Maresin-1 protects against lipopolysaccharide (LPS)-induced depressive-like behavior in adolescent mice and promotes M2 microglial polarization via ERK/NF-κB signaling.

Adolescence is a critical developmental stage characterized by heightened vulnerability to psychiatric symptoms associated with neuroimmune challenges. Maresin-1 (MaR1), a specialized pro-resolving mediator, exerts potent anti-inflammatory actions; however, its effects on inflammation-associated mood-related behavioral alterations during adolescence remain unclear. This study investigated the prophylactic effects of MaR1 in a lipopolysaccharide (LPS)-induced acute inflammatory challenge model using male adolescent C57BL/6J mice. MaR1 (5 μg/kg, i.p.) was administered 1 h before LPS challenge, and behavioral assessments were conducted 24 h later, a time point selected to reduce, but not eliminate, potential confounding by acute sickness-like responses. MaR1 pretreatment attenuated LPS-induced reductions in sucrose preference and increases in tail suspension immobility. MaR1 also reduced hippocampal inflammatory responses, as indicated by decreased TNF-α and IL-1β levels and changes in M1/M2-associated microglial marker profiles. Whole hippocampal tissue analyses showed that MaR1 dampened LPS-induced hippocampal ERK/NF-κB activation in vivo, while BV-2 cell experiments showed that MaR1 suppressed LPS-induced ERK and NF-κB phosphorylation in vitro. The MEK inhibitor U0126 partially mimicked the behavioral and inflammatory effects of MaR1, and co-administration did not produce additive behavioral benefits, consistent with the involvement of an ERK-related component. Collectively, these findings suggest that MaR1 pretreatment mitigates LPS-induced inflammation-associated depressive-like behavioral alterations in male adolescent mice, accompanied by reduced hippocampal inflammatory signaling and modulation of microglia-associated inflammatory marker profiles. These results support further investigation of MaR1 and related pro-resolving mediators as candidate modulators of inflammation-associated mood-related disturbances during development.