Saikosaponin D exerts antidepressant effect by regulating Homer1-mGluR5 and mTOR signaling in a rat model of chronic unpredictable mild stress

Abstract

Background Many studies about depression have focused on the dysfunctional synaptic signaling in the hippocampus that drives the pathophysiology of depression. Radix Bupleuri has been used in China for over 2000 years to regulate liver-qi. Extracted from Radix Bupleuri, Saikosaponin D (SSD) is a pharmacologically active substance that has antidepressant effects. However, its underlying mechanism remains unknown. Materials and methods A chronic unpredictable mild stress (CUMS) paradigm was used as a rat model of depression. SD rats were randomly assigned to a normal control (NC) group or one exposed to a CUMS paradigm. Of the latter group, rats were assigned to four subgroups: no treatment (CUMS), fluoxetine-treated (FLU), high-dose and low-dose SSD-treated (SSDH and SSDL). SSD was orally administrated of 1.50 mg/kg and 0.75 mg/kg/days for three weeks in the SSDH and SSDL groups, respectively. Fluoxetine was administrated at a dose of 2.0 mg/kg/days. SSD’s antidepressant effects were assessed using the open field test, forced swim test, and sucrose preference test. Glutamate levels were quantified by ELISA. Western blot and immunochemical analyses were conducted to quantify proteins in the Homer protein homolog 1 (Homer1)-metabotropic glutamate receptor 5 (mGluR5) and mammalian target of rapamycin (mTOR) pathways in the hippocampal CA1 region. To measure related gene expression, RT-qPCR was employed. Results CUMS-exposed rats treated with SSD exhibited increases in food intake, body weight, and improvements in the time spent in the central are and total distance traveled in the OFT, and less pronounced pleasure-deprivation behaviors. SSD also decreased glutamate levels in CA1. In CA1 region of CUMS-exposed rats, SSD treatment increased mGluR5 expression while decreasing Homer1 expression. SSD also increased expressions of postsynaptic density protein 95 (PSD95) and synapsin I (SYP), and the ratios of p-mTOR/mTOR, p-p70S6k/p70S6k, and p-4E-BP1/4E-BP1 in the CA1 region in CUMS-exposed rats. Conclusions SSD treatment reduces glutamate levels in the CA1 region and promotes the expression of the synaptic proteins PSD-95 and SYP via the regulation of the Homer1-mGluR5 and downstream mTOR signaling pathways. These findings suggest that SSD could act as a natural neuroprotective agent in the prevention of depression.

Potential antidepressant effects of Traditional Chinese botanical drug formula Chaihu-Shugan-San and its active ingredients

“…Therefore, SSD may alleviate depressive-like behavior in CUMS-exposed rats by modulating the Homer1-mGluR5 and mTOR signaling pathways. These findings suggest that SSD can serve as a natural neuroprotective agent for the prevention of depression ( Liu et al, 2022b ). Therefore, saikosaponin A and saikosaponin D are promising ingredients in inhibiting the inflammatory response, which might be a potential mechanism underlying their antidepressant effects.…”

Quercetin alleviates chronic unpredictable mild stress‐induced depression‐like behavior by inhibiting NMDAR1 with α2δ‐1 in rats

“…After a week of adaptive feeding, the rats were randomly divided into six groups with eight rats in each group: (1) Control, (2) CUMS, (3) CUMS + Flu (2 mg/kg), (4) CUMS + L‐Que (low dose: 20 mg/kg), (5) CUMS + M‐Que (middle dose: 40 mg/kg), and (6) CUMS + H‐Que (high dose: 60 mg/kg). The doses of Que and Flu were determined based on previous studies and appropriate modifications 30,31 . The drugs were administered by gavage daily for 4 weeks.…”

“…The doses of Que and Flu were determined based on previous studies and appropriate modifications. 30 , 31 The drugs were administered by gavage daily for 4 weeks. The control group was fed normally without any stimulation.…”

Local neurovascular coupling in the amygdala is responsible for context-dependent emotional adjustment

“…The setup of open field test (OFT) referred to published papers (33-36). Each mouse was placed in the central area of a 40*40 cm or 35*35 cm box for the OFT.…”