Interleukin-1 Receptor Antagonist Decreases Hypothalamic Oxidative Stress During Experimental Sepsis

• DOI: 10.1007/s12035-015-9338-4
• Publication Date: 2015-07-15T23:13:15Z
• Authors: Fazal Wahab; Nilton N. Santos-...; Rodrigo Pereira d...; Luis Henrique A. ...; Carlos Henrique R...; Maria Jose A. Rocha
• Keywords: 0301 basic medicine; Caspase 3; Interleukin-1beta; Hypothalamus; Nitric Oxide Synthase Type II; Hypoxia-Inducible Factor 1, alpha Subunit; 3. Good health; Interleukin 1 Receptor Antagonist Protein; Oxidative Stress; 03 medical and health sciences; Gene Expression Regulation; Sepsis; Animals; Humans; Rats, Wistar

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.