Targeting TLR4/PPARα-mediated neuroinflammation in the prefrontal cortex: S-ketamine and S-HNK rapidly alleviate depression-like behaviors

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.

Study at a glance

Abstract

Neuroinflammation, particularly Toll-like receptor 4 (TLR4)-mediated signaling, plays a critical role in the pathophysiology of depression. This study aimed to investigate the mechanisms by which S-ketamine (S-ket) and S-hydroxynorketamine (S-HNK) modulate TLR4 and peroxisome proliferator-activated receptor alpha (PPARα) signaling in the prefrontal cortex (PFC) to exert antidepressant effects. Male C57BL/6 J mice were subjected to chronic social defeat stress (CSDS) to induce depression-like behaviors. Mice received intraperitoneal administration of S-ket or S-HNK. In a subset of mice, adeno-associated virus expressing TLR4 (AAV-TLR4) or a negative control (NC) was stereotaxically injected into the medial prefrontal cortex (mPFC). Behavioral assessments included the sucrose preference test (SPT), forced swim test (FST), and social interaction test (SIT). Levels of monoaminergic neurotransmitters, including dopamine (DA), serotonin (5-hydroxytryptamine, 5-HT), and norepinephrine (NA), pro-inflammatory cytokines (interleukin (IL)-1β, IL-6, IL-8, and tumor necrosis factor-α (TNF-α)), TLR4, PPARα, indoleamine 2,3-dioxygenase 1 (IDO1), and kynurenine (Kyn) in the PFC were analyzed. CSDS induced depression-like behaviors, decreased DA, 5-HT, and NA levels in the PFC, and increased the expression of pro-inflammatory cytokines IL-1β, IL-6, IL-8, and TNF-α. Treatment with S-ket or S-HNK significantly reversed these behavioral deficits, neurotransmitter alterations, and neuroinflammatory responses. Both compounds also reduced plasma and PFC Kyn levels, upregulated PPARα expression, and downregulated TLR4 and IDO1. Notably, TLR4 overexpression partially abolished the antidepressant and anti-inflammatory effects of S-ket and S-HNK. S-ket and its metabolite S-HNK exert antidepressant effects by modulating the TLR4/PPARα signaling pathway, restoring monoaminergic neurotransmission, and attenuating neuroinflammation.