Alleviation of Depression-Like Symptoms Through Orientin-Mediated Regulation of Neuroinflammation and PI3K/AKT Signaling

Neuroinflammation is vital in depression's onset and development, making its relief a key treatment goal. Orientin (ORI), a natural flavonoid, is known to modulate inflammation, but whether it can ease depression by regulating neuro-inflammation remains uncertain. This study aimed to uncover ORI's antineuroinflammation mechanisms for treating depression. It utilized LPS-induced cell and mouse models and Chronic Unpredictable Mild Stress (CUMS) model. Enzyme-linked immunoassay, Western blotting, and immunofluorescence staining gauged ORI's anti-inflammatory effects. Behavioral tests assessed the impact on depressive symptoms. Network pharmacology and molecular biology methods probed its action mechanism and anti-inflammation targets. ORI effectively curbed inflammation, blocked M1 polarization, and reduced the inflammatory mediator release in LPS-induced BV2 cells and mice. In LPS-induced and CUMS depression mouse models, ORI notably alleviated depression-like behavior and neuroinflammation in the prefrontal cortex (PFC). Also, ORI treatment reduced the LPS-induced spike in the frequency of spontaneous excitatory postsynaptic currents (sEPSC) in PFC neurons. The PI3K/AKT signaling pathway was found to underpin ORI's effects. Overall, ORI shows potential as a natural remedy for depression, influencing neuroinflammation and regulating microglial polarization and neuronal excitability to improve symptoms.