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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

The role of Nox2-derived ROS in the development of cognitive impairment after sepsis

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Hernandes, Marina S. [1, 2] ; D'Avila, Joana C. [3] ; Trevelin, Silvia C. [4] ; Reis, Patricia A. [3] ; Kinjo, Erika R. [1] ; Lopes, Lucia R. [5] ; Castro-Faria-Neto, Hugo C. [3] ; Cunha, Fernando Q. [4] ; Britto, Luiz R. G. [1] ; Bozza, Fernando A. [6, 7, 8]
Total Authors: 10
[1] Univ Sao Paulo, Dept Physiol & Biophys, Sao Paulo - Brazil
[2] Univ Sao Paulo, Inst Biomed Sci, Lab Cellular Neurobiol, BR-05508900 Sao Paulo - Brazil
[3] Fiocruz MS, Inst Oswaldo Cruz, Lab Imunofarmacol, BR-21045900 Rio De Janeiro - Brazil
[4] Univ Sao Paulo, Fac Med Ribeirao Preto, Dept Pharmacol, Sao Paulo - Brazil
[5] Univ Sao Paulo, Inst Biomed Sci, Dept Pharmacol, Sao Paulo - Brazil
[6] Fiocruz MS, Inst Pesquisa Clin Evandro Chagas, BR-21045900 Rio De Janeiro - Brazil
[7] Inst DOr Pesquisa Ensino IDOR, Rio De Janeiro - Brazil
[8] Fundacao Oswaldo Cruz, Inst Pesquisa Clin Evandro Chagas, Intens Care Unit, BR-21040900 Rio De Janeiro, RJ - Brazil
Total Affiliations: 8
Document type: Journal article
Web of Science Citations: 58

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. (AU)

FAPESP's process: 11/03293-3 - Role of Nox2 derived products in the pathogenesis of sepsis
Grantee:Silvia Cellone Trevelin
Support Opportunities: Scholarships in Brazil - Doctorate