title: Brain-Defective Insulin Signaling Is Associated to Late Cognitive Impairment in Post-Septic Mice.
abstract: Sepsis survivors frequently develop late cognitive impairment. Because little is known on the mechanisms of post-septic memory deficits, there are no current effective approaches to prevent or treat such symptoms. Here, we subjected mice to severe sepsis induced by cecal ligation and puncture (CLP) and evaluated the sepsis-surviving animals in the open field, novel object recognition (NOR), and step-down inhibitory avoidance (IA) task at different times after surgery. Post-septic mice (30 days post-surgery) failed in the NOR and IA tests but exhibited normal performance when re-evaluated 45 days after surgery. Cognitive impairment in post-septic mice was accompanied by reduced hippocampal levels of proteins involved in synaptic plasticity, including synaptophysin, cAMP response element-binding protein (CREB), CREB phosphorylated at serine residue 133 (CREBpSer133), and GluA1 phosphorylated at serine residue 845 (GluA1pSer845). Expression of tumor necrosis factor α (TNF-α) was increased and brain insulin signaling was disrupted, as indicated by increased hippocampal IRS-1 phosphorylation at serine 636 (IRS-1pSer636) and decreased phosphorylation of IRS-1 at tyrosine 465 (IRS-1pTyr465), in the hippocampus 30 days after CLP. Phosphorylation of Akt at serine 473 (AktpSer473) and of GSK3 at serine 9 (GSK3βpSer9) were also decreased in hippocampi of post-septic animals, further indicating that brain insulin signaling is disrupted by sepsis. We then treated post-septic mice with liraglutide, a GLP-1 receptor agonist with insulinotropic activity, or TDZD-8, a GSK3β inhibitor, which rescued NOR memory. In conclusion, these results establish that hippocampal inflammation and disrupted insulin signaling are induced by sepsis and are linked to late memory impairment in sepsis survivors.
authors.affiliation: School of Pharmacy, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, 21944-590, Brazil.
authors.forename: Fernanda S
authors.initials: FS
authors.lastname: Neves
authors.affiliation: School of Pharmacy, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, 21944-590, Brazil.
authors.forename: Patrícia T
authors.initials: PT
authors.lastname: Marques
authors.affiliation: School of Pharmacy, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, 21944-590, Brazil.|Institute of Biomedical Sciences, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, 21944-590, Brazil.
authors.forename: Fernanda
authors.initials: F
authors.lastname: Barros-Aragão
authors.affiliation: Institute of Biomedical Sciences, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, 21944-590, Brazil.
authors.forename: José Bruno
authors.initials: JB
authors.lastname: Nunes
authors.affiliation: Center for Biological Sciences, Federal University of Santa Catarina, Florianópolis, SC, Brazil.
authors.forename: Aline M
authors.initials: AM
authors.lastname: Venancio
authors.affiliation: School of Pharmacy, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, 21944-590, Brazil.
authors.forename: Danielle
authors.initials: D
authors.lastname: Cozachenco
authors.affiliation: Institute of Medical Biochemistry Leopoldo de Meis, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, 21944-590, Brazil.
authors.forename: Rudimar L
authors.initials: RL
authors.lastname: Frozza
authors.affiliation: School of Pharmacy, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, 21944-590, Brazil.
authors.forename: Giselle F
authors.initials: GF
authors.lastname: Passos
authors.affiliation: School of Pharmacy, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, 21944-590, Brazil.
authors.forename: Robson
authors.initials: R
authors.lastname: Costa
authors.affiliation: Center for Biological Sciences, Federal University of Santa Catarina, Florianópolis, SC, Brazil.
authors.forename: Jade
authors.initials: J
authors.lastname: de Oliveira
authors.affiliation: Center for Biological Sciences, Federal University of Santa Catarina, Florianópolis, SC, Brazil.
authors.forename: Daiane F
authors.initials: DF
authors.lastname: Engel
authors.affiliation: Center for Biological Sciences, Federal University of Santa Catarina, Florianópolis, SC, Brazil.
authors.forename: Andreza F
authors.initials: AF
authors.lastname: De Bem
authors.affiliation: Institute of Biomedical Sciences, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, 21944-590, Brazil.
authors.forename: Claudia F
authors.initials: CF
authors.lastname: Benjamim
authors.affiliation: Centre for Neuroscience Studies, Department of Biomedical and Molecular Sciences, Queen's University, Kingston, ON, Canada.
authors.forename: Fernanda G
authors.initials: FG
authors.lastname: De Felice
authors.affiliation: Institute of Medical Biochemistry Leopoldo de Meis, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, 21944-590, Brazil.|Institute of Biophysics Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, 21944-590, Brazil.
authors.forename: Sergio T
authors.initials: ST
authors.lastname: Ferreira
authors.affiliation: School of Pharmacy, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, 21944-590, Brazil. juclarke@gmail.com.
authors.forename: Julia R
authors.initials: JR
authors.lastname: Clarke
authors.affiliation: School of Pharmacy, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, 21944-590, Brazil. claufig@gmail.com.
authors.forename: Claudia P
authors.initials: CP
authors.lastname: Figueiredo
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D060825:Cognitive Dysfunction / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D005106:Exploratory Behavior / Q000502:physiology; D007328:Insulin / Q000378:metabolism*; D008297:Male; D051379:Mice; D018805:Sepsis / Q000150:complications / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D007328:Insulin
keywords: Cognitive impairment; Glycogen synthase kinase 3 β (GSK3β); Insulin receptor substrate-1 (IRS-1) inhibition; Late cognitive impairment; Liraglutide; Sepsis survivors; TDZD-8