Data-driven optimization of Bupleurum chinense DC.–Paeonia lactiflora Pall. herb pair into Jieyu-1 formula: Remodeling neuroinflammation–HPA axis–synaptic plasticity network for antidepressant effects

A B S T R A C T Objective To develop an optimized formula Jieyu-1 (JY-1) from the herb pair Bupleurum chinense DC.– Paeonia lactiflora Pall., and evaluate its antidepressant efficacy and mechanisms, particularly regulating neuroinflammation, hypothalamic-pituitary-adrenal (HPA) axis dysfunction, and synaptic plasticity impairment. Methods Data mining was performed on 330 clinical antidepressant prescriptions to identify the core herbal combinations. Based on the core herb pair, JY-1 was rationally designed with adjunctive herbs. Its efficacy was evaluated in lipopolysaccharide (LPS)-induced acute inflammation and chronic unpredictable mild stress (CUMS) mouse models. Depression-like behaviors were assessed via behavioral tests. Serum and cortical HPA axis hormones and proinflammatory cytokines were measured by enzyme-linked immunosorbent assay. Neuronal integrity and microglial polarization were examined by hematoxylin and eosin (H&E), Nissl, and immunofluorescence stainings. Synaptic plasticity- and neuroinflammation-related proteins and mRNAs were assessed by western blotting and quantitative real-time polymerase chain reaction. Flow cytometry was used to analyze M1/M2 phenotypic shifts in LPS-stimulated BV-2 microglia. Molecular docking was performed to predict binding affinities between active compounds and target proteins. Results Data mining confirmed the Bupleurum – Paeonia pair as the core herb combination. JY-1 significantly alleviated depression-like behaviors, as evidenced by increased sucrose preference ( P LPS = .003; P CUMS = .005) and reduced immobility time (both P < .001). Mechanistically, JY-1 attenuated HPA axis hyperactivity (e.g., serum corticotropin-releasing hormone, P < .001; serum corticosterone, P = .002), reduced neuroinflammation (e.g., cortical IL-6, P LPS = .017; P CUMS = .040), and restored synaptic plasticity by upregulating postsynaptic density protein 95 (PSD95, P LPS = .007). These effects were dose-dependent, and JY-1 exhibited no hepatorenal toxicity. Molecular docking indicated strong binding affinities of its active components to brain-derived neurotrophic factor and PSD95. Conclusion JY-1 exerts antidepressant effects through coordinated regulation of HPA axis hyperactivity, neuroinflammation with microglial M2 polarization, and synaptic plasticity restoration, in a dose-dependent manner without hepatorenal toxicity.