Spinosin improves anxiety disorders in mice with chronic restraint stress via the ERK1/2-CREB-BDNF pathway

Anxiety disorders, a prevalent mental health condition often stemming from chronic stress, are characterized by uncontrollable emotional responses, heightened psychological stress, and cognitive impairment. Ziziphi Spinosae Semen, a traditional Chinese medicine (TCM), is widely used for its calming effects. Among its flavonoid components, spinosin serves as a primary bioactive compound, playing a significant role in treating psychiatric disorders. However, the mechanisms underlying the anxiolytic effects of spinosin are not fully elucidated. This study explores the protective effects of spinosin against anxiety in mice subjected to chronic restraint stress (CRS). Male C57BL/6J mice were subjected to restraint stress modeling for 10 consecutive days, and the treatment groups were gavaged with spinosin at doses of 1.25 mg/kg, 2.5 mg/kg, and 5 mg/kg, respectively. Behavioral experiments including the elevated plus maze test (EPM), open field test (OFT), and novelty suppressed feeding test (NSF) were conducted to confirm the successful establishment of the CRS model and the anxiolytic effect of spinosin. Additionally, spinosin normalized neurotransmitter levels and mitigated inflammation and neuronal damage in the hippocampus (HPC) and prefrontal cortex (PFC). Mechanistically, spinosin treatment significantly modulated the extracellular signal-regulated kinase 1/2 (ERK1/2)/cyclic adenosine monophosphate response element-binding protein (CREB)/brain-derived neurotrophic factor (BDNF) signaling pathway, a key axis in anxiety regulation. The upregulation of ERK1/2, p-CREB, and BDNF proteins significantly alleviated anxiety, suggesting that spinosin plays a pivotal role in treating CRS-induced anxiety disorders. Our findings indicate that spinosin treatment can ameliorate anxiety and that it verifies a previously unrecognized mechanism, providing crucial evidence for future research on anti-anxiety medications.