Esketamine alleviates LPS-induced depression-like behavior by activating Nrf2-mediated anti-inflammatory response in adolescent mice.

Abstract

The mechanisms underlying esketamine's therapeutic effects remain elusive. The study aimed to explore the impact of single esketamine treatment on LPS-induced adolescent depressive-like behaviors and the role of Nrf2 regulated neuroinflammatory response in esketamine-produced rapid antidepressant efficacy. Adolescent male C57BL/6J mice were randomly assigned to three groups: control, LPS, and LPS + esketamine (15 mg/kg, i.p.). Depressive-like behaviors were evaluated via the OFT, NFST, and TST. Protein expression of Nrf2 and inflammatory cytokines, including TNF-α, IL-1β, and iNOS in the hippocampus and mPFC, were measured by western blot. Moreover, the Nrf2 inhibitor, ML385, was also applied in the current study. The depressive-like behaviors and the protein expression of Nrf2, TNF-α, IL-1β, and iNOS in mPFC and hippocampus were also measured. Additionally, the plasma's pro-inflammatory cytokines and anti-inflammatory cytokines were assessed using ELISA methods with or without ML385. A single administration of esketamine treatment alleviated the LPS-induced depressive-like behaviors. Esketamine increased the expression of Nrf2 and reduced the expression of the inflammatory cytokines, including TNF-α, IL-1β, and iNOS, in the mPFC and hippocampus. Notably, pharmacological inhibition of Nrf2 via ML385 administration abrogated the antidepressive-like behaviors and anti-inflammatory effects induced by esketamine. In the periphery, esketamine mitigated the LPS-induced elevation of pro-inflammatory cytokines, and the reduction of anti-inflammatory cytokines, and this effect was reversed by Nrf2 inhibition. Esketamine treatment exerts rapid antidepressant effects and attenuates neuroinflammation in LPS-induced adolescent depressive-like behaviors, potentially through the activation of Nrf2-mediated anti-inflammatory signaling.