Anti-depressant-like effect of fermented Gastrodia elata Bl. by regulating monoamine levels and BDNF/NMDAR pathways in mice

Gastrodia elata Blume (GE) is a Chinese medicinal herb commonly used to treat central nervous system-related diseases, including headaches, dizziness, epilepsy, numbness of the limbs and depression.Microbial-based fermentation has been successfully used to increase the extract efficiency of medicinal herbs in recent years. However, no study has hitherto explored the anti-depressant-like effect of GE processed by microorganisms. Herein, this subject aimed to clarify the anti-depressant-like effect of fermented Gastrodia elata Bl. (FGE) and its active chemical constituents.The chronic unpredictable mild stress (CUMS) model, a well-established animal model of depression, was induced in Kunming (KM) mice. The mice were administrated with FGE for 3 weeks. The sucrose preference test (SPT), open field test (OFT) and tail suspension test (TST) were conducted. Moreover, the levels of serotonin (5-HT) and dopamine (DA) in brain tissue homogenates, the concentration of Ca2+ and the activity of MAO in serum, H&E and Nissl staining in the hippocampus, and the hippocampus protein expressions of BDNF, NMDAR1, NMDAR2A and NMDAR2B relevant to depression were detected. Furthermore, chemical constituents of FGE were further isolated, and the protective activity of the obtained compounds against NMDA-induced PC-12 cell damage was assessed.FGE could alleviate the depression state in CUMS-induced mice and reduce apoptosis of neuronal cells in the hippocampus. Furthermore, FGE could improve the contents of 5-HT, DA and decrease the concentration of Ca2+ and MAO activity in brain tissue and serum compared with the control group. It could reverse the decreased expression of BDNF, NMDAR2A and NMDAR2B and increase NMDAR1 protein expression. Investigation of the active constituents from FGE yielded two new compounds, (4-(((4-ethoxybenzyl) oxy)methyl)-phenol 1 and 3-((4-hydroxy benzyl)oxy)propane-1,2-diol) 2, with twelve known compounds (3-14). The compounds (3-((4-hydroxybenzyl)oxy)propane-1,2-diol 2, 4, 4'-dihydroxyd iphenyl methane 3, and bungein A 4) protected against NMDA-induced PC-12 cells damage.This study demonstrated that FGE could improve the depressive behavior of CUMS-induced mice and exert a protective effect on nerve cells in the brain. Importantly, compounds 2-4 are the active components of FGE. Overall, the above findings suggest that FGE has huge prospects for application in treating depression-related diseases.