LC–MS/MS-Based Quantification of Kynurenine Metabolites, Tryptophan, Monoamines and Neopterin in Plasma, Cerebrospinal Fluid and Brain

Fuertig, René; Ceci, Angelo; Camus, Sandrine; Bézard, Erwan; Luippold, Andreas H.; Hengerer, Bastian

doi:10.4155/bio-2016-0111

Cited by 111 publications

(80 citation statements)

References 54 publications

(63 reference statements)

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“…Both before and after PWM treatment, Quin levels are lowest in the brain and highest in the spleen (92), which is consistent with our current findings. Quin levels in normal mouse brain tissue are at detection limits by LC/MS-MS (99). In a comprehensive evaluation of the mechanisms controlling Quin levels in the brain, Morrison et al showed that three primary factors maintained low brain concentrations.…”

Section: Quin-ir In the Brain Vs Peripherymentioning

confidence: 99%

Quinolinate as a Marker for Kynurenine Metabolite Formation and the Unresolved Question of NAD+ Synthesis During Inflammation and Infection

et al. 2020

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Quinolinate (Quin) is a classic example of a biochemical double-edged sword, acting as both essential metabolite and potent neurotoxin. Quin is an important metabolite in the kynurenine pathway of tryptophan catabolism leading to the de novo synthesis of nicotinamide adenine dinucleotide (NAD + ). As a precursor for NAD + , Quin can direct a portion of tryptophan catabolism toward replenishing cellular NAD + levels in response to inflammation and infection. Intracellular Quin levels increase dramatically in response to immune stimulation [e.g., lipopolysaccharide (LPS) or pokeweed mitogen (PWM)] in macrophages, microglia, dendritic cells, and other cells of the immune system. NAD + serves numerous functions including energy production, the poly ADP ribose polymerization (PARP) reaction involved in DNA repair, and the activity of various enzymes such as the NAD + -dependent deacetylases known as sirtuins. We used highly specific antibodies to protein-coupled Quin to delineate cells that accumulate Quin as a key aspect of the response to immune stimulation and infection. Here, we describe Quin staining in the brain, spleen, and liver after LPS administration to the brain or systemic PWM administration. Quin expression was strong in immune cells in the periphery after both treatments, whereas very limited Quin expression was observed in the brain even after direct LPS injection. Immunoreactive cells exhibited diverse morphology ranging from foam cells to cells with membrane extensions related to cell motility. We also examined protein expression changes in the spleen after kynurenine administration. Acute (8 h) and prolonged (48 h) kynurenine administration led to significant changes in protein expression in the spleen, including multiple changes involved with cytoskeletal rearrangements associated with cell motility. Kynurenine administration resulted in several expression level changes in proteins associated with heat shock protein 90 (HSP90), a chaperone for the aryl-hydrocarbon receptor (AHR), which is the primary kynurenine Moffett et al.Quinolinate as Kynurenine Marker and NAD + Source metabolite receptor. We propose that cells with high levels of Quin are those that are currently releasing kynurenine pathway metabolites as well as accumulating Quin for sustained NAD + synthesis from tryptophan. Further, we propose that the kynurenine pathway may be linked to the regulation of cell motility in immune and cancer cells.

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Section: Quin-ir In the Brain Vs Peripherymentioning

confidence: 99%

Quinolinate as a Marker for Kynurenine Metabolite Formation and the Unresolved Question of NAD+ Synthesis During Inflammation and Infection

et al. 2020

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“…In recent years, LC coupled to a tandem mass spectrometer (MS/MS) via an electrospray ionization (ESI) interface has been introduced for NT analyses, mainly owing to the higher selectivity of this technique. Generally, the LC–ESI–MS/MS methods published so far for brain analysis use simple extraction procedures without further sample clean‐up before injection onto the analytical column (Fuertig et al, ; Gonzáles, Fernández, Vidal, Frenich, & Pérez, ; He et al, ; Huang et al, ; Kim, Choi, Kim, & Kim, ; Kim, Kim, Hong, & Kim, ; Liu et al, ; Marcos et al, ; Najmanová et al, ; Tareke, Bowyer, & Doerge, ; Wojnicz et al, ; Xu et al, ; Zheng et al, ). The crude extract, which is often pre‐concentrated using solvent evaporation, contains matrix components that may affect the accuracy of the results and compromise the lower limit of quantification (LLOQ) owing to interferences and ion suppression in the ESI interface (Peters, Drummer, & Musshoff, ; Srinivas, ; van Eeckhaut, Lanckmans, Sarre, Smolders, & Michotte, ).…”

