Mifepristone attenuates depression-like changes induced by chronic central administration of interleukin-1β in rats

Increased proinflammatory cytokines, such as interleukin (IL)-l beta, may play an important role in the etiology of depression because they cause the hypothalamic-pituitary-adrenal axis to release glucocorticoids (GC) and induce dysfunction of serotonin and norepinephrine neurotransmission. Sustained increase in GC may activate microglia to induce neuroinflammation, and suppress astrocytes to produce neurotrophins, which lead to neuronal apoptosis. Here, we tested the hypothesis that glucocorticoid receptor (GR) antagonist mifepristone (RU486) may attenuate IL-1 beta-induced depression-like behavior by regulating the neuroinflammation and neurotrophin functions of microglia and astrocytes. Rats received intracerebroventricular injections of IL 1 beta (10 ng) and/or subcutaneous injections of RU486 for 14 days. Then animal depression-like behaviors, serum corticosterone concentration, the levels of pro-inflammatory cytokines (TNF-alpha, IL-6), mRNA and protein expressions of CD11b, GFAP and neurotrophins (pro-BDNF, BDNF, GDNF and their receptors TrkB, p75, GFR alpha-1 and GFR alpha-2) in the amygdala were studied. Compared to controls, significantly decreased rearing score and increased defecation in the open field test, decreases in ratio of open/closed time in the elevated plus maze and in sucrose preference, while increased level of corticosterone in the serum were found in the rats administrated with IL-1 beta. IL-1 beta administration also reduced the expressions of GFAP, BDNF, GDNF and its receptor GFR-alpha l, but increased the expressions of CD11b, pro-BDNF, p75 and pro-inflammatory cytokines (TNF-alpha, IL-6) concentrations, RU486 treatment markedly attenuated these changes induced by IL-1 beta, except for the expressions of GFR-alpha 1. In conclusion, RU486 may improve depression-like changes by suppressing microglia and inflammation and promoting astrocytes to restore neurotrophin function.