Repeated LPS Injection Induces Distinct Changes in the Kynurenine Pathway in Mice
- 548 Downloads
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.
KeywordsKynurenic acid Lipopolysaccharide Quinolinic acid Neuroinflammation Psychiatric disorders Kynurenine pathway
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).
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.
Compliance with Ethical Standards
Conflict of interest
- 3.Schwieler L, Larsson MK, Skogh E, Orhan F, Bhat M, Samuelsson M et al (2015) Increased levels of IL-6 in the cerebrospinal fluid of patients with chronic schizophrenia—significance for activation of the kynurenine pathway. J Psychiatry Neurosci 40:126–133. doi: 10.1503/jpn.140126 PubMedPubMedCentralGoogle Scholar
- 25.Alexander KS, Pocivavsek A, Wu HQ, Pershing ML, Schwarcz R, Bruno JP (2013) Early developmental elevations of brain kynurenic acid impair cognitive flexibility in adults: reversal with galantamine. Neuroscience 238:19–28. doi: 10.1016/j.neuroscience.2013.01.063 CrossRefPubMedPubMedCentralGoogle Scholar
- 29.Forrest CM, McNair K, Pisar M, Khalil OS, Darlington LG, Stone TW (2015) Altered hippocampal plasticity by prenatal kynurenine administration, kynurenine-3-monoxygenase (KMO) deletion or galantamine. Neuroscience 310:91–105. doi: 10.1016/j.neuroscience.2015.09.022 CrossRefPubMedPubMedCentralGoogle Scholar
- 30.O’Connor JC, André C, Wang Y, Lawson MA, Szegedi SS, Lestage J, Castanon N, Kelley KW, Dantzer R (2009) Interferon-γ and tumor necrosis factor-α mediate the upregulation of indoleamine 2,3-dioxygenase and the induction of depressive-like behavior in mice in response to bacillus Calmette-Guerin. J Neurosci 29:4200–4209. doi: 10.1523/JNEUROSCI.5032-08.2009 CrossRefPubMedPubMedCentralGoogle Scholar
- 31.Connor JC, Lawson MA, André C, Briley EM, Szegedi SS, Lestage J, Castanon N, Herkenham M, Dantzer R, Kelley KW (2009) Induction of IDO by Bacille Calmette-Guérin is responsible for development of murine depressive-like behavior. J Immunol 182:3202–3212. doi: 10.4049/jimmunol.0802722 CrossRefGoogle Scholar
- 41.Lavebratt C, Olsson SK, Backlund L, Frisén L, Sellgren C, Priebe L et al (2014) The KMO allele encoding Arg452 is associated with psychotic features in bipolar disorder type 1, and with increased CSF KYNA level and reduced KMO expression. Mol Psychiatry 19:334–341. doi: 10.1038/mp.2013.11 CrossRefPubMedGoogle Scholar
- 43.Bay-Richter C, Linderholm KR, Lim CK, Samuelsson M, Träskman-Bendz L, Guillemin GJ et al (2015) A role for inflammatory metabolites as modulators of the glutamate N-methyl-d-aspartate receptor in depression and suicidality. Brain Behav Immun 43:110–117. doi: 10.1016/j.bbi.2014.07.012 CrossRefPubMedGoogle Scholar
- 47.Salazar A, Gonzalez-Rivera BL, Redus L, Parrott JM, O’Connor JC (2012) Indoleamine 2,3-dioxygenase mediates anhedonia and anxiety-like behaviors caused by peripheral lipopolysaccharide immune challenge. Horm Behav 62:202–209. doi: 10.1016/j.yhbeh.2012.03.010 CrossRefPubMedPubMedCentralGoogle Scholar
- 48.Czerniawski J, Miyashita T, Lewandowski G, Guzowski JF (2015) Systemic lipopolysaccharide administration impairs retrieval of context-object discrimination, but not spatial, memory: evidence for selective disruption of specific hippocampus-dependent memory functions during acute neuroinflammation. Brain Behav Immun 44:159–166. doi: 10.1016/j.bbi.2014.09.014 CrossRefPubMedGoogle Scholar
- 49.Haba R, Shintani N, Onaka Y, Wang H, Takenaga R, Hayata A et al (2012) Lipopolysaccharide affects exploratory behaviors toward novel objects by impairing cognition and/or motivation in mice: possible role of activation of the central amygdala. Behav Brain Res 228:423–431. doi: 10.1016/j.bbr.2011.12.027 CrossRefPubMedGoogle Scholar
- 62.Mormède C, Palin K, Kelley KW, Castanon N, Dantzer R (2004) Conditioned taste aversion with lipopolysaccharide and peptidoglycan does not activate cytokine gene expression in the spleen and hypothalamus of mice. Brain Behav Immun 18:186–200. doi: 10.1016/S0889-1591(03)00133-8 CrossRefPubMedGoogle Scholar
- 66.André C, Dinel A-L, Ferreira G, Layé S, Castanon N (2014) Diet-induced obesity progressively alters cognition, anxiety-like behavior and lipopolysaccharide-induced depressive-like behavior: focus on brain indoleamine 2,3-dioxygenase activation. Brain Behav Immun 41:10–21. doi: 10.1016/j.bbi.2014.03.012 CrossRefPubMedGoogle Scholar
- 67.Cunningham C, Wilcockson DC, Campion S, Lunnon K, Perry VH (2005) Central and systemic endotoxin challenges exacerbate the local inflammatory response and increase neuronal death during chronic neurodegeneration. J Neurosci 25:9275–9284. doi: 10.1523/JNEUROSCI.2614-05.2005 CrossRefPubMedGoogle Scholar
- 69.Miura H, Ozaki N, Sawada M, Isobe K, Ohta T, Nagatsu T (2008) A link between stress and depression: shifts in the balance between the kynurenine and serotonin pathways of tryptophan metabolism and the etiology and pathophysiology of depression. Stress 11:198–209. doi: 10.1080/10253890701754068 CrossRefPubMedGoogle Scholar
- 71.van Heesch F, Prins J, Konsman JP, Korte-Bouws GAH, Westphal KGC, Rybka J et al (2014) Lipopolysaccharide increases degradation of central monoamines: an in vivo microdialysis study in the nucleus accumbens and medial prefrontal cortex of mice. Eur J Pharmacol 725:55–63. doi: 10.1016/j.ejphar.2014.01.014 CrossRefPubMedGoogle Scholar
- 72.Helkamaa T, Reenilä I, Tuominen RK, Soinila S, Väänänen A, Tilgmann C, Rauhala P (2007) Increased catechol-O-methyltransferase activity and protein expression in OX-42-positive cells in the substantia nigra after lipopolysaccharide microinfusion. Neurochem Int 51:412–423. doi: 10.1016/j.neuint.2007.04.020 CrossRefPubMedGoogle Scholar