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Neurotoxic kynurenine metabolism is increased in the dorsal hippocampus and drives distinct depressive behaviors during inflammation

The kynurenine pathway of tryptophan metabolism has an important role in mediating the behavioral effects of inflammation, which has implications in understanding neuropsychiatric comorbidity and for the development of novel therapies. Inhibition of the rate-limiting enzyme, indoleamine 2,3-dioxygen...

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Autores principales: Parrott, J M, Redus, L, Santana-Coelho, D, Morales, J, Gao, X, O'Connor, J C
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5315555/
https://www.ncbi.nlm.nih.gov/pubmed/27754481
http://dx.doi.org/10.1038/tp.2016.200
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author Parrott, J M
Redus, L
Santana-Coelho, D
Morales, J
Gao, X
O'Connor, J C
author_facet Parrott, J M
Redus, L
Santana-Coelho, D
Morales, J
Gao, X
O'Connor, J C
author_sort Parrott, J M
collection PubMed
description The kynurenine pathway of tryptophan metabolism has an important role in mediating the behavioral effects of inflammation, which has implications in understanding neuropsychiatric comorbidity and for the development of novel therapies. Inhibition of the rate-limiting enzyme, indoleamine 2,3-dioxygenase (IDO), prevents the development of many of these inflammation-induced preclinical behaviors. However, dysregulation in the balance of downstream metabolism, where neuroactive kynurenines are generated, is hypothesized to be a functionally important pathogenic feature of inflammation-induced depression. Here we utilized two novel transgenic mouse strains to directly test the hypothesis that neurotoxic kynurenine metabolism causes depressive-like behavior following peripheral immune activation. Wild-type (WT) or kynurenine 3-monooxygenase (KMO)-deficient (KMO(−/−)) mice were administered either lipopolysaccharide (LPS, 0.5 mg kg(−1)) or saline intraperitoneally. Depressive-like behavior was measured across multiple domains 24 h after immune challenge. LPS precipitated a robust depressive-like phenotype, but KMO(−/−) mice were specifically protected from LPS-induced immobility in the tail suspension test (TST) and reduced spontaneous alternations in the Y-maze. Direct administration of 3-hydroxykynurenine, the metabolic product of KMO, caused a dose-dependent increase in depressive-like behaviors. Mice with targeted deletion of 3-hydroxyanthranilic acid dioxygenase (HAAO), the enzyme that generates quinolinic acid, were similarly challenged with LPS. Similar to KMO(−/−) mice, LPS failed to increase immobility during the TST. Whereas kynurenine metabolism was generally increased in behaviorally salient brain regions, a distinct shift toward KMO-dependent kynurenine metabolism occurred in the dorsal hippocampus in response to LPS. Together, these results demonstrate that KMO is a pivotal mediator of hippocampal-dependent depressive-like behaviors induced by peripheral LPS challenge.
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spelling pubmed-53155552017-02-27 Neurotoxic kynurenine metabolism is increased in the dorsal hippocampus and drives distinct depressive behaviors during inflammation Parrott, J M Redus, L Santana-Coelho, D Morales, J Gao, X O'Connor, J C Transl Psychiatry Original Article The kynurenine pathway of tryptophan metabolism has an important role in mediating the behavioral effects of inflammation, which has implications in understanding neuropsychiatric comorbidity and for the development of novel therapies. Inhibition of the rate-limiting enzyme, indoleamine 2,3-dioxygenase (IDO), prevents the development of many of these inflammation-induced preclinical behaviors. However, dysregulation in the balance of downstream metabolism, where neuroactive kynurenines are generated, is hypothesized to be a functionally important pathogenic feature of inflammation-induced depression. Here we utilized two novel transgenic mouse strains to directly test the hypothesis that neurotoxic kynurenine metabolism causes depressive-like behavior following peripheral immune activation. Wild-type (WT) or kynurenine 3-monooxygenase (KMO)-deficient (KMO(−/−)) mice were administered either lipopolysaccharide (LPS, 0.5 mg kg(−1)) or saline intraperitoneally. Depressive-like behavior was measured across multiple domains 24 h after immune challenge. LPS precipitated a robust depressive-like phenotype, but KMO(−/−) mice were specifically protected from LPS-induced immobility in the tail suspension test (TST) and reduced spontaneous alternations in the Y-maze. Direct administration of 3-hydroxykynurenine, the metabolic product of KMO, caused a dose-dependent increase in depressive-like behaviors. Mice with targeted deletion of 3-hydroxyanthranilic acid dioxygenase (HAAO), the enzyme that generates quinolinic acid, were similarly challenged with LPS. Similar to KMO(−/−) mice, LPS failed to increase immobility during the TST. Whereas kynurenine metabolism was generally increased in behaviorally salient brain regions, a distinct shift toward KMO-dependent kynurenine metabolism occurred in the dorsal hippocampus in response to LPS. Together, these results demonstrate that KMO is a pivotal mediator of hippocampal-dependent depressive-like behaviors induced by peripheral LPS challenge. Nature Publishing Group 2016-10 2016-10-18 /pmc/articles/PMC5315555/ /pubmed/27754481 http://dx.doi.org/10.1038/tp.2016.200 Text en Copyright © 2016 The Author(s) http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
spellingShingle Original Article
Parrott, J M
Redus, L
Santana-Coelho, D
Morales, J
Gao, X
O'Connor, J C
Neurotoxic kynurenine metabolism is increased in the dorsal hippocampus and drives distinct depressive behaviors during inflammation
title Neurotoxic kynurenine metabolism is increased in the dorsal hippocampus and drives distinct depressive behaviors during inflammation
title_full Neurotoxic kynurenine metabolism is increased in the dorsal hippocampus and drives distinct depressive behaviors during inflammation
title_fullStr Neurotoxic kynurenine metabolism is increased in the dorsal hippocampus and drives distinct depressive behaviors during inflammation
title_full_unstemmed Neurotoxic kynurenine metabolism is increased in the dorsal hippocampus and drives distinct depressive behaviors during inflammation
title_short Neurotoxic kynurenine metabolism is increased in the dorsal hippocampus and drives distinct depressive behaviors during inflammation
title_sort neurotoxic kynurenine metabolism is increased in the dorsal hippocampus and drives distinct depressive behaviors during inflammation
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5315555/
https://www.ncbi.nlm.nih.gov/pubmed/27754481
http://dx.doi.org/10.1038/tp.2016.200
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