Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Lippincott Williams & Wilkins 2023
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
_version_ 1785118944711933952
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
work_keys_str_mv AT maglioccaaurora indoleamine23dioxygenasedeletiontomodulatekynureninepathwayandtopreventbraininjuryaftercardiacarrestinmice
AT peregocarlo indoleamine23dioxygenasedeletiontomodulatekynureninepathwayandtopreventbraininjuryaftercardiacarrestinmice
AT mottafrancesca indoleamine23dioxygenasedeletiontomodulatekynureninepathwayandtopreventbraininjuryaftercardiacarrestinmice
AT merigogiulia indoleamine23dioxygenasedeletiontomodulatekynureninepathwayandtopreventbraininjuryaftercardiacarrestinmice
AT micottiedoardo indoleamine23dioxygenasedeletiontomodulatekynureninepathwayandtopreventbraininjuryaftercardiacarrestinmice
AT olivaridavide indoleamine23dioxygenasedeletiontomodulatekynureninepathwayandtopreventbraininjuryaftercardiacarrestinmice
AT fumagallifrancesca indoleamine23dioxygenasedeletiontomodulatekynureninepathwayandtopreventbraininjuryaftercardiacarrestinmice
AT lucchettijacopo indoleamine23dioxygenasedeletiontomodulatekynureninepathwayandtopreventbraininjuryaftercardiacarrestinmice
AT gobbimarco indoleamine23dioxygenasedeletiontomodulatekynureninepathwayandtopreventbraininjuryaftercardiacarrestinmice
AT mandellialessandra indoleamine23dioxygenasedeletiontomodulatekynureninepathwayandtopreventbraininjuryaftercardiacarrestinmice
AT furlanroberto indoleamine23dioxygenasedeletiontomodulatekynureninepathwayandtopreventbraininjuryaftercardiacarrestinmice
AT skrifvarsmarkusb indoleamine23dioxygenasedeletiontomodulatekynureninepathwayandtopreventbraininjuryaftercardiacarrestinmice
AT latiniroberto indoleamine23dioxygenasedeletiontomodulatekynureninepathwayandtopreventbraininjuryaftercardiacarrestinmice
AT bellanigiacomo indoleamine23dioxygenasedeletiontomodulatekynureninepathwayandtopreventbraininjuryaftercardiacarrestinmice
AT ichinosefumito indoleamine23dioxygenasedeletiontomodulatekynureninepathwayandtopreventbraininjuryaftercardiacarrestinmice
AT ristagnogiuseppe indoleamine23dioxygenasedeletiontomodulatekynureninepathwayandtopreventbraininjuryaftercardiacarrestinmice