A single dose of esketamine alleviates depressive-like behaviors in adolescent male mice exposed to the inflammatory agent LPS. The antidepressant effect is linked to increased expression of the Nrf2 protein and reduced levels of inflammatory cytokines (TNF-α, IL-1β, iNOS) in the brain's prefrontal cortex and hippocampus. Blocking Nrf2 with the inhibitor ML385 reversed both the behavioral and anti-inflammatory effects of esketamine. In the blood, esketamine also reduced pro-inflammatory and increased anti-inflammatory cytokines, an effect again blocked by Nrf2 inhibition. The findings suggest esketamine's rapid antidepressant action may work through activating Nrf2-mediated anti-inflammatory signaling.
A single dose of esketamine rapidly alleviated depressive- and anxiety-like behaviors in mice exposed to chronic variable stress, an effect comparable to seven days of repeated fluoxetine treatment. The stress protocol increased plasma levels of multiple inflammatory cytokines (IL-1β, IL-6, IL-8, IL-17A, TNFα, IL-4, IL-9, IL-24, IL-37, IFN-β, and CXCL12) and decreased IL-10 and IL-33. Both esketamine and fluoxetine partially normalized these inflammatory disturbances. The findings suggest that esketamine's rapid antidepressant action may involve normalizing inflammatory cytokine expression.