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Brain-Defective Insulin Signaling Is Associated to Late Cognitive Impairment in Post-Septic Mice

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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.

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Acknowledgements

This work was supported by grants from Brazilian funding agencies Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro (F.S.N., C.F.B., F.G.D. F, S.T. F, J.R.C., C.P.F.), Conselho Nacional de Desenvolvimento Científico e Tecnológico (R.L.F., F.B.A., C.F.B., A.F.D.B., F.G.D.F., S.T.F., , J.R.C., C.P.F.), and Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (J.D.O, D.F.E., C.P.F.). We thank Maíra Oliveira, Katia Laia, and Mariangela M. Viana for the technical support, and Ana Claudia Rangel for the competent lab and project management.

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Authors and Affiliations

  1. School of Pharmacy, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, 21944-590, Brazil

    Fernanda S. Neves, Patrícia T. Marques, Fernanda Barros‑Aragão, Danielle Cozachenco, Giselle F. Passos, Robson Costa, Julia R. Clarke & Claudia P. Figueiredo

  2. Institute of Biomedical Sciences, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, 21944-590, Brazil

    Fernanda Barros‑Aragão, José Bruno Nunes & Claudia F. Benjamim

  3. Center for Biological Sciences, Federal University of Santa Catarina, Florianópolis, SC, Brazil

    Aline M. Venancio, Jade de Oliveira, Daiane F. Engel & Andreza F. De Bem

  4. Institute of Medical Biochemistry Leopoldo de Meis, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, 21944-590, Brazil

    Rudimar L. Frozza & Sergio T. Ferreira

  5. Centre for Neuroscience Studies, Department of Biomedical and Molecular Sciences, Queen’s University, Kingston, ON, Canada

    Fernanda G. De Felice

  6. Institute of Biophysics Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, 21944-590, Brazil

    Sergio T. Ferreira

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  1. Fernanda S. Neves
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Correspondence to Julia R. Clarke or Claudia P. Figueiredo.

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Fernanda S. Neves and Patrícia T. Marques contributed equally to this work.

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Neves, F.S., Marques, P.T., Barros‑Aragão, F. et al. Brain-Defective Insulin Signaling Is Associated to Late Cognitive Impairment in Post-Septic Mice. Mol Neurobiol 55, 435–444 (2018). https://doi.org/10.1007/s12035-016-0307-3

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