Saikosaponins alleviate depression-like behaviors of chronic unpredictable mild stress exposed mice through ERK signaling pathway.

Depressive disorder is the most common mental disorder with limited treatments. The aim of this study was to investigate the antidepressant effects of saikosaponins (SS) and its mechanism. The depression-like behaviors of chronic unpredictable mild stress (CS)-exposed mice were evaluated by sucrose preference test, forced swimming test (FST), and open field test (OFT). The proteome profiler mouse phospho-kinase array kit was used to reveal possible phosphorylated kinases and signaling nodes that SS treatment affected. TUNEL staining of brain tissues and protein levels of brain-derived neurotrophic factor (BDNF) and caspase-3 were combined to evaluate cell apoptosis. The U0126 was applied to pharmacologically inhibit ERK signaling pathway to verify the regulatory role of SS treatment on depression-like behaviors and cell apoptosis was achieved through ERK pathway. SS ameliorated chronic unpredictable mild stress‑induced depressive‑like behaviors by prominently increasing the sucrose preference, total traveling distance, standing number, and grooming number, and decreasing immobility time. SS also inhibited apoptosis of hippocampal neurons by down-regulating caspase-3 protein and up-regulating BDNF protein levels. SS treatment specifically up-regulated the phosphorylation of ERK through the proteome profiler mouse phospho-kinase array analysis. Moreover, the ERK inhibitor, U0126, pharmacological inhibited the phosphorylation levels of ERK induced by SS treatment, and further weakened the treatments of SS on depression-like behaviors and cell apoptosis. SS alleviates depression-like behaviors and protects neuron by activating the ERK signaling pathway, indicating that SS may be a potential therapeutic drug for treatment of depression.