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Repeated LPS Injection Induces Distinct Changes in the Kynurenine Pathway in Mice

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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.

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Acknowledgments

This work was supported by grants from the Swedish Medical Research Council (2009-7053; 2013-2838), the Swedish Brain foundation, Petrus och Augusta Hedlunds Stiftelse, Torsten Söderbergs Stiftelse, the Mayo Clinic—Karolinska Institutet Collaborative Research Grants, the AstraZeneca-Karolinska Institutet Joint Research Program in Translational Science and the Karolinska Institutet (KID).

Authors’ contributions

M.L., and S.E. collected and analyzed data, contributed to discussion, and wrote, reviewed, and edited the manuscript. F.O., XC.L., D.S.C. L.S., G.E., M.G., M.B., S.S., K.S. and A.O. researched data and reviewed and critically revised the manuscript. A.F. and S.I analyzed data, wrote, reviewed and edited the manuscript. S.E. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

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Authors and Affiliations

  1. Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden

    M. K. Larsson, A. Faka, S. Imbeault, M. Goiny, F. Orhan, X. C. Liu, K. Sandberg, G. Engberg, L. Schwieler & S. Erhardt

  2. Protein Biomarkers, Personalized Healthcare and Biomarkers Laboratories, Innovative Medicines, AstraZeneca, Gothenburg, Sweden

    M. Bhat

  3. Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic College of Medicine, Rochester, MN, 55905, USA

    A. Oliveros, D. S. Choi & K. Sandberg

  4. Translational Science Centre, Personalized Healthcare and Biomarkers Laboratories, Innovative Medicines, Science for Life Laboratory, AstraZeneca, Stockholm, Sweden

    S. Ståhl

  5. Neurobiology of Disease Program, Mayo Clinic College of Medicine, Rochester, MN, 55905, USA

    D. S. Choi

  6. Department of Psychiatry and Psychology, Mayo Clinic College of Medicine, Rochester, MN, 55905, USA

    D. S. Choi

  7. Department of Clinical Neuroscience, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden

    K. Sandberg

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M. K. Larsson and A. Faka are shared first author.

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Larsson, M.K., Faka, A., Bhat, M. et al. Repeated LPS Injection Induces Distinct Changes in the Kynurenine Pathway in Mice. Neurochem Res 41, 2243–2255 (2016). https://doi.org/10.1007/s11064-016-1939-4

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