Shandong Co-Innovation Center of Classic TCM Formula, Shandong University of Traditional Chinese Medicine, Jinan, 250355, PR China.
Shandong Co-Innovation Center of Classic TCM Formula, Shandong University of Traditional Chinese Medicine, Jinan, 250355, PR China; Institute of Virology, Jinan Municipal Center for Disease Control and Prevention, Jinan, 250021, PR China.
J Ethnopharmacol. 2022 Jun 28;292:115218. doi: 10.1016/j.jep.2022.115218. Epub 2022 Mar 22.
Baihe Dihuang Decoction is a well-known traditional Chinese medicine prescription (Also known as Lilium Henryi Baker and Rehmannia Glutinosa Decoction, LBRD) composed of Lilium Henryi Baker bulb and raw juice from Rehmannia Glutinosa (Gaertn) DC with the curative efficacy of nourishing yin and clearing heat based on the Chinese herbal medicine theory. It has been used as routine medication in treating depression combined with conventional western medicine in China for years.
LBRD can attenuates GABAergic deficits in the medial prefrontal cortex (mPFC) of depression. This study aimed to investigate the mechanism of antidepressive properties of LBRD in the prefrontal GABAergic interneuron subtypes, including parvalbumin (PV), somatostatin (SST), vasoactive intestinal peptide (VIP)-positive neuron.
In this project, chronic unpredicted mild stress paradigm was adopted to construct depression model. After treated with LBRD standard decoction and behaviors test, the level of GABA associated miRNA/mRNA and GABAergic subtype-specific markers were detected by qRT-PCR and Western blot. The lncRNAs/miRNAs/GABA regulatory axis was verified by luciferase reporter assay, RNA immunoprecipitation, RNA pull-down assay, and theses changes were measured in LBRD administration with the use of immunofluorescence staining and RNA-fluorescence in situ hybridization.
In the current study, we found that LBRD exhibited high efficacy based on the results of behavioral tests. Meanwhile, LBRD also improved the reduced GABA levels in depression by increasing the expression of lncRNA Neat1 and Malat1, as well as decreasing miRNA-144-3p and miRNA-15b-5p. Moreover, the level of Sst mRNA and protein that were harvested from the mPFC tissues of depression group was significantly lower than those in the control mice. While, these changes can be reverted by LBRD standard decoction administration. Whereas, neither chronic stress nor treatment can change the level of PV and VIP mRNAs and protein expression. In the SST-positive neuron of mPFC tissues, treatment with LBRD standard decoction resulted in the elevation of Gad-67, VGAT, GAT-3 and a reduction of miRNA-144-3p expression.
These findings suggested that LBRD antidepressant activities may be related to ameliorating the SST-positive neuron deficits via regulating the miRNA-144-3p mediated GABA synthesis and release.
百合地黄汤是一种著名的中药方剂（又称百合亨利贝克和地黄，LBRD），由百合亨利贝克鳞茎和地黄生汁组成，基于中草药理论，具有滋阴清热的疗效。多年来，它一直被用作中国治疗抑郁症的常规药物，并与传统的西药联合使用。
LBRD 可减轻抑郁症患者内侧前额叶皮质（mPFC）的 GABA 能缺陷。本研究旨在探讨 LBRD 对前额叶 GABA 能中间神经元亚型（包括 PV、SST、VIP 阳性神经元）的抗抑郁作用机制。
在本项目中，采用慢性不可预测轻度应激范式构建抑郁模型。用 LBRD 标准汤剂处理并进行行为测试后，通过 qRT-PCR 和 Western blot 检测 GABA 相关 miRNA/mRNA 和 GABA 能亚型特异性标志物的水平。通过荧光素酶报告测定、RNA 免疫沉淀、RNA 下拉测定验证 lncRNA/miRNA/GABA 调节轴，并用免疫荧光染色和 RNA 荧光原位杂交测量 LBRD 给药后的这些变化。
在本研究中，我们发现 LBRD 在行为测试结果中表现出高疗效。同时，LBRD 通过增加 lncRNA Neat1 和 Malat1 的表达以及降低 miRNA-144-3p 和 miRNA-15b-5p 的表达，改善了抑郁症中 GABA 水平的降低。此外，来自抑郁症组 mPFC 组织的 Sst mRNA 和蛋白质水平明显低于对照组小鼠。然而，这些变化可以通过 LBRD 标准汤剂给药来逆转。然而，慢性应激或治疗都不能改变 PV 和 VIP mRNAs 和蛋白质表达水平。在 mPFC 组织的 SST 阳性神经元中，LBRD 标准汤剂处理导致 Gad-67、VGAT、GAT-3 升高和 miRNA-144-3p 表达降低。
这些发现表明，LBRD 的抗抑郁活性可能与通过调节 miRNA-144-3p 介导的 GABA 合成和释放来改善 SST 阳性神经元缺陷有关。
