Polygonatum sibiricum Polysaccharides Alleviate Depressive-like Symptoms in Chronic Restraint Stress-Induced Mice via Microglial Regulation in Prefrontal Cortex

Microglia respond to stressors by secreting cytokines or growth factors, playing a crucial role in maintaining brain homeostasis. While the antidepressant-like effects of <i>Polygonatum sibiricum</i> polysaccharides (PSPs) have been observed in mice, their potential effectiveness involving microglial regulation remains unknown. This study investigates the antidepressant-like mechanism of PSP by regulating microglial phenotype and signaling pathways in the prefrontal cortex of chronic restraint stress (CRS)-induced mice. PSP was extracted, purified, characterized, and orally administered to CRS mice. High-performance gel permeation chromatography (HPGPC) revealed that PSP has a molecular weight of 5.6 kDa. Scanning electron microscopy (SEM) and atomic force microscopy (AFM) showed that PSP exhibited a layered structure with densely packed, irregular surfaces. PSP treatment significantly increased sucrose preference (low: 71%, <i>p</i> < 0.01; medium: 69%, <i>p</i> < 0.05; high: 75%, <i>p</i> < 0.001 vs. CRS: 58%) and reduced immobility time (low: 74 s, <i>p</i> < 0.01; medium: 68 s, <i>p</i> < 0.01; high: 79 s, <i>p</i> < 0.05 vs. CRS: 129 s), indicating the alleviation of depressive-like behaviors. PSP inhibited microglial activation (PSP, 131/mm² vs. CRS, 173/mm², <i>p</i> = 0.057), reversing CRS-induced microglial hypertrophy and hyper-ramification. Furthermore, PSP inactivated microglial activation by inhibiting NLRP3/ASC/caspase-1/IL-1β signaling pathways, increasing BDNF synthesis and activating brain-derived neurotrophic factor (BDNF)-mediated neurogenesis (PSP, 80/per DG vs. CRS, 49/per DG, <i>p</i> < 0.01). In conclusion, PSP exerts antidepressant-like effects through the regulation of microglial activity and neuroinflammatory pathways, indicating it as a potential natural compound for depression treatment.