title: Repeated LPS Injection Induces Distinct Changes in the Kynurenine Pathway in Mice.
abstract: The immune system has been recognized as a potential contributor to psychiatric disorders. In animals, lipopolysaccharide (LPS) is used to induce inflammation and behaviors analogous to some of the symptoms in these disorders. Recent data indicate that the kynurenine pathway contributes to LPS-induced aberrant behaviors. However, data are inconclusive regarding optimal LPS dose and treatment strategy. Here, we therefore aimed to evaluate the effects of single versus repeated administration of LPS on the kynurenine pathway. Adult C57BL6 mice were given 0.83 mg/kg LPS as a single or a repeated injection (LPS + LPS) and sacrificed after 24, 48, 72, or 120 h. Mice receiving LPS + LPS had significantly elevated brain kynurenine levels at 24 and 48 h, and elevated serum kynurenine at 24, 48 and 72 h. Brain kynurenic acid and quinolinic acid were significantly increased at 24 and 48 h in mice receiving LPS + LPS, whereas serum kynurenic acid levels were significantly decreased at 24 h. The increase of brain kynurenic acid by LPS + LPS was likely unrelated to the higher total dose as a separate group of mice receiving 1.66 mg/kg LPS as single injection 24 h prior to sacrifice did not show increased brain kynurenic acid. Serum quinolinic acid levels were not affected by LPS + LPS compared to vehicle. Animals given repeated injections of LPS showed a more robust induction of the kynurenine pathway in contrast to animals receiving a single injection. These results may be valuable in light of data showing the importance of the kynurenine pathway in psychiatric disorders.
authors.affiliation: Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: M K
authors.initials: MK
authors.lastname: Larsson
authors.affiliation: Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: A
authors.initials: A
authors.lastname: Faka
authors.affiliation: Protein Biomarkers, Personalized Healthcare and Biomarkers Laboratories, Innovative Medicines, AstraZeneca, Gothenburg, Sweden.
authors.forename: M
authors.initials: M
authors.lastname: Bhat
authors.affiliation: Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: S
authors.initials: S
authors.lastname: Imbeault
authors.affiliation: Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: M
authors.initials: M
authors.lastname: Goiny
authors.affiliation: Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: F
authors.initials: F
authors.lastname: Orhan
authors.affiliation: Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic College of Medicine, Rochester, MN, 55905, USA.
authors.forename: A
authors.initials: A
authors.lastname: Oliveros
authors.affiliation: Translational Science Centre, Personalized Healthcare and Biomarkers Laboratories, Innovative Medicines, Science for Life Laboratory, AstraZeneca, Stockholm, Sweden.
authors.forename: S
authors.initials: S
authors.lastname: Ståhl
authors.affiliation: Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: X C
authors.initials: XC
authors.lastname: Liu
authors.affiliation: Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic College of Medicine, Rochester, MN, 55905, USA.|Neurobiology of Disease Program, Mayo Clinic College of Medicine, Rochester, MN, 55905, USA.|Department of Psychiatry and Psychology, Mayo Clinic College of Medicine, Rochester, MN, 55905, USA.
authors.forename: D S
authors.initials: DS
authors.lastname: Choi
authors.affiliation: Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.|Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic College of Medicine, Rochester, MN, 55905, USA.|Department of Clinical Neuroscience, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: K
authors.initials: K
authors.lastname: Sandberg
authors.affiliation: Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: G
authors.initials: G
authors.lastname: Engberg
authors.affiliation: Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: L
authors.initials: L
authors.lastname: Schwieler
authors.affiliation: Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden. sophie.erhardt@ki.se.
authors.forename: S
authors.identifier: http://orcid.org/0000-0001-7359-5250
authors.initials: S
authors.lastname: Erhardt
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D007107:Immune System / Q000187:drug effects; D007249:Inflammation / Q000188:drug therapy / Q000378:metabolism; D007736:Kynurenic Acid / Q000378:metabolism; D007737:Kynurenine / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D008810:Mice, Inbred C57BL; D017378:Quinolinic Acid / Q000378:metabolism*
chemical_list: D008070:Lipopolysaccharides; D007737:Kynurenine; D017378:Quinolinic Acid; D007736:Kynurenic Acid
keywords: Kynurenic acid; Kynurenine pathway; Lipopolysaccharide; Neuroinflammation; Psychiatric disorders; Quinolinic acid