Elevated quinolinic acid levels in cerebrospinal fluid in subacute sclerosing panencephalitis

Inoue, Hirofumi; Matsushige, Takeshi; Ichiyama, Takashi; Okuno, Alato; Takikawa, Osamu; Tomonaga, Shozo; Anlar, Banu; Yüksel, Deniz; Otsuka, Yasushi; Kohno, Fumitaka; Hoshide, Madoka; Ohga, Shouichi; Hasegawa, Shunji

doi:10.1016/j.jneuroim.2019.577088

Cited by 12 publications

(7 citation statements)

References 34 publications

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“…The tryptophan‐kynurenine pathway has been predominantly evaluated in human immunodeficiency virus 22–25 and neurodegenerative disorders 26–29 . In our study, an increased kynurenine/tryptophan ratio in encephalitis patients suggests activation of the indoleamine 2,3‐dioxygenase enzyme resulting in the catabolism of tryptophan forming imbalanced levels of neuroprotective and neurotoxic kynurenine pathway metabolites, such as quinolinic acid and kynurenic acid 30–33 . However, it has been recently highlighted that only measuring the indoleamine 2,3‐dioxygenase enzyme itself can definitely demonstrate activation of the enzyme, and measuring the kynurenine/tryptophan ratio alone can only infer activation of the enzyme 31 .…”

Section: Discussionmentioning

confidence: 75%

“…[26][27][28][29] In our study, an increased kynurenine/tryptophan ratio in encephalitis patients suggests activation of the indoleamine 2,3-dioxygenase enzyme resulting in the catabolism of tryptophan forming imbalanced levels of neuroprotective and neurotoxic kynurenine pathway metabolites, such as quinolinic acid and kynurenic acid. [30][31][32][33] However, it has been recently highlighted that only measuring the indoleamine 2,3dioxygenase enzyme itself can definitely demonstrate activation of the enzyme, and measuring the kynurenine/tryptophan ratio alone can only infer activation of the enzyme. 31 The anthranilic acid/3-hydroxyanthranilic acid ratio was also a potentially useful biomarker of neuroinflammation, inferring 3-hydroxyanthranilic acid oxidase activation during inflammation.…”

Section: Discussionmentioning

confidence: 99%

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Cerebrospinal fluid metabolites in tryptophan‐kynurenine and nitric oxide pathways: biomarkers for acute neuroinflammation

Yan

Kuzhiumparambil

Bandodkar

et al. 2020

Develop Med Child Neuro

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AIM To explore the cerebrospinal fluid (CSF) metabolite features in acute neuroinflammatory diseases and identify potential biomarkers to diagnose and monitor neuroinflammation. METHOD A cohort of 14 patients (five females, nine males; mean [median] age 7y 9mo [9y], range 6mo-13y) with acute encephalitis (acute disseminated encephalomyelitis n=6, unknown suspected viral encephalitis n=3, enteroviral encephalitis n=2, seronegative autoimmune encephalitis n=2, herpes simplex encephalitis n=1) and age-matched non-inflammatory neurological disease controls (n=14) were investigated using an untargeted metabolomics approach. CSF metabolites were analyzed with liquid chromatography coupled to high resolution mass spectrometry, followed by subsequent multivariate and univariate statistical methods. RESULTS A total of 35 metabolites could be discriminated statistically between the groups using supervised orthogonal partial least squares discriminant analysis and analysis of variance. The tryptophan-kynurenine pathway contributed nine key metabolites. There was a statistical increase of kynurenine, quinolinic acid, and anthranilic acid in patients with encephalitis, whereas tryptophan, 3-hydroxyanthrnailic acid, and kynurenic acid were decreased. The nitric oxide pathway contributed four metabolites, with elevated asymmetric dimethylarginine and argininosuccinic acid, and decreased arginine and citrulline in patients with encephalitis. An increase in the CSF kynurenine/tryptophan ratio (p<0.001), anthranilic acid/3-hydroxyanthranilic acid ratio (p<0.001), asymmetric dimethylarginine/arginine ratio (p<0.001), and neopterin (p<0.001) strongly predicted neuroinflammation. INTERPRETATION The combination of alterations in the tryptophan-kynurenine pathway, nitric oxide pathway, and neopterin represent a useful potential panel for neuroinflammation and holds potential for clinical translation practice.

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Section: Discussionmentioning

confidence: 75%

Section: Discussionmentioning

confidence: 99%

Cerebrospinal fluid metabolites in tryptophan‐kynurenine and nitric oxide pathways: biomarkers for acute neuroinflammation

Yan

Kuzhiumparambil

Bandodkar

et al. 2020

Develop Med Child Neuro

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“…In plasma, QA circulates at low micromolar level, but it significantly increases following infections or immune challenge [40], likely deriving from cells of the immune system that accumulate substantial levels of QA upon stimulation [41]. Increased levels of QA are also found in the cerebrospinal fluid of patients with neurodegenerative disorders [42]. Both NA and QA can be taken up by cells and used to synthetize NAD after their intracellular conversion to NAMN by the enzymes NAPRT and QAPRT, respectively [21] ( Fig.…”

Section: Extracellular Pyridine Metabolitesmentioning

confidence: 99%

Enzymology of extracellular NAD metabolism

Gasparrini

Sorci

Raffaelli

2021

Cell. Mol. Life Sci.

