Intravenous administration of LPS activates the kynurenine pathway in healthy male human subjects: a prospective placebo-controlled cross-over trial.
Background: Administration of lipopolysaccharide (LPS) from Gram-negative bacteria, also known as the human endotoxemia model, is a standardized and safe model of human inflammation. Experimental studies have revealed that peripheral administration of LPS leads to induction of the kynurenine pathway...
| Publicado en: | Journal of Neuroinflammation Vol. 18; no. 1; pp. 1 - 12 |
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| Autores principales: | , , , , , , , , , |
| Formato: | research randomized controlled trial Journal Article |
| Publicado: |
BioMed Central
7/17/2021
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| Acceso en línea: | Ver este registro en EBSCOhost |
| fields | @attributes: recordID: 1 pdfLink: plink: https://search.ebscohost.com/login.aspx?direct=true&db=ccm&AN=151456420&site=ehost-live header: @attributes: shortDbName: ccm uiTerm: 151456420 longDbName: CINAHL Complete uiTag: AN controlInfo: bkinfo: dissinfo: jinfo: jid: 17422094 1CUD jtl: Journal of Neuroinflammation issn: 17422094 maglogo: N pubinfo: dt: 7/17/2021 vid: 18 iid: 1 pid: 24147 pub: BioMed Central artinfo: ui: 151456420 151456420 NLM34273987 151456420 10.1186/s12974-021-02196-x NLM34273987 151456420 ppf: 1 ppct: 11 formats: tig: atl: Intravenous administration of LPS activates the kynurenine pathway in healthy male human subjects: a prospective placebo-controlled cross-over trial. aug: au: Millischer, Vincent Heinzl, Matthias Faka, Anthi Resl, Michael Trepci, Ada Klammer, Carmen Egger, Margot Dieplinger, Benjamin Clodi, Martin Schwieler, Lilly affil: Department of Molecular Medicine and Surgery (MMK), Karolinska Institutet, Stockholm, Sweden sug: subj: Amino Acids Metabolism Lipopolysaccharides Administration and Dosage Tryptophan Metabolism Amino Acids Blood Tryptophan Blood Lipopolysaccharides Metabolism Male Human Adolescence Inflammation Lipopolysaccharides Immunology Adult Interleukins Metabolism Interleukins Blood Research Subjects Placebos C-Reactive Protein Analysis C-Reactive Protein Metabolism Administration, Intravenous Single-Blind Studies Crossover Design Prospective Studies Comparative Studies Multicenter Studies Randomized Controlled Trials Evaluation Research Validation Studies Adolescent: 13-18 years Adult: 19-44 years Male ab: Background: Administration of lipopolysaccharide (LPS) from Gram-negative bacteria, also known as the human endotoxemia model, is a standardized and safe model of human inflammation. Experimental studies have revealed that peripheral administration of LPS leads to induction of the kynurenine pathway followed by depressive-like behavior and cognitive dysfunction in animals. The aim of the present study is to investigate how acute intravenous LPS administration affects the kynurenine pathway in healthy male human subjects.Methods: The present study is a prospective, single-blinded, randomized, placebo-controlled cross-over study to investigate the effects of intravenously administered LPS (Escherichia coli O113, 2 ng/kg) on tryptophan and kynurenine metabolites over 48 h and their association with interleukin-6 (IL-6) and C-reactive protein (CRP). The study included 10 healthy, non-smoking men (18-40 years) free from medication. Statistical differences in tryptophan and kynurenine metabolites as well as associations with IL-6 and CRP in LPS and placebo treated subjects were assessed with linear mixed-effects models.Results: Systemic injection of LPS was associated with significantly lower concentrations of plasma tryptophan and kynurenine after 4 h, as well as higher concentrations of quinolinic acid (QUIN) after 48 h compared to the placebo injection. No differences were found in kynurenic acid (KYNA) or picolinic acid plasma concentrations between LPS or placebo treatment. The KYNA/kynurenine ratio peaked at 6 h post LPS injection while QUIN/kynurenine maintained significantly higher from 3 h post LPS injection until 24 h. The kynurenine/tryptophan ratio was higher at 24 h and 48 h post LPS treatment. Finally, we report an association between the kynurenine/tryptophan ratio and CRP.Conclusions: Our findings strongly support the concept that an inflammatory challenge with LPS induces the kynurenine pathway in humans, activating both the neurotoxic (QUIN) and neuroprotective (KYNA) branch of the kynurenine pathway.Trial Registration: This study is based on a study registered at ClinicalTrials.gov, NCT03392701 . Registered 21 December 2017. pubtype: Academic Journal doctype: research randomized controlled trial Journal Article ougenre: Article language: English refInfo: holdings: @attributes: islocal: N |
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