Influência dos glicocorticoides no comportamento doentio induzido pelo LPS de E. coli em camundongos prenhes

Abstract

Administration of LPS from Escherichia coli generates endocrine and immune response, such as the production of proinflammatory cytokines and prostaglandin production. Furthermore, endotoxemia promotes neuroendocrine changes such as alteration on the metabolism of norepinephrine and serotonin in the brain beyond the activation of HPA axis resulting in sickness behavior evidenced by the reduction of exploratory locomotor ability and anorexia, pyrexia, anhedonia, drowsiness, reduction behavior social and sexual behavior similar to anxiety and depression. Has been shown in the literature that endotoxemia is able to cause hypothermia in pregnant animals as well as presenting significant abortion and pregnancy failure. In addition, it has been shown that pregnant animals also exhibit the sickness behavior in response to LPS administration with important changes in the components of the maternal-fetal interface for establishing uterine homeostasis. Since the activation of the HPA axis is one of the most prominent responses of endotoxemia, the present study investigated the interference of glucocorticoids in sickness behavior in pregnant females. For this purpose, we used exogenous glucocorticoid, dexamethasone, as well as glucocorticoid synthesis inhibitors, metyrapone and mifepristone. The metyrapone is an inhibitor of the enzyme 11-β-hydroxylase, which inhibits the last step of precursors of corticosterone. The mifepristone is an antagonist of glucocorticoid receptors, and progesterone receptor binding. SWISS female mice at 10th day of pregnancy were pre-treated with said drug, 30 minutes before the LPS treatment. Two hours after, the rectal temperature was measured and behavioral tests were performed to investigate the behavior like anxiety, depression, addition to observing the exploratory ability and short-term information retention. Gestational viability was also investigated observing, for this, the number of pups born per litter. It was observed that the treatment with LPS caused hypothermia in pregnant animals and that pretreatment with dexamethasone was the only one able to avoid this effect by reducing TNF-α synthesis. These findings provide evidence for use of dexamethasone as an antipyretic in endotoxemia frames during pregnancy. Furthermore, was noted that the LPS treatment, regardless of pretreatment employed provoked sickness behavior evidenced by the reduction in the exploratory and locomotor ability in the pregnant animals subjected to behavioral testing. Behavioral study findings corroborate with the vast literature, indicating additionally that sickness behavior is dependent on proinflammatory cytokine, and that pretreatment with glucocorticoids, or inhibitors of its synthesis are not able of preventing sickness behavior. Pretreatment with metyrapone was the only one capable of preventing abortion caused by LPS through elevated plasma levels of progesterone, which in turn protects the fetus from maternal immune attack during pregnancy and assures delivery. Thereby metyrapone can be used to prevent immunological abortions caused by LPS administration. These findings are significant to prevent pregnancy loss caused by endotoxemia indicating metyrapone an important pharmacological agent. Pretreatment with mifepristone, with or without exposure to LPS provoked a total loss of the pregnancy. These findings run counter to scientific literature and characterize the mifepristone as powerful abortive agent able to interrupt pregnancy even when administered after a period of embryo implantation.