Physical or psychological stress can cause an immunologic imbalance that disturbs the central nervous system followed by
neuroinflammation. The association between
inflammation and depression has been widely studied in recent years, though the molecular mechanism is still largely unknown. Thus, targeting the signaling pathways that link stress to
neuroinflammation might be a useful strategy against depression. The current study investigated the protective effect of
melatonin against
lipopolysaccharide (LPS)-induced
neuroinflammation and depression. Our results showed that LPS treatment significantly induced depressive-like behavior in mice. Moreover, LPS-treatment enhanced oxidative stress, pro-inflammatory
cytokines including TNFα,
IL-6, and IL-1β, NF-κB phosphorylation, and glial cell activation markers including GFAP and Iba-1 in the brain of mice.
Melatonin treatment significantly abolished the effect of LPS, as indicated by improved depressive-like behaviors, reduced
cytokines level, reduced oxidative stress, and normalized LPS-altered
Sirt1, Nrf2, and HO-1 expression. However, the
melatonin protective effects were reduced after
luzindole administration. Collectively, it is concluded that
melatonin receptor-dependently protects against LPS-induced depressive-like behaviors via counteracting LPS-induced
neuroinflammation.