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Indoleamine 2,3-Dioxygenase Deletion to Modulate Kynurenine Pathway and to Prevent Brain Injury after Cardiac Arrest in Mice
BACKGROUND: The catabolism of the essential amino acid tryptophan to kynurenine is emerging as a potential key pathway involved in post–cardiac arrest brain injury. The aim of this study was to evaluate the effects of the modulation of kynurenine pathway on cardiac arrest outcome through genetic del...
Autores principales: | , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Lippincott Williams & Wilkins
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10566599/ https://www.ncbi.nlm.nih.gov/pubmed/37487175 http://dx.doi.org/10.1097/ALN.0000000000004713 |
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author | Magliocca, Aurora Perego, Carlo Motta, Francesca Merigo, Giulia Micotti, Edoardo Olivari, Davide Fumagalli, Francesca Lucchetti, Jacopo Gobbi, Marco Mandelli, Alessandra Furlan, Roberto Skrifvars, Markus B. Latini, Roberto Bellani, Giacomo Ichinose, Fumito Ristagno, Giuseppe |
author_facet | Magliocca, Aurora Perego, Carlo Motta, Francesca Merigo, Giulia Micotti, Edoardo Olivari, Davide Fumagalli, Francesca Lucchetti, Jacopo Gobbi, Marco Mandelli, Alessandra Furlan, Roberto Skrifvars, Markus B. Latini, Roberto Bellani, Giacomo Ichinose, Fumito Ristagno, Giuseppe |
author_sort | Magliocca, Aurora |
collection | PubMed |
description | BACKGROUND: The catabolism of the essential amino acid tryptophan to kynurenine is emerging as a potential key pathway involved in post–cardiac arrest brain injury. The aim of this study was to evaluate the effects of the modulation of kynurenine pathway on cardiac arrest outcome through genetic deletion of the rate-limiting enzyme of the pathway, indoleamine 2,3-dioxygenase. METHODS: Wild-type and indoleamine 2,3-dioxygenase–deleted (IDO(−/−)) mice were subjected to 8-min cardiac arrest. Survival, neurologic outcome, and locomotor activity were evaluated after resuscitation. Brain magnetic resonance imaging with diffusion tensor and diffusion-weighted imaging sequences was performed, together with microglia and macrophage activation and neurofilament light chain measurements. RESULTS: IDO(−/−) mice showed higher survival compared to wild-type mice (IDO(−/−) 11 of 16, wild-type 6 of 16, log-rank P = 0.036). Neurologic function was higher in IDO(−/−) mice than in wild-type mice after cardiac arrest (IDO(−/−) 9 ± 1, wild-type 7 ± 1, P = 0.012, n = 16). Indoleamine 2,3-dioxygenase deletion preserved locomotor function while maintaining physiologic circadian rhythm after cardiac arrest. Brain magnetic resonance imaging with diffusion tensor imaging showed an increase in mean fractional anisotropy in the corpus callosum (IDO(−/−) 0.68 ± 0.01, wild-type 0.65 ± 0.01, P = 0.010, n = 4 to 5) and in the external capsule (IDO(−/−) 0.47 ± 0.01, wild-type 0.45 ± 0.01, P = 0.006, n = 4 to 5) in IDO(−/−) mice compared with wild-type ones. Increased release of neurofilament light chain was observed in wild-type mice compared to IDO(−/−) (median concentrations [interquartile range], pg/mL: wild-type 1,138 [678 to 1,384]; IDO(−/−) 267 [157 to 550]; P < 0.001, n = 3 to 4). Brain magnetic resonance imaging with diffusion-weighted imaging revealed restriction of water diffusivity 24 h after cardiac arrest in wild-type mice; indoleamine 2,3-dioxygenase deletion prevented water diffusion abnormalities, which was reverted in IDO(−/−) mice receiving l-kynurenine (apparent diffusion coefficient, μm(2)/ms: wild-type, 0.48 ± 0.07; IDO(−/−), 0.59 ± 0.02; IDO(−/−) and l-kynurenine, 0.47 ± 0.08; P = 0.007, n = 6). CONCLUSIONS: The kynurenine pathway represents a novel target to prevent post–cardiac arrest brain injury. The neuroprotective effects of indoleamine 2,3-dioxygenase deletion were associated with preservation of brain white matter microintegrity and with reduction of cerebral cytotoxic edema. |
format | Online Article Text |
id | pubmed-10566599 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Lippincott Williams & Wilkins |
record_format | MEDLINE/PubMed |
