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The role of Nox2-derived ROS in the development of cognitive impairment after sepsis
BACKGROUND: Sepsis- associated encephalopathy (SAE) is an early and common feature of severe infections. Oxidative stress is one of the mechanisms associated with the pathophysiology of SAE. The goal of this study was to investigate the involvement of NADPH oxidase in neuroinflammation and in the lo...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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BioMed Central
2014
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3974031/ https://www.ncbi.nlm.nih.gov/pubmed/24571599 http://dx.doi.org/10.1186/1742-2094-11-36 |
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author | Hernandes, Marina S D’Avila, Joana C Trevelin, Silvia C Reis, Patricia A Kinjo, Erika R Lopes, Lucia R Castro-Faria-Neto, Hugo C Cunha, Fernando Q Britto, Luiz RG Bozza, Fernando A |
author_facet | Hernandes, Marina S D’Avila, Joana C Trevelin, Silvia C Reis, Patricia A Kinjo, Erika R Lopes, Lucia R Castro-Faria-Neto, Hugo C Cunha, Fernando Q Britto, Luiz RG Bozza, Fernando A |
author_sort | Hernandes, Marina S |
collection | PubMed |
description | BACKGROUND: Sepsis- associated encephalopathy (SAE) is an early and common feature of severe infections. Oxidative stress is one of the mechanisms associated with the pathophysiology of SAE. The goal of this study was to investigate the involvement of NADPH oxidase in neuroinflammation and in the long-term cognitive impairment of sepsis survivors. METHODS: Sepsis was induced in WT and gp91(phox) knockout mice (gp91(phox-/-)) by cecal ligation and puncture (CLP) to induce fecal peritonitis. We measured oxidative stress, Nox2 and Nox4 gene expression and neuroinflammation in the hippocampus at six hours, twenty-four hours and five days post-sepsis. Mice were also treated with apocynin, a NADPH oxidase inhibitor. Behavioral outcomes were evaluated 15 days after sepsis with the inhibitory avoidance test and the Morris water maze in control and apocynin-treated WT mice. RESULTS: Acute oxidative damage to the hippocampus was identified by increased 4-HNE expression in parallel with an increase in Nox2 gene expression after sepsis. Pharmacological inhibition of Nox2 with apocynin completely inhibited hippocampal oxidative stress in septic animals. Pharmacologic inhibition or the absence of Nox2 in gp91(phox-/-) mice prevented glial cell activation, one of the central mechanisms associated with SAE. Finally, treatment with apocynin and inhibition of hippocampal oxidative stress in the acute phase of sepsis prevented the development of long-term cognitive impairment. CONCLUSIONS: Our results demonstrate that Nox2 is the main source of reactive oxygen species (ROS) involved in the oxidative damage to the hippocampus in SAE and that Nox2-derived ROS are determining factors for cognitive impairments after sepsis. These findings highlight the importance of Nox2-derived ROS as a central mechanism in the development of neuroinflammation associated with SAE. |
format | Online Article Text |
id | pubmed-3974031 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-39740312014-04-04 The role of Nox2-derived ROS in the development of cognitive impairment after sepsis Hernandes, Marina S D’Avila, Joana C Trevelin, Silvia C Reis, Patricia A Kinjo, Erika R Lopes, Lucia R Castro-Faria-Neto, Hugo C Cunha, Fernando Q Britto, Luiz RG Bozza, Fernando A J Neuroinflammation Research BACKGROUND: Sepsis- associated encephalopathy (SAE) is an early and common feature of severe infections. Oxidative stress is one of the mechanisms associated with the pathophysiology of SAE. The goal of this study was to investigate the involvement of NADPH oxidase in neuroinflammation and in the long-term cognitive impairment of sepsis survivors. METHODS: Sepsis was induced in WT and gp91(phox) knockout mice (gp91(phox-/-)) by cecal ligation and puncture (CLP) to induce fecal peritonitis. We measured oxidative stress, Nox2 and Nox4 gene expression and neuroinflammation in the hippocampus at six hours, twenty-four hours and five days post-sepsis. Mice were also treated with apocynin, a NADPH oxidase inhibitor. Behavioral outcomes were evaluated 15 days after sepsis with the inhibitory avoidance test and the Morris water maze in control and apocynin-treated WT mice. RESULTS: Acute oxidative damage to the hippocampus was identified by increased 4-HNE expression in parallel with an increase in Nox2 gene expression after sepsis. Pharmacological inhibition of Nox2 with apocynin completely inhibited hippocampal oxidative stress in septic animals. Pharmacologic inhibition or the absence of Nox2 in gp91(phox-/-) mice prevented glial cell activation, one of the central mechanisms associated with SAE. Finally, treatment with apocynin and inhibition of hippocampal oxidative stress in the acute phase of sepsis prevented the development of long-term cognitive impairment. CONCLUSIONS: Our results demonstrate that Nox2 is the main source of reactive oxygen species (ROS) involved in the oxidative damage to the hippocampus in SAE and that Nox2-derived ROS are determining factors for cognitive impairments after sepsis. These findings highlight the importance of Nox2-derived ROS as a central mechanism in the development of neuroinflammation associated with SAE. BioMed Central 2014-02-27 /pmc/articles/PMC3974031/ /pubmed/24571599 http://dx.doi.org/10.1186/1742-2094-11-36 Text en Copyright © 2014 Hernandes et al.; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. 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 Hernandes, Marina S D’Avila, Joana C Trevelin, Silvia C Reis, Patricia A Kinjo, Erika R Lopes, Lucia R Castro-Faria-Neto, Hugo C Cunha, Fernando Q Britto, Luiz RG Bozza, Fernando A The role of Nox2-derived ROS in the development of cognitive impairment after sepsis |
title | The role of Nox2-derived ROS in the development of cognitive impairment after sepsis |
title_full | The role of Nox2-derived ROS in the development of cognitive impairment after sepsis |
title_fullStr | The role of Nox2-derived ROS in the development of cognitive impairment after sepsis |
title_full_unstemmed | The role of Nox2-derived ROS in the development of cognitive impairment after sepsis |
title_short | The role of Nox2-derived ROS in the development of cognitive impairment after sepsis |
title_sort | role of nox2-derived ros in the development of cognitive impairment after sepsis |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3974031/ https://www.ncbi.nlm.nih.gov/pubmed/24571599 http://dx.doi.org/10.1186/1742-2094-11-36 |
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