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Extracellular NAD represents a key signaling molecule in different physiological and pathological conditions. It exerts such function both directly, through the activation of specific purinergic receptors, or indirectly, serving as substrate of ectoenzymes, such as CD73, nucleotide pyrophosphatase/phosphodiesterase 1, CD38 and its paralog CD157, and ecto ADP ribosyltransferases. By hydrolyzing NAD, these enzymes dictate extracellular NAD availability, thus regulating its direct signaling role. In addition, they can generate from NAD smaller signaling molecules, like the immunomodulator adenosine, or they can use NAD to ADP-ribosylate various extracellular proteins and membrane receptors, with significant impact on the control of immunity, inflammatory response, tumorigenesis, and other diseases. Besides, they release from NAD several pyridine metabolites that can be taken up by the cell for the intracellular regeneration of NAD itself. The extracellular environment also hosts nicotinamide phosphoribosyltransferase and nicotinic acid phosphoribosyltransferase, which inside the cell catalyze key reactions in NAD salvaging pathways. The extracellular forms of these enzymes behave as cytokines, with pro-inflammatory functions. This review summarizes the current knowledge on the extracellular NAD metabolome and describes the major biochemical properties of the enzymes involved in extracellular NAD metabolism, focusing on the contribution of their catalytic activities to the biological function. By uncovering the controversies and gaps in their characterization, further research directions are suggested, also to better exploit the great potential of these enzymes as therapeutic targets in various human diseases.

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“…Patients with bacterial and viral meningitis displayed even more drastic phenotypes, with QA levels raised by approximately an order of magnitude compared to uninfected control patients. SSPE patients, however, did not show significantly altered KYN/TRP ratios ( Inoue et al, 2020 ). Moreover, infection of mice with hamster neurotropic measles virus leads to the development of encephalitis as well as a marked increase in levels of QA and 3-HK (but again, not KYN) in the hippocampus ( Lehrmann et al, 2008 ).…”

Section: Impact Of Infection On Kyn Pathway Metabolites and Nad +mentioning

confidence: 99%

NAD+ Metabolism, Metabolic Stress, and Infection

Groth

Venkatakrishnan

Lin

2021

Front. Mol. Biosci.

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Nicotinamide adenine dinucleotide (NAD+) is an essential metabolite with wide-ranging and significant roles in the cell. Defects in NAD+ metabolism have been associated with many human disorders; it is therefore an emerging therapeutic target. Moreover, NAD+ metabolism is perturbed during colonization by a variety of pathogens, either due to the molecular mechanisms employed by these infectious agents or by the host immune response they trigger. Three main biosynthetic pathways, including the de novo and salvage pathways, contribute to the production of NAD+ with a high degree of conservation from bacteria to humans. De novo biosynthesis, which begins with l-tryptophan in eukaryotes, is also known as the kynurenine pathway. Intermediates of this pathway have various beneficial and deleterious effects on cellular health in different contexts. For example, dysregulation of this pathway is linked to neurotoxicity and oxidative stress. Activation of the de novo pathway is also implicated in various infections and inflammatory signaling. Given the dynamic flexibility and multiple roles of NAD+ intermediates, it is important to understand the interconnections and cross-regulations of NAD+ precursors and associated signaling pathways to understand how cells regulate NAD+ homeostasis in response to various growth conditions. Although regulation of NAD+ homeostasis remains incompletely understood, studies in the genetically tractable budding yeast Saccharomyces cerevisiae may help provide some molecular basis for how NAD+ homeostasis factors contribute to the maintenance and regulation of cellular function and how they are regulated by various nutritional and stress signals. Here we present a brief overview of recent insights and discoveries made with respect to the relationship between NAD+ metabolism and selected human disorders and infections, with a particular focus on the de novo pathway. We also discuss how studies in budding yeast may help elucidate the regulation of NAD+ homeostasis.

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Elevated quinolinic acid levels in cerebrospinal fluid in subacute sclerosing panencephalitis

Cited by 12 publications

References 34 publications

Cerebrospinal fluid metabolites in tryptophan‐kynurenine and nitric oxide pathways: biomarkers for acute neuroinflammation

Cerebrospinal fluid metabolites in tryptophan‐kynurenine and nitric oxide pathways: biomarkers for acute neuroinflammation

Enzymology of extracellular NAD metabolism

NAD+ Metabolism, Metabolic Stress, and Infection

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