Tetramethylpyrazine Protects Against Depression-Like Behaviors through CREB/CRTC1 Signaling Pathway in a Depression Mouse Model

Abstract Objective Traditional Chinese Medicine is a clinically recognized alternative approach for depression treatment in clinic. This study investigates the effects and mechanisms of tetramethylpyrazine (TMP), one of the most important active ingredients of Ligusticum wallichii , in the progression of depression. Methods The depression mouse model was established using the chronic unpredictable mild stress method. Mice with depression were treated with fluoxetine hydrochloride (FLX; 10 mg/kg) and different concentrations of TMP (5, 10 and 20 mg/kg, respectively). Open Field Test (OFT), Forced Swimming Test (FST) and Tail Suspension Test (TST) were used to evaluate depression behaviors in mice. The effects of TMP on hippocampal neurons were assessed through Nissl staining and measuring neurotransmitter levels. CREB/CRTC1 pathway-related gene expression and protein levels were ascertained via qRT-PCR and Western blotting. Results A higher concentration of TMP (20 mg/kg) induced a pronounced reduction in the immobility time in FST ( P < 0.0001) and TST ( P < 0.01). However, TMP administration did not affect the path length in OFT. TMP treatment significantly increased the number of neurons ( P < 0.05) and the level of PSD95 ( P < 0.01), indicating that it improved the neuronal damage caused by depression. Meanwhile, 20 mg/kg of TMP dramatically elevated neurotransmitter levels, including 5-hydroxytryptamine, dopamine and norepinephrine ( P < 0.001). TMP (5, 10 and 20 mg/kg) significantly repressed SIK2 expression ( P < 0.001), and 20 mg/kg of TMP distinctly induced the expression of CRTC1 ( P < 0.001), Calcineurin ( P < 0.001), CREB ( P < 0.001), and BDNF ( P < 0.001). Similar results were observed in the CREB/CRTC1 pathway-related protein levels ( P < 0.05). Conclusions These findings indicated that TMP can alleviate depression via the CREB/CRTC1 signaling pathway in a mouse model. This study provides a theoretical basis for the use of TMP as depression therapy in clinical practice.