Targeting TLR4/PPARα-mediated neuroinflammation in the prefrontal cortex: S-ketamine and S-HNK rapidly alleviate depression-like behaviors
Journal of Neuroimmunology July 1, 2026 Quanfeng Zhu, Xiaoyue Zhou, Huangling Gao et al.
Chronic social defeat stress in male mice induced depression-like behaviors, reduced dopamine, serotonin, and norepinephrine in the prefrontal cortex, and increased pro-inflammatory cytokines. Treatment with S-ketamine or its metabolite S-hydroxynorketamine reversed these behavioral deficits, neurotransmitter changes, and neuroinflammation. Both compounds reduced kynurenine levels, increased PPARα expression, and decreased TLR4 and IDO1 expression. Overexpressing TLR4 partially blocked these antidepressant and anti-inflammatory effects, suggesting S-ketamine and S-hydroxynorketamine act through the TLR4/PPARα signaling pathway to restore neurotransmission and reduce inflammation.