Minocycline ameliorates depressive behaviors and neuro-immune dysfunction induced by chronic unpredictable mild stress in the rat.

Activated microglia-induced neuroinflammation can stimulate the hypothalamic- pituitary-adrenal (HPA) axis to release glucocorticoids and suppress astrocyte functions, such as reducing neurotrophin production, which occur in depression. However, the balance between M1 (pro-inflammation) and M2 (anti-inflammation) microglial phenotypes and the interaction between these two glial cells are unclear in the depression. Hence, the chronic unpredictable mild stress (CUMS)-induced depression model was chosen to study depression- and anxiety-like behaviors, the concentration of corticosterone and relevant hippocampal cytokines, mRNA and protein expressions of microglial and astrocyte markers. To demonstrate the role of M1 phenotype activation in depression, the effect of microglial inhibitor minocycline on these aspects was also evaluated. Six weeks after CUMS exposure, behaviors were tested. Compared to the control group, CUMS increased serum corticosterone concentration and depression-like behaviors, like anhedonia, helplessness and anxiety. Moreover, CUMS increased microglia M1 marker CD11b expression and tumor necrosis factor (TNF)-α, interferon (INF)-γ, interleukin (IL)-1ß and IL-17 concentrations, but decreased the concentration of M2 cytokines, IL-4, IL-10 and IL-13. Meanwhile, CUMS inhibited the expressions of astrocyte marker glial fibrillary acidic protein (GFAP), brain-derived neurotrophic factor (BDNF) and TrKB. Minocycline (40 mg/kg, 45 days) treatment significantly attenuated CUMS-induced behavioral abnormalities, which were associated with the suppressed M1 response, restored GFAP, BDNF and its receptor expression. In conclusion, CUMS-induced depression- and anxiety-like behavior may result from an imbalance between M1 and M2 and suppressed astrocyte function. Minocycline treatment reversed M1 response, which was associated with behavioral normalization.

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

Increased proinflammatory cytokines, such as interleukin (IL)-1ß, 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-1ß-induced depression-like behavior by regulating the neuroinflammation and neurotrophin functions of microglia and astrocytes. Rats received intracerebroventricular injections of IL-1ß (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-α, IL-6), mRNA and protein expressions of CD11b, GFAP and neurotrophins (pro-BDNF, BDNF, GDNF and their receptors TrkB, p75, GFRα-1 and GFRα-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-1ß. IL-1ß administration also reduced the expressions of GFAP, BDNF, GDNF and its receptor GFR-α1, but increased the expressions of CD11b, pro-BDNF, p75 and pro-inflammatory cytokines (TNF-α, IL-6) concentrations. RU486 treatment markedly attenuated these changes induced by IL-1ß, except for the expressions of GFR-α1. In conclusion, RU486 may improve depression-like changes by suppressing microglia and inflammation and promoting astrocytes to restore neurotrophin function.