title: Anti-RAGE antibody selectively blocks acute systemic inflammatory responses to LPS in serum, liver, CSF and striatum.
abstract: Systemic inflammation induces transient or permanent dysfunction in the brain by exposing it to soluble inflammatory mediators. The receptor for advanced glycation endproducts (RAGE) binds to distinct ligands mediating and increasing inflammatory processes. In this study we used an LPS-induced systemic inflammation model in rats to investigate the effect of blocking RAGE in serum, liver, cerebrospinal fluid (CSF) and brain (striatum, prefrontal cortex, ventral tegmental area and substantia nigra). Intraperitoneal injection of RAGE antibody (50μg/kg) was followed after 1h by a single LPS (5mg/kg) intraperitoneal injection. Twenty-four hours later, tissues were isolated for analysis. RAGE antibody reduced LPS-induced inflammatory effects in both serum and liver; the levels of proinflammatory cytokines (TNF-α, IL-1β) were decreased and the phosphorylation/activation of RAGE downstream targets (ERK1/2, IκB and p65) in liver were significantly attenuated. RAGE antibody prevented LPS-induced effects on TNF-α and IL-1β in CSF. In striatum, RAGE antibody inhibited increases in IL-1β, Iba-1, GFAP, phospho-ERK1/2 and phospho-tau (ser202), as well as the decrease in synaptophysin levels. These effects were caused by systemic RAGE inhibition, as RAGE antibody did not cross the blood-brain barrier. RAGE antibody also prevented striatal lipoperoxidation and activation of mitochondrial complex II. In conclusion, blockade of RAGE is able to inhibit inflammatory responses induced by LPS in serum, liver, CSF and brain.
authors.affiliation: Centro de Estudos em Estresse Oxidativo, Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.
authors.forename: Juciano
authors.initials: J
authors.lastname: Gasparotto
authors.affiliation: Centro de Estudos em Estresse Oxidativo, Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.
authors.forename: Camila Tiefensee
authors.initials: CT
authors.lastname: Ribeiro
authors.affiliation: Centro de Estudos em Estresse Oxidativo, Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.
authors.forename: Rafael Calixto
authors.initials: RC
authors.lastname: Bortolin
authors.affiliation: Centro de Estudos em Estresse Oxidativo, Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.
authors.forename: Nauana
authors.initials: N
authors.lastname: Somensi
authors.affiliation: Centro de Estudos em Estresse Oxidativo, Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.
authors.forename: Henrique Schaan
authors.initials: HS
authors.lastname: Fernandes
authors.affiliation: Centro de Estudos em Estresse Oxidativo, Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.
authors.forename: Alexsander Alves
authors.initials: AA
authors.lastname: Teixeira
authors.affiliation: Centro de Estudos em Estresse Oxidativo, Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.
authors.forename: Marcelo Otavio Rodrigues
authors.initials: MOR
authors.lastname: Guasselli
authors.affiliation: Centro de Estudos em Estresse Oxidativo, Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.
authors.forename: Crepin Aziz Jose O
authors.initials: CAJO
authors.lastname: Agani
authors.affiliation: Centro de Tecnologia e Recursos Naturais, Universidade Federal de Campina Grande, Campina Grande, PB, Brazil.
authors.forename: Natália Cabral
authors.initials: NC
authors.lastname: Souza
authors.affiliation: Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.
authors.forename: Mateus
authors.initials: M
authors.lastname: Grings
authors.affiliation: Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.
authors.forename: Guilhian
authors.initials: G
authors.lastname: Leipnitz
authors.affiliation: Centro de Estudos em Estresse Oxidativo, Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.
authors.forename: Henrique Mautone
authors.initials: HM
authors.lastname: Gomes
authors.affiliation: Centro de Tecnologia e Recursos Naturais, Universidade Federal de Campina Grande, Campina Grande, PB, Brazil.
authors.forename: Matheus Augusto
authors.initials: MA
authors.lastname: de Bittencourt Pasquali
authors.affiliation: School of Biomedical Sciences and Pharmacy and Hunter Medical Research Institute, University of Newcastle, Australia.
authors.forename: Peter R
authors.initials: PR
authors.lastname: Dunkley
authors.affiliation: School of Biomedical Sciences and Pharmacy and Hunter Medical Research Institute, University of Newcastle, Australia.
authors.forename: Phillip W
authors.initials: PW
authors.lastname: Dickson
authors.affiliation: Centro de Estudos em Estresse Oxidativo, Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.
authors.forename: José Claudio Fonseca
authors.initials: JCF
authors.lastname: Moreira
authors.affiliation: Centro de Estudos em Estresse Oxidativo, Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil. Electronic address: daniel.gelain@ufrgs.br.
authors.forename: Daniel Pens
authors.initials: DP
authors.lastname: Gelain
mesh_terms: D000818:Animals; D000906:Antibodies / Q000494:pharmacology* / Q000627:therapeutic use; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D007249:Inflammation / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D000067759:Receptor for Advanced Glycation End Products / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: C000593874:Ager protein, rat; D000906:Antibodies; D016207:Cytokines; D018836:Inflammation Mediators; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D000067759:Receptor for Advanced Glycation End Products; D014409:Tumor Necrosis Factor-alpha
keywords: LPS; Neurodegeneration; Neuroinflammation; RAGE; Striatum; Systemic inflammation