Xiaoyaosan Alleviates Hippocampal Glutamate-Induced Toxicity in the CUMS Rats via NR2B and PI3K/Akt Signaling Pathway

Abstract

Purpose: It is revealed that Xiaoyaosan could reduce glutamate level in the hippocampus of depressed rats, whose metabolism leads to the pathophysiology of depression. However, the underlying mechanism remains unclear. This study aims to explore the effect of Xiaoyaosan on glutamate metabolism, and how to regulate the excitatory injury caused by glutamate.Methods: Rats were induced by chronic unpredictable mild stress, then divided into control, vehicle (distilled water), Xiaoyaosan, fluoxetine, vehicle (DMSO), Xiaoyaosan + Ly294002 and Ly294002 groups. Ly294002 was microinjected into the lateral ventricular catheterization at 5 mM. Xiaoyaosan (2.224 g/kg) and fluoxetine (2.0 mg/kg) were orally administered for three weeks. The open field test (OFT), forced swimming test (FST), and sucrose preference test (SPT) were used to assess depressive behavior. The glutamate and corticosterone (CORT) levels were detected by ELISA. Western blot, immunochemistry or immunofluorescence were used to detect the expressions of NR2B, MAP2, PI3K and P-AKT/Akt in the hippocampal CA1 region. The mRNA level of MAP2, NR2B and PI3K were detected by RT-qPCR.Results: Compared to the rats in control group, body weight and food intake of CUMS rats was decreased. CUMS rats also showed depression-like behavior as well as down regulate the NR2B and PI3K/Akt signaling pathway. Xiaoyaosan treatments could increase food intake and body weight as well as improved time spent in the central area, total distance traveled in the OFT. Xiaoyaosan could also decrease the immobility time as well as increase the sucrose preference in SPT. Moreover, xiaoyaosan decreased the level of glutamate in the hippocampal CA1 region and serum CORT in CUMS rats. Furthermore, xiaoyaosan improved the expression of MAP2 as well as increased the expression of NR2B, PI3K and the P-AKT/AKT ratio in the hippocampal CA1 region in the CUMS rats.Conclusion: Xiaoyaosan treatment can exert the antidepressant effect by rescuing hippocampal neurons loss induced by the glutamate-mediated excitotoxicity in CUMS rats. The underlying pathway maybe through NR2B and PI3K/Akt signaling pathways. These results may suggest the potential of Xiaoyaosan in preventing the development of depression.

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

“…Homer1b/c, mGluR5, p-mTOR, mTOR, p70S6 kinase, p-p70S6 kinase, p-4E-BP1, 4E-BP1, PSD-95 and SYP expressions in hippocampal CA1 region of experimental rats were detected by Western blot analysis according to the protocol [ 6 ]. Details are listed at Additional file 1 : Materials and Methods.…”

“…or Bupleurum scorzonerifolium Willd. , is a common component of Chinese herbal prescriptions such as Xiaoyaosan [ 6 ] and Chaihu-Shugan-San [ 7 ], which are administered clinically to improve symptoms of depression . Saikosaponin D (SSD) is a pharmacologically active ingredient extracted from Radix Bupleuri [ 8 , 9 ], which is capable of ‘dispersing stagnated liver qi for relieving qi stagnation’ according to traditional Chinese Medicine (TCM) theory.…”

Total Triterpenes of Wolfiporia cocos (Schwein.) Ryvarden & Gilb Exerts Antidepressant-Like Effects in a Chronic Unpredictable Mild Stress Rat Model and Regulates the Levels of Neurotransmitters, HPA Axis and NLRP3 Pathway

“…CUMS, acknowledged as a putative animal model of depressive-like behavior and an imitation of life stress, is reliable and stable ( Willner 1997 ; Mineur et al, 2006 ). Lack of pleasure is an essential manifestation of depression, and SPT is the gold standard for evaluating the degree of pleasure deficiency in depressed animals ( Weiss 1997 ; Zhou et al, 2021 ). In this study, compared with rats in unstressed group, CUMS rats showed a lower degree of preference for sucrose after 4 weeks of CUMS treatment, which increased the sucrose preference index and demonstrated an antidepressant-like effect.…”

“…According to the results, the CUMS-exposed group was then divided into five groups: model, FH (1.8 mg/kg), TTWC-L (low), TTWC-M (middle), and TTWC-H (high) dose groups (60, 120, 240 mg/kg), with eight rats in each group. The dose of FH was converted from the clinical dose of 20 mg/d ( Zhou et al, 2021 ). The unstressed and vehicle treated CUMS groups were administered saline every day, while the other groups received intragastric administration of the corresponding drugs for 2 weeks.…”

DataSheet1.ZIP

“…The classic Chinese formula Xiaoyaosan, originated from the book Prescriptions of the Bureau of Taiping People's Welfare Pharmacy in Song Dynasty of China, is one of the effective traditional Chinese compound recipes in treating psychoemotional related symptoms and diseases (Zhang et al, 2019). According to the recent clinical and basic studies, Xiaoyaosan has a multi-target regulating effect which is reflected in the treatment of depression-related diseases (Li et al, 2015;Jiao et al, 2019;Xiong et al, 2019;Liu et al, 2020;Zhou et al, 2021). In the pathogenesis study of depression, it is found that psychological and physical stressors can activate the immune system, lead to inflammation, and then participate in the development of depression (Iwata et al, 2013).…”