Cargando…

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

BACKGROUND: 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 pr...

Descripción completa

Detalles Bibliográficos
Autores principales: Parrott, Jennifer M., Redus, Laney, O’Connor, Jason C.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4884395/
https://www.ncbi.nlm.nih.gov/pubmed/27233247
http://dx.doi.org/10.1186/s12974-016-0590-y
_version_ 1782434368244940800
author Parrott, Jennifer M.
Redus, Laney
O’Connor, Jason C.
author_facet Parrott, Jennifer M.
Redus, Laney
O’Connor, Jason C.
author_sort Parrott, Jennifer M.
collection PubMed
description BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
format Online
Article
Text
id pubmed-4884395
institution National Center for Biotechnology Information
language English
publishDate 2016
publisher BioMed Central
record_format MEDLINE/PubMed
spelling pubmed-48843952016-05-29 Kynurenine metabolic balance is disrupted in the hippocampus following peripheral lipopolysaccharide challenge Parrott, Jennifer M. Redus, Laney O’Connor, Jason C. J Neuroinflammation Research BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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. BioMed Central 2016-05-27 /pmc/articles/PMC4884395/ /pubmed/27233247 http://dx.doi.org/10.1186/s12974-016-0590-y Text en © The Author(s). 2016 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research
Parrott, Jennifer M.
Redus, Laney
O’Connor, Jason C.
Kynurenine metabolic balance is disrupted in the hippocampus following peripheral lipopolysaccharide challenge
title Kynurenine metabolic balance is disrupted in the hippocampus following peripheral lipopolysaccharide challenge
title_full Kynurenine metabolic balance is disrupted in the hippocampus following peripheral lipopolysaccharide challenge
title_fullStr Kynurenine metabolic balance is disrupted in the hippocampus following peripheral lipopolysaccharide challenge
title_full_unstemmed Kynurenine metabolic balance is disrupted in the hippocampus following peripheral lipopolysaccharide challenge
title_short Kynurenine metabolic balance is disrupted in the hippocampus following peripheral lipopolysaccharide challenge
title_sort kynurenine metabolic balance is disrupted in the hippocampus following peripheral lipopolysaccharide challenge
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4884395/
https://www.ncbi.nlm.nih.gov/pubmed/27233247
http://dx.doi.org/10.1186/s12974-016-0590-y
work_keys_str_mv AT parrottjenniferm kynureninemetabolicbalanceisdisruptedinthehippocampusfollowingperipherallipopolysaccharidechallenge
AT reduslaney kynureninemetabolicbalanceisdisruptedinthehippocampusfollowingperipherallipopolysaccharidechallenge
AT oconnorjasonc kynureninemetabolicbalanceisdisruptedinthehippocampusfollowingperipherallipopolysaccharidechallenge