses of trophoblast subpopulations in situ would lend new insights into the role of these cells in preeclampsia pathogenesis. OBJECTIVE: Our goal was to enrich syncytiotrophoblasts, invasive cytotrophoblasts, or endovascular cytotrophoblasts from the placentas of severe preeclampsia cases. Total RNA was subjected to global transcriptional profiling to identify RNAs that were misexpressed compared with controls. STUDY DESIGN: This was a cross-sectional analysis of placentas from women who had been diagnosed with severe preeclampsia. Gestational age-matched controls were placentas from women who had a preterm birth with no signs of infection. Laser microdissection enabled enrichment of syncytiotrophoblasts, invasive cytotrophoblasts, or endovascular cytotrophoblasts. After RNA isolation, a microarray approach was used for global transcriptional profiling. Immunolocalization identified changes in messenger RNA expression that carried over to the protein level. Differential expression of noneprotein-coding RNAs was confirmed by in situ hybridization. A 2-way analysis of variance of non-coding RNA expression identified particular classes that distinguished trophoblasts in cases vs controls. Cajal body foci were visualized by coilin immunolocalization. RESULTS: Comparison of the trophoblast subtype data within each group (severe preeclampsia or noninfected preterm birth) identified many highly differentially expressed genes. They included molecules that are known to be expressed by each subpopulation, which is evidence that the method worked. Genes that were expressed differentially between the 2 groups, in a cell-typeespecific manner, encoded a combination of molecules that previous studies associated with severe preeclampsia and those that were not known to be dysregulated in this pregnancy

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L-Tryptophan-kynurenine pathway enzymes are therapeutic target for neuropsychiatric diseases: Focus on cell type differences

Cited by 131 publications

References 167 publications

Metabolomic changes demonstrate reduced bioavailability of tyrosine and altered metabolism of tryptophan via the kynurenine pathway with ingestion of medical foods in phenylketonuria

Metabolomic changes demonstrate reduced bioavailability of tyrosine and altered metabolism of tryptophan via the kynurenine pathway with ingestion of medical foods in phenylketonuria

Microglial Activation in the Pathogenesis of Huntington’s Disease

Preeclampsia: novel insights from global RNA profiling of trophoblast subpopulations

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