Monophosphoryl lipid A induces tolerance against single prolonged stress-induced PTSD-like behavior and neuroinflammatory responses in mice.

Neuroinflammation is a pathological process that favors the development of post-traumatic stress disorder (PTSD). Our previous studies have reported that pre-stimulation of microglia by low-dose lipopolysaccharide (LPS) before stress stimulation prevents PTSD by blocking neuroinflammation. Since monophosphoryl lipid A (MPL) is a derivative of LPS that lacks the undesirable properties of LPS but still has immune-enhancing effects, we investigated its effect on PTSD-like behaviors induced by single prolonged stress (SPS). The results showed that a single injection of MPL at a dose of 400, 800 or 1600, but not 200 μg/kg one day before stress stimulation prevented SPS-induced fear- and anxiety-like behaviors. A single injection of MPL (800 μg/kg) either 1 day or 5 days but not 10 days before stress stimulation resulted in tolerance to SPS-induced fear- and anxiety-like behaviors. In addition, a second MPL injection 10 days after the first injection or a 4 × MPL injection 10 days before stress stimulation prevented SPS-induced fear- and anxiety-like behaviors. These effects of MPL were associated with decreases in tumor necrosis factor-α (Tnf-α), interleukin-1β (Il-1β), Il-6, and ionized calcium-binding adaptor molecule 1 (Iba-1) mRNA in the brains of SPS mice. Inhibition or depletion of microglia abolished the preventive effect of MPL on PTSD-like behavior and neuroinflammatory responses. These results suggest that MPL prevents the occurrence of PTSD-like behaviors by blocking the progression of neuroinflammation in the brain. Due to its low toxicity, MPL could be developed as a drug to prevent the onset of PTSD, at least in animals.