Section: Introductionmentioning

confidence: 99%

Sensitive determination of monoamine neurotransmitters, their main metabolites and precursor amino acids in different mouse brain components by liquid chromatography–electrospray tandem mass spectrometry after selective sample clean‐up

Sørensen

Johannsen

2019

Biomedical Chromatography

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For the assessment of diets and supplements formulated for the treatment of phenylketonuria, a highly sensitive and selective method was developed and validated for the quantification of dopamine (DA), serotonin (5‐HT), 3,4‐dihydroxyphenylacetic acid (DOPAC), 5‐hydroxyindoleacetic acid (5‐HIAA), phenylalanine, tyrosine and tryptophan in mouse cerebellum, brain stem, hypothalamus, parietal cortex, anterior piriform cortex and bulbus olfactorius. Samples were extracted by deproteinization with acetonitrile, and the extracts were cleaned up by strong anion exchange and weak cation exchange applied sequentially. The substances were detected by rapid liquid chromatography tandem mass spectrometry. Matrix components were largely removed by the clean‐up, resulting in low matrix effects. The lower limits of quantification for an extracted tissue mass of 100 mg were 0.3, 0.3, 0.2 and 2 ng/g for DA, 5‐HT, 5‐HIAA and DOPAC, respectively. The mean true extraction recoveries were 80–102%. The relative intra‐laboratory reproducibility standard deviations were generally <11% at concentrations of 20–1000 ng/g for DA, 5‐HT, 5‐HIAA and DOPAC and 7% at concentrations of 5–50 μg/g for the amino acids. This method was successfully used in a phenylketonuria mice study including nearly 300 brain tissue samples and for small sample masses (for example, 2 mg of bulbus olfactorius).

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“…Another LC‐MS/MS method for the determination of tryptophan and its seven metabolites was reported, but tryptophan had the highest intensity over its calibration range so that the samples needed to be 10‐fold diluted and re‐analyzed (Choi, Park, Song, Lee, & Jung, ). Moreover, tryptophan and its eight metabolites were measured in biological matrices from mice and nonhuman primates (Fuertig et al, ). Taken together, none of these previously developed methods were applied to the analysis of human plasma samples or to evaluate the relationship between tryptophan metabolites and cardiovascular disease.…”

Section: Introductionmentioning

confidence: 99%

Simultaneous determination of tryptophan, kynurenine, kynurenic acid, xanthurenic acid and 5‐hydroxytryptamine in human plasma by LC‐MS/MS and its application to acute myocardial infarction monitoring

Tong

Song

Yang

et al. 2017

Biomedical Chromatography

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Reliable methods for the determination of tryptophan and its metabolites are vital to the monitoring of biochemical states during the initiation and progression of cardiovascular disease. In the present study, a single-run liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed for the simultaneous determination of tryptophan (Trp) and its metabolites, including kynurenine (Kyn), kynurenic acid (KA), xanthurenic acid (XA) and 5-hydroxytryptamine (5-HT), in human plasma. The plasma samples were prepared using a protein precipitation approach, and the chromatographic separation was performed by gradient elution on a C column within a total analysis time of 3.5 min. The calibration ranges were 40-20,000 ng/mL for Trp, 4-2000 ng/mL for Kyn, 0.2-100 ng/mL for KA, 0.4-200 ng/mL for XA and 1-500 ng/mL for 5-HT, and the precision and accuracy were acceptable. The evaluation of recovery and internal standard-normalized matrix effect proved that the sample preparation approach was effective and the matrix effect could be negligible. The newly developed method was successfully applied to the analysis of plasma samples from healthy individuals and myocardial infarction patients. The findings suggested that the plasma concentrations of Trp, Kyn, 5-HT as well as the concentration ratios of Kyn/Trp and Trp/5-HT might serve as biomarkers for the monitoring of acute myocardial infarction.

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LC–MS/MS-Based Quantification of Kynurenine Metabolites, Tryptophan, Monoamines and Neopterin in Plasma, Cerebrospinal Fluid and Brain

Cited by 111 publications

References 54 publications

Quinolinate as a Marker for Kynurenine Metabolite Formation and the Unresolved Question of NAD+ Synthesis During Inflammation and Infection

Quinolinate as a Marker for Kynurenine Metabolite Formation and the Unresolved Question of NAD+ Synthesis During Inflammation and Infection

Sensitive determination of monoamine neurotransmitters, their main metabolites and precursor amino acids in different mouse brain components by liquid chromatography–electrospray tandem mass spectrometry after selective sample clean‐up

Simultaneous determination of tryptophan, kynurenine, kynurenic acid, xanthurenic acid and 5‐hydroxytryptamine in human plasma by LC‐MS/MS and its application to acute myocardial infarction monitoring

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