title: The role of Nox2-derived ROS in the development of cognitive impairment after sepsis.
abstract: 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.
authors.affiliation: Department of Physiology and Biophysics, University of São Paulo, São Paulo, Brazil. marinash@icb.usp.br.
authors.forename: Marina S
authors.initials: MS
authors.lastname: Hernandes
authors.forename: Joana C
authors.initials: JC
authors.lastname: D'Avila
authors.forename: Silvia C
authors.initials: SC
authors.lastname: Trevelin
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Reis
authors.forename: Erika R
authors.initials: ER
authors.lastname: Kinjo
authors.forename: Lucia R
authors.initials: LR
authors.lastname: Lopes
authors.forename: Hugo C
authors.initials: HC
authors.lastname: Castro-Faria-Neto
authors.forename: Fernando Q
authors.initials: FQ
authors.lastname: Cunha
authors.forename: Luiz R G
authors.initials: LR
authors.lastname: Britto
authors.forename: Fernando A
authors.initials: FA
authors.lastname: Bozza
mesh_terms: D000098:Acetophenones / Q000627:therapeutic use; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use; D001362:Avoidance Learning / Q000187:drug effects; D001426:Bacterial Proteins / Q000378:metabolism*; D018932:Chemokine CCL2 / Q000378:metabolism; D003072:Cognition Disorders / Q000209:etiology*; D004195:Disease Models, Animal; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009247:NADH, NADPH Oxidoreductases / Q000378:metabolism*; D019255:NADPH Oxidases / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*; D011971:Receptors, Immunologic / Q000172:deficiency; D018805:Sepsis / Q000150:complications* / Q000188:drug therapy / Q000473:pathology; D053706:Typhlitis / Q000150:complications / Q000209:etiology
chemical_list: D000098:Acetophenones; D000894:Anti-Inflammatory Agents, Non-Steroidal; D001426:Bacterial Proteins; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; C105949:Pirb protein, mouse; D017382:Reactive Oxygen Species; D011971:Receptors, Immunologic; C056165:acetovanillone; D009247:NADH, NADPH Oxidoreductases; D019255:NADPH Oxidases; C121789:Nox-2 protein, bacteria