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

AIM: Sepsis has been associated with acute behavioural changes in humans and rodents, which consists of a motivational state and an adaptive response that improve survival. However, the involvement of peripheral cytokines synthesized during systemic inflammation as modulators of the tonic immobility (TI) defensive behaviour remains a literature gap. Our purposes were to characterize the TI defensive behaviour in endotoxemia guinea-pigs at acute phase and after recovery from the initial inflammatory challenge. Furthermore, we investigated whether peri-aqueductal grey matter (PAG) exists as a brain structure related to this behaviour and also pro-inflammatory cytokines, tumour necrosis factor (TNF)-α and interleukin (IL)-1ß, act at this mesencephalic nucleus. METHODS: Endotoxemia was induced by lipopolysaccharide (LPS) administration in guinea-pigs. The parameters evaluated included TI defensive behaviour, survival, cytokines production, as well as neuronal activation and apoptosis in the PAG. RESULTS: Endotoxemia guinea-pigs exhibited a reduction in the duration of TI episodes, starting at 2 h after LPS administration and persisting throughout the experimental period evaluated over 7 days. Moreover, endotoxemia increased the c-FOS immunoreactivity of neurones in the ventrolateral PAG (vlPAG), as well as the caspase-3 expression. The LPS microinjection into vlPAG reproduces the same compromise, that is a decrease in the duration of TI defensive behaviour, observed after the peripheral administration. The immunoneutralization against IL-1ß and TNF-α into vlPAG reverts all the effects produced by peripheral LPS administration. CONCLUSION: Our findings confirm that vlPAG is an important brain structure involved in the behavioural alterations induced by endotoxemia, possibly changing the neuronal activity caused by pro-inflammatory cytokines produced peripherally.

Estradiol and thermoregulation in adult endotoxemic rats exposed to lipopolysaccharide in neonatal life.

AIMS: Early life immune challenge has been considered an adaptive defense strategy against potential pathogens when the innate immune system is not completely developed. This study assesses whether neonatal endotoxin challenge alters body temperature response in adult female rats during endotoxemic shock and also, whether ovarian hormones may participate in this response. METHODS: Rats were intraperitoneally injected with lipopolysacharide (LPS) or saline at post-natal day 14, then as adults they were submitted to endotoxemic shock. RESULTS: The LPS injection in adult neonatal Saline rats caused an initial hypothermia, followed by a febrile response. However, neonatal LPS showed an increased hypothermic response and an attenuation of fever. The bilateral ovariectomy abolished the difference in body temperature between the neonatal LPS and saline rats. To determine the dependence of ovarian hormones, ovariectomized rats treated with estradiol cypionate (ECP) restored hypothermia and the suppressed febrile response. However, the same results were not obtained when the animals were supplemented with ECP and medroxyprogesterone acetate (MPA). The neonatal LPS rats displayed a significant reduction in TNF-α levels and an increase in IL-10 levels when compared with saline animals. The ECP injection significantly enhanced IL-10 and suppressed TNF-α in neonatal LPS, but it did not change the inflammatory response in the saline rats. The ECP + MPA regiment in the neonatal LPS rats reduced TNF-α, but eliminated IL-10 stimulation in comparison with the saline group. CONCLUSION: The present investigation shows that neonatal LPS challenge alters the thermoregulatory response during endotoxemic shock in adulthood and the mechanism for this difference could be mediated by sex hormones, especially estradiol.