spelling | pubmed-105665992023-10-12 Indoleamine 2,3-Dioxygenase Deletion to Modulate Kynurenine Pathway and to Prevent Brain Injury after Cardiac Arrest in Mice Magliocca, Aurora Perego, Carlo Motta, Francesca Merigo, Giulia Micotti, Edoardo Olivari, Davide Fumagalli, Francesca Lucchetti, Jacopo Gobbi, Marco Mandelli, Alessandra Furlan, Roberto Skrifvars, Markus B. Latini, Roberto Bellani, Giacomo Ichinose, Fumito Ristagno, Giuseppe Anesthesiology Critical Care Medicine: Basic Science BACKGROUND: The catabolism of the essential amino acid tryptophan to kynurenine is emerging as a potential key pathway involved in post–cardiac arrest brain injury. The aim of this study was to evaluate the effects of the modulation of kynurenine pathway on cardiac arrest outcome through genetic deletion of the rate-limiting enzyme of the pathway, indoleamine 2,3-dioxygenase. METHODS: Wild-type and indoleamine 2,3-dioxygenase–deleted (IDO(−/−)) mice were subjected to 8-min cardiac arrest. Survival, neurologic outcome, and locomotor activity were evaluated after resuscitation. Brain magnetic resonance imaging with diffusion tensor and diffusion-weighted imaging sequences was performed, together with microglia and macrophage activation and neurofilament light chain measurements. RESULTS: IDO(−/−) mice showed higher survival compared to wild-type mice (IDO(−/−) 11 of 16, wild-type 6 of 16, log-rank P = 0.036). Neurologic function was higher in IDO(−/−) mice than in wild-type mice after cardiac arrest (IDO(−/−) 9 ± 1, wild-type 7 ± 1, P = 0.012, n = 16). Indoleamine 2,3-dioxygenase deletion preserved locomotor function while maintaining physiologic circadian rhythm after cardiac arrest. Brain magnetic resonance imaging with diffusion tensor imaging showed an increase in mean fractional anisotropy in the corpus callosum (IDO(−/−) 0.68 ± 0.01, wild-type 0.65 ± 0.01, P = 0.010, n = 4 to 5) and in the external capsule (IDO(−/−) 0.47 ± 0.01, wild-type 0.45 ± 0.01, P = 0.006, n = 4 to 5) in IDO(−/−) mice compared with wild-type ones. Increased release of neurofilament light chain was observed in wild-type mice compared to IDO(−/−) (median concentrations [interquartile range], pg/mL: wild-type 1,138 [678 to 1,384]; IDO(−/−) 267 [157 to 550]; P < 0.001, n = 3 to 4). Brain magnetic resonance imaging with diffusion-weighted imaging revealed restriction of water diffusivity 24 h after cardiac arrest in wild-type mice; indoleamine 2,3-dioxygenase deletion prevented water diffusion abnormalities, which was reverted in IDO(−/−) mice receiving l-kynurenine (apparent diffusion coefficient, μm(2)/ms: wild-type, 0.48 ± 0.07; IDO(−/−), 0.59 ± 0.02; IDO(−/−) and l-kynurenine, 0.47 ± 0.08; P = 0.007, n = 6). CONCLUSIONS: The kynurenine pathway represents a novel target to prevent post–cardiac arrest brain injury. The neuroprotective effects of indoleamine 2,3-dioxygenase deletion were associated with preservation of brain white matter microintegrity and with reduction of cerebral cytotoxic edema. Lippincott Williams & Wilkins 2023-07-24 2023-11 /pmc/articles/PMC10566599/ /pubmed/37487175 http://dx.doi.org/10.1097/ALN.0000000000004713 Text en Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Society of Anesthesiologists. https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY) (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Critical Care Medicine: Basic Science Magliocca, Aurora Perego, Carlo Motta, Francesca Merigo, Giulia Micotti, Edoardo Olivari, Davide Fumagalli, Francesca Lucchetti, Jacopo Gobbi, Marco Mandelli, Alessandra Furlan, Roberto Skrifvars, Markus B. Latini, Roberto Bellani, Giacomo Ichinose, Fumito Ristagno, Giuseppe Indoleamine 2,3-Dioxygenase Deletion to Modulate Kynurenine Pathway and to Prevent Brain Injury after Cardiac Arrest in Mice |
title | Indoleamine 2,3-Dioxygenase Deletion to Modulate Kynurenine Pathway and to Prevent Brain Injury after Cardiac Arrest in Mice |
title_full | Indoleamine 2,3-Dioxygenase Deletion to Modulate Kynurenine Pathway and to Prevent Brain Injury after Cardiac Arrest in Mice |
title_fullStr | Indoleamine 2,3-Dioxygenase Deletion to Modulate Kynurenine Pathway and to Prevent Brain Injury after Cardiac Arrest in Mice |
title_full_unstemmed | Indoleamine 2,3-Dioxygenase Deletion to Modulate Kynurenine Pathway and to Prevent Brain Injury after Cardiac Arrest in Mice |
title_short | Indoleamine 2,3-Dioxygenase Deletion to Modulate Kynurenine Pathway and to Prevent Brain Injury after Cardiac Arrest in Mice |
title_sort | indoleamine 2,3-dioxygenase deletion to modulate kynurenine pathway and to prevent brain injury after cardiac arrest in mice |
topic | Critical Care Medicine: Basic Science |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10566599/ https://www.ncbi.nlm.nih.gov/pubmed/37487175 http://dx.doi.org/10.1097/ALN.0000000000004713 |
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