Chaihu-Baishao confers antidepressant effects in CSDS mice by ameliorating hippocampal synaptic plasticity impairment via blocking α2δ-1-NR2B interaction

ETHNOPHARMACOLOGICAL RELEVANCE: The herbal combination of Bupleurum chinense DC (Chaihu) and Paeonia lactiflora Pall (Baishao), collectively referred to as Chaihu-Baishao (CB), has been historically utilized in traditional Chinese medicine for the treatment of depression. However, the mechanisms underlying its therapeutic benefits have not been clearly defined. AIM OF THE STUDY: This study investigated whether CB alleviates depressive symptoms by modulating the interaction between the voltage-gated calcium channel subunit α2δ-1 and the N-methyl-D-aspartate receptor (NMDAR) subunit NMDAR2B (NR2B), thereby restoring hippocampal synaptic plasticity. MATERIALS AND METHODS: In vivo, the chronic social defeat stress (CSDS) mouse model was employed to assess the impact of CB on depression-like behaviors, hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis, impairments in hippocampal neuronal and synaptic plasticity, as well as the expression and interaction of α2δ-1 and NR2B. In vitro, corticosterone (CORT) was utilized to induce cellular injury. In PC12 cells, the therapeutic effects of CB-containing serum and the α2δ-1 inhibitor gabapentin (GBP) were assessed, focusing on the interaction between α2δ-1 and NR2B, as well as the expression levels of synaptic proteins postsynaptic density protein 95 (PSD95) and synaptophysin (SYN). The role of CB was further corroborated using Cacna2d1 gene knockout cells. Molecular docking techniques were employed to predict the key active components within CB that target α2δ-1 and NR2B, hereby exerting antidepressant effects. RESULTS: In vivo studies demonstrated that CB significantly alleviated depression-like behaviors in mice, decreased levels of adrenocorticotropic hormone (ACTH) and CORT. Furthermore, CB relieved structural damage to hippocampal neurons and synapses, downregulated the expression of α2δ-1 and NR2B, inhibited their interaction and restored synaptic protein expression. In vitro experiments revealed that CB mitigated CORT-induced cellular damage, suppressed the α2δ-1-NR2B interaction, and enhanced synaptic proteins expression. Additionally, studies involving GBP treatment and Cacna2d1-knockout confirmed that α2δ-1 plays a regulatory role in NR2B expression and synaptic plasticity. Molecular docking analyses identified Saikosaponin C, Saikosaponin B4, and Bupleuroside I as potential key components. CONCLUSION: The findings of this study elucidate a novel mechanism through which CB exerts its antidepressant effects, specifically by modulating the α2δ-1-NR2B interaction and restoring of synaptic plasticity within the hippocampus.