Objective To investigate the antidepressant effects of Yuanzhi (Polygalae Radix, PR) aqueous extract on chronic unpredictable mild stress (CUMS)-induced depression rat models and the underlying mechanisms.

Methods A total of 40 male Sprague Dawley (SD) rats were randomly divided into control, model, low dose of PR (PR-L, 0.5 g/kg), high dose of PR (PR-H, 1 g/kg), and fluoxetine (10 mg/kg) groups, with 8 rats in each group. Except for the rats in control group, those in the other four groups underwent CUMS-induced depression modeling. PR and fluoxetine were administered intragastrically once daily, 30 min prior to the CUMS procedure, for 14 consecutive days until the behavioral tests were performed. After CUMS modeling, the sucrose preference test (SPT), open field test (OFT), novelty-suppressed feeding test (NSFT), forced swim test (FST), and tail suspension test (TST) were employed to assess the pharmacological effects of PR on the mitigation of depressive-like behaviors in rat models. Additionally, the enzyme-linked immunosorbent assay (ELISA) was utilized to quantify the serum levels of tumor necrosis factor (TNF)-α, interleukin (IL)-6, and IL-1β in the rats. Western blot analysis was also conducted to evaluate the protein expression levels of nuclear factor kappa-B (NF-κB), inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), nucleotide-binding oligomerization domain (NOD)-like receptor family pyrin domain containing 3 (NLRP3), apoptosis-associated speck-like protein containing caspase recruitment domain (ASC), and caspase-1 in the hippocampal tissues of the rats. Immunofluorescence staining was performed to observe the morphological changes in ionized calcium-binding adapter molecule 1 positive (Iba-1⁺) cells in the dentate gyrus (DG) of rats with CUMS-induced depression.

Results (i) Treatment with PR-H and fluoxetine resulted in significant enhancements in both the total distance and time the rats moved during tests (P < 0.01 and P < 0.05, respectively). Post-administration of PR-H and fluoxetine also led to statistically significant increase in sucrose preference among rats (P < 0.05). Besides, PR-L, PR-H, and fluoxetine treatment markedly decreased the latency of ingestion (P < 0.05, P < 0.05, and P < 0.01, respectively). As observed from the FST, PR-L, PR-H, and fluoxetine presented antidepressant effects on rats with CUMS-induced depression, leading to the reduction in time of their immobility (P < 0.05, P < 0.01, and P < 0.01, respectively). The results of TST indicated reduced immobility time in rats receiving PR-H and fluoxetine treatment as well (P < 0.01). (ii) Rats in model group showed an increase in the levels of Iba-1⁺ microglia in their left and right brains in comparison with control group (P < 0.01). However, such increase was negated post PR treatment (P < 0.01). Treatment with PR-L, PR-H, and fluoxetine considerably reduced the levels of inflammatory factors (TNF-α, IL-1β, and IL-6, P < 0.01). In addition, treatment of PR-L and PR-H effectively counteracted the elevated levels of NLRP3, ASC, and caspase-1, and markedly down-regulated the expression levels of phosphorylated p65 (p-p65), COX-2, and iNOS in rats’ hippocampus (P < 0.01).

Conclusion Collectively, these findings indicate that PR exerts an antidepressant effect on rats with CUMS-induced depression partially through the modulation of the NLRP3 and NF-κB signaling pathways.