title: Kynurenine metabolic balance is disrupted in the hippocampus following peripheral lipopolysaccharide challenge.
abstract: Inflammation increases the risk of developing depression-related symptoms, and tryptophan metabolism is an important mediator of these behavior changes. Peripheral immune activation results in central up-regulation of pro-inflammatory cytokine expression, microglia activation, and the production of neurotoxic kynurenine metabolites. The neuroinflammatory and kynurenine metabolic response to peripheral immune activation has been largely characterized at the whole brain level. It is unknown if this metabolic response exhibits regional specificity even though the unique indoleamine 2,3-dioxygenase (IDO)-dependent depressive-like behaviors are known to be controlled by discrete brain regions. Therefore, regional characterization of neuroinflammation and kynurenine metabolism might allow for better understanding of the potential mechanisms that mediate inflammation-associated behavior changes.
  
  
  
  Following peripheral immune challenge with lipopolysaccharide (LPS), brain tissue from behaviorally relevant regions was analyzed for changes in mRNA of neuroinflammatory targets and kynurenine pathway enzymes. The metabolic balance of the kynurenine pathway was also determined in the peripheral circulation and these brain regions.
  
  
  
  Peripheral LPS treatment resulted in region-independent up-regulation of brain expression of pro-inflammatory cytokines and glial cellular markers indicative of a neuroinflammatory response. The expression of kynurenine pathway enzymes was also largely region-independent. While the kynurenine/tryptophan ratio was elevated significantly in both the plasma and in each brain regions evaluated, the balance of kynurenine metabolism was skewed toward production of neurotoxic metabolites in the hippocampus.
  
  
  
  The upstream neuroinflammatory processes, such as pro-inflammatory cytokine production, glial cell activation, and kynurenine production, may be similar throughout the brain. However, it appears that the balance of downstream kynurenine metabolism is a tightly regulated brain region-dependent process.
authors.affiliation: Department of Pharmacology, School of Medicine, Center for Biomedical Neuroscience, University of Texas Health Science Center at San Antonio, 422D Medical Building MC-7764, 7703 Floyd Curl Drive, San Antonio, TX, 78229-3900, USA.
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Parrott
authors.affiliation: Department of Pharmacology, School of Medicine, University of Texas Health Science Center at San Antonio, 418D Medical Building MC-7764, 7703 Floyd Curl Drive, San Antonio, TX, 78229-3900, USA.
authors.forename: Laney
authors.initials: L
authors.lastname: Redus
authors.affiliation: Department of Pharmacology, School of Medicine, Center for Biomedical Neuroscience and Mood Disorders Translational Research Core, University of Texas Health Science Center at San Antonio, 216B Medical Building MC-7764, 7703 Floyd Curl Drive, San Antonio, TX, 78229-3900, USA. oconnorj@uthscsa.edu.|Audie L. Murphy Memorial VA Hospital, South Texas Veterans Health System, 7400 Merton Minter, San Antonio, Texas, 78229-4404, USA. oconnorj@uthscsa.edu.
authors.forename: Jason C
authors.initials: JC
authors.lastname: O'Connor
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002853:Chromatography, Liquid; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000235:genetics / Q000378:metabolism; D007737:Kynurenine / Q000235:genetics / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000633:toxicity*; D008297:Male; D013058:Mass Spectrometry; D051379:Mice; D008810:Mice, Inbred C57BL; D008840:Microfilament Proteins / Q000378:metabolism; D020078:Neurogenic Inflammation / Q000139:chemically induced* / Q000473:pathology*; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics; D013997:Time Factors
chemical_list: C491049:Aif1 protein, mouse; D002135:Calcium-Binding Proteins; D016207:Cytokines; D005904:Glial Fibrillary Acidic Protein; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D008070:Lipopolysaccharides; D008840:Microfilament Proteins; D012333:RNA, Messenger; D007737:Kynurenine
keywords: Brain regions; Hippocampus; Indoleamine 2,3-dioxygenase; Kynurenine; Kynurenine 3-monooxygenase; Microglia; Neuroinflammation; Pro-inflammatory cytokines