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.

Alterations in hypothalamic synaptophysin and death markers may be associated with vasopressin impairment in sepsis survivor rats

“…28 In previous studies, we found low amounts of Bcl-2 and high levels of cleaved caspase-3 in the hypothalamus of septic animals, associated with a deficit in AVP secretion. 15,16 In the present study, we observed a persistent alteration of these cellular death markers even after recovery from sepsis.…”

“…The present study was designed to bring together insights from previous studies conducted by our group where we had demonstrated that: (i) sepsis promotes morphological changes in hypothalamic microglial cells that are compatible with their activation; 16 (ii) the administration of an IL-1 receptor antagonist caused a decrease in hypothalamic oxidative stress, improving AVP secretion; 15,19 and (iii) there is an impairment in AVP secretion, persistent plasma inflammatory mediators and an attenuated activation of magnocellular neurones after an acute osmotic stimulus in sepsis survivor. 21 Therefore, we hypothesised that a decrease of hypothalamic synaptic density may lead to a dysfunction in the osmotic regulatory response in sepsis survivors.…”

“…They promote attenuated hypothalamic activation of osmoregulatory, volume regulatory and AVP-producing magnocellular neurones, 7,[15][16][17][18] resulting in impaired AVP synthesis and secretion. 9,19,20 Although this scenario is now reasonably well understood during sepsis, we know relatively little about whether and how these neuroendocrine abnormalities persist in sepsis survivors.…”

Rat Model of Cecal Ligation and Puncture versus Colon Ascendens Stent Peritonitis: Comparative Study for Oxidative Stress

“…However, the anti-oxidative T-SOD was decreased (P < 0.05), which was consistent with the previously published literature [22] [23]. Meanwhile, the oxidative stress condition in the CLP and CASP groups was similar within 72 hours, and there was no significant difference between the two groups regarding MDA and T-SOD levels (P > 0.05), but 72 hours later, it became greatly improved as shown by the decreased MDA (P < 0.05) and increased T-SOD in the CASP group (P < 0.05).…”

Pro‐inflammatory cytokines, IL‐1β and TNF‐α, produce persistent compromise in tonic immobility defensive behaviour in endotoxemia guinea‐pigs

“…, Wahab et al . ). The neuronal apoptosis starts at few hours after the sepsis induction and may persist for long time (weeks or months) (Semmler et al .…”