Monophosphoryl Lipid A Tolerance Against Chronic Stress-Induced Depression-Like Behaviors in Mice

Abstract

Backgrounds: Our recent studies reported that a single injection with lipopolysaccharide (LPS) before stress exposure prevents depression-like behaviors in stressed mice. Monophosphoryl lipid A (MPL) is a derivative of LPS that lacks the undesirable properties of LPS. We hypothesize that MPL can exert a prophylactic effect on depression. Methods: The experimental mice were pre-injected with MPL before stress exposure. Depression in mice was induced through chronic social defeat stress (CSDS). Behavioral tests were conducted to identify depression-like behaviors. Real-time polymerase chain reaction and biochemical assays were performed to examine the gene and protein expression levels of pro-inflammatory cytokines. Results: A single MPL injection 1 day before stress exposure at the dosages of 400, 800, and 1600 μg/kg but not 200 μg/kg prevented CSDS-induced depression-like behaviors in mice. This effect of MPL, however, vanished with the extension of the interval time between drug injection and stress exposure from 1 day or 5 days to 10 days, which was rescued by a second MPL injection 10 days after the first MPL injection or by a 4× MPL injection 10 days before stress exposure. A single MPL injection (800 μg/kg) before stress exposure prevented CSDS-induced increases in the gene expression levels of pro-inflammatory cytokines in the hippocampus and prefrontal cortex. Pre-inhibiting the innate immune stimulation by minocycline pretreatment (40 mg/kg) abrogated the preventive effect of MPL on CSDS-induced depression-like behaviors and neuroinflammatory responses in animal brains. Conclusions: MPL, through innate immune stimulation, prevents stress-induced depression-like behaviors in mice by preventing neuroinflammatory responses.