title: Interleukin-1 Receptor Antagonist Decreases Hypothalamic Oxidative Stress During Experimental Sepsis.
abstract: In our previous work, we demonstrated that the intracerebroventricular (i.c.v.) injection of an interleukin-1 receptor antagonist (IL-1ra) prevented the impairment in vasopressin secretion and increased survival rate in septic rats. Additionally, we saw a reduction in nitric oxide (NO) levels in cerebroventricular spinal fluid (CSF), suggesting that the IL-1ra prevents apoptosis that seems to occur in vasopressinergic neurons. Here, we investigated the effect of IL-1ra pre-treatment on the sepsis-induced increase in oxidative stress markers in the hypothalamus of rats. The animals were pre-treated by an i.c.v. injection of IL-1ra (9 nmol) or vehicle (0.01 M PBS) before being subjected to cecal ligation and puncture (CLP) or left as control (sham-operation or naive). After 4, 6, and 24 h, the animals were decapitated (n = 9/group) and the brain removed for hypothalamic tissue collection. Transcript and protein levels of IL-1, inducible nitric oxide synthase (iNOS), caspase-3, and hypoxia-inducible factor 1-alpha (HIF-1α) were measured by quantitative polymerase chain reaction (qPCR) and western blot, respectively. Hypothalamic mRNA levels of all these genes were significantly (P < 0.005) increased at 4, 6, and 24 h CLP, as compared to sham-operated animals. IL-1ra pre-treatment in these CLP animals significantly decreased IL-1 gene expression at all time points and also of iNOS, caspase-3, and HIF-1α at 24 h when compared to vehicle-treated CLP animals. The effect of the pre-treatment on protein expression was most clearly seen for IL-1β and iNOS at 24 h. Our results showed that blocking the IL-1-IL-1r signaling pathway by central administration of an IL-1ra decreases hypothalamic oxidative stress markers during sepsis.
authors.affiliation: Departmento de Morfologia Fisiologia e Patologia Básica, Faculdade de Odontologia de Ribeirão Preto, Universidade de São Paulo, Avenida do Café, s/n, Ribeirão Preto, 14040-904, SP, Brazil.
authors.forename: Fazal
authors.initials: F
authors.lastname: Wahab
authors.affiliation: Departamento de Neurociências e Ciências Comportamentais, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Avenida dos Bandeirantes, 3900, CEP 14040-900, Ribeirão Preto, SP, Brazil.
authors.forename: Nilton N
authors.initials: NN
authors.lastname: Santos-Junior
authors.affiliation: Departmento de Morfologia Fisiologia e Patologia Básica, Faculdade de Odontologia de Ribeirão Preto, Universidade de São Paulo, Avenida do Café, s/n, Ribeirão Preto, 14040-904, SP, Brazil.
authors.forename: Rodrigo Pereira
authors.initials: RP
authors.lastname: de Almeida Rodrigues
authors.affiliation: Departamento de Neurociências e Ciências Comportamentais, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Avenida dos Bandeirantes, 3900, CEP 14040-900, Ribeirão Preto, SP, Brazil.
authors.forename: Luis Henrique A
authors.initials: LHA
authors.lastname: Costa
authors.affiliation: Departamento de Neurociências e Ciências Comportamentais, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Avenida dos Bandeirantes, 3900, CEP 14040-900, Ribeirão Preto, SP, Brazil.
authors.forename: Carlos Henrique R
authors.initials: CHR
authors.lastname: Catalão
authors.affiliation: Departmento de Morfologia Fisiologia e Patologia Básica, Faculdade de Odontologia de Ribeirão Preto, Universidade de São Paulo, Avenida do Café, s/n, Ribeirão Preto, 14040-904, SP, Brazil. mjrocha@forp.usp.br.|Departamento de Neurociências e Ciências Comportamentais, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Avenida dos Bandeirantes, 3900, CEP 14040-900, Ribeirão Preto, SP, Brazil. mjrocha@forp.usp.br.
authors.forename: Maria Jose A
authors.initials: MJA
authors.lastname: Rocha
mesh_terms: D000818:Animals; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D007031:Hypothalamus / Q000378:metabolism / Q000473:pathology*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D053590:Interleukin 1 Receptor Antagonist Protein / Q000494:pharmacology* / Q000627:therapeutic use*; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D017208:Rats, Wistar; D018805:Sepsis / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology*
chemical_list: C497444:Hif1a protein, rat; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D053590:Interleukin 1 Receptor Antagonist Protein; D053583:Interleukin-1beta; D052247:Nitric Oxide Synthase Type II; D053148:Caspase 3
keywords: Apoptosis; Caspases; Cytokines; Neuroendocrine dysfunction; Nitric oxide