Kynurenine metabolic balance is disrupted in the hippocampus following peripheral lipopolysaccharide challenge

• Published in: Journal of neuroinflammation 2016-05, Vol.13 (1), p.124, Article 124
• Main Authors: Parrott, Jennifer M, Redus, Laney, O'Connor, Jason C
• Format: Article
• Language: English
• Subjects: Animals; Brain - drug effects; Brain - metabolism; Calcium-Binding Proteins - metabolism; Care and treatment; Chromatography, Liquid; Complications and side effects; Cytokines - genetics; Cytokines - metabolism; Depression, Mental; Disease Models, Animal; Glial Fibrillary Acidic Protein - metabolism; Health aspects; Immunotherapy; Indoleamine-Pyrrole 2,3,-Dioxygenase - genetics; Indoleamine-Pyrrole 2,3,-Dioxygenase - metabolism; Inflammation; Kynurenine - genetics; Kynurenine - metabolism; Lipopolysaccharides - toxicity; Male; Mass Spectrometry; Mice; Mice, Inbred C57BL; Microfilament Proteins - metabolism; Neurogenic Inflammation - chemically induced; Neurogenic Inflammation - pathology; Risk factors; RNA, Messenger - metabolism; Signal Transduction - drug effects; Signal Transduction - genetics; Time Factors
• ISSN: 1742-2094; 1742-2094
• DOI: 10.1186/s12974-016-0590-y

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.