Linoleic acid alleviates mood disorders in mice by modulating microglia differentiation and arachidonic acid metabolism

In previous research, we demonstrated that long-term consumption of thermally oxidized oil leads to neuroinflammation and anxiety in mice. Therefore, in this study, we employed polar lipid components from thermo-induced oxidized oil to induce neurodamage. Behavioral assessments revealed that both the linoleic acid and AUDA (a classical inhibitor of soluble epoxide hydrolase) groups exhibited significantly reduced anxiety-like behaviors compared to the model group (P < 0.05). Immunofluorescence analysis indicated that microglial activation in the hippocampus was attenuated in both the linoleic acid and AUDA groups relative to the model group, accompanied by a reduction in the mRNA expression of pro-inflammatory cytokines (IL-1β, IL-6, NOS2, TNF-α) and an upregulation of neuroprotective factors (IL-4, IL-10, BDNF). Lipidomic profiling of hippocampal tissue revealed that the lipid composition of the linoleic acid group closely resembled that of the AUDA group, with a significant downregulation of cardiolipin (CL) compared to the control group, consistent with alterations in the membrane potential channel receptor TRPC1. Both linoleic acid and AUDA inhibited the mRNA expression of EPHX2, leading to an increase in epoxyeicosatrienoic acids (EETs) levels. Furthermore, linoleic acid upregulated the expression of cytochrome P450 enzymes (CYP2J6) and lipoxygenase (LOX2S), which further upregulated the synthesis of EETs, and increased the content of 9-HODE and 13-HODE. These findings collectively suggest that linoleic acid alleviates neuroinflammation by modulating microglial differentiation and attenuates neurodegeneration induced by thermally oxidized oil through the regulation of arachidonic acid metabolism and the linoleic acid metabolic pathway, leading to the production of neuroprotective lipid mediators. Therefore, linoleic acid may serve as a potential neuro-nutrient for the treatment of anxiety disorders. This provided a scientific basis for the development of specialized medical foods aimed at protecting neural health.