Xiaoyaosan Exerts Antidepressant-like Effects by Regulating the Functions of Astrocytes and EAATs in the Prefrontal Cortex of Mice | Chapter 8 | Insights into the Prevention and Treatment of Depression with Famous TCM Prescription Xiaoyaosan

 Background: Mounting evidence indicates that the cerebral cortex is an important physiological system of emotional activity, and its dysfunction may be the main cause of stress. Glutamate is the primary excitatory neurotransmitter in the central nervous system (CNS), which initiates rapid signal transmission in the synapse before its reuptake into the surrounding glia, specifically astrocytes (ASTs). The astrocytic excitatory amino acid transporters 1 (EAAT1) and 2 (EAAT2) are the major transporters that take up synaptic glutamate to maintain optimal extracellular glutamic levels, thus preventing accumulation in the synaptic cleft and ensuing excitotoxicity. Growing evidence has shown that excitotoxicity is associated with depression. Therefore, we hypothesized that the underlying antidepressant-like mechanism of Xiaoyaosan (XYS), a Chinese herbal formula, may be related to the regulation of astrocytic EAATs. Therefore, we studied the antidepressant mechanism of XYS on the basis of EAAT dysfunction in ASTs.

Methods: Eighty adult C57BL/6 J mice were randomly divided into 4 groups: a control group, a chronic unpredictable mild stress (CUMS) group, a Xiaoyaosan (XYS) treatment group and a fluoxetine hydrochloride (Flu) treatment group. Except for the control group, mice in the other groups all received chronic unpredictable mild stress for 21 days. Mice in the control and CUMS groups received gavage administration with 0.5 mL of normal saline (NS) for 21 days, and mice in the XYS and Flu treatment groups were administered dosages of 0.25 g/kg/d and 2.6mg/kg/d by gavage. The effects of XYS on the depressive- like behavioral tests, including the open field test (OFT), forced swimming test (FST) and sucrose preference test (SPT), were examined. The glutamate (Glu) concentrations of the prefrontal cortex (PFC) were detected with colorimetry. The morphology of neurons in the PFC was observed by Nissl staining. The expression of glial fibrillary acidic protein (GFAP), NeuN, EAAT1 and EAAT2 proteins in the PFC of mice was detected by using Western blotting and immunohistochemistry. Quantitative real-time PCR (qPCR) was used to detect the expression of the GFAP, NeuN, EAAT1 and EAAT2 genes in the PFC of mice.

Results: The results of behavioral tests showed that CUMS-induced mice exhibited depressive-like behavior, which could be improved in some tests with XYS and Flu treatment. Immunohistochemistry and Western blot analysis showed that the protein levels of GFAP, NeuN, EAAT1 and EAAT2 in the PFC of CUMS mice were significantly lower than those in the control group, and these changes could be reversed by XYS and Flu. The results of qPCR analysis showed that the expression of GFAP, NeuN, EAAT1 and EAAT2 mRNAs in the PFC of CUMS mice was not significantly changed, with the exception of EAAT2, compared with that of the control group, while the expression of the above mRNAs was significantly higher in the XYS and Flu groups than that in the CUMS group.

Conclusion: XYS may exert antidepressant-like effects by improving the functions of AST and EAATs and attenuating glutamate-induced neuronal damage in the frontal cortex.

Author(s) Details:

Yan Liu,
School of Pre-clinical Medicine, Hubei University of Chinese Medicine, Wuhan-430065, China and School of Pre-clinical Medicine, Henan University of Chinese Medicine, Zhengzhou-450046, China.

Xiu-fang Ding,
School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, No. 11 North Third Ring Road Chaoyang District, Beijing-100029, China.

Xin-xing Wang,
School of Pre-clinical Medicine, Henan University of Chinese Medicine, Zhengzhou-450046, China.

Xiao-juan Zou,
School of Pre-clinical Medicine, Hubei University of Chinese Medicine, Wuhan-430065, China.

Xiao-juan Li,
School of Pre-clinical Medicine, Hubei University of Chinese Medicine, Wuhan-430065, China and School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, No. 11 North Third Ring Road Chaoyang District, Beijing-100029, China.

Yue-yun Liu,
School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, No. 11 North Third Ring Road Chaoyang District, Beijing-100029, China.

Jie Li,
School of Pre-clinical Medicine, Henan University of Chinese Medicine, Zhengzhou-450046, China.

Xiu-yun Qian,
School of Pre-clinical Medicine, Henan University of Chinese Medicine, Zhengzhou-450046, China.

Jiaxu Chen,
School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, No. 11 North Third Ring Road Chaoyang District, Beijing-100029, China and Formula-pattern Research Center, School of Traditional Chinese Medicine, Jinan University, Guangzhou-510632, Guangdong, China.

Please see the link here: https://stm.bookpi.org/IPTDFTPX/article/view/11269

Effect of Xiaoyaosan on Colon Morphology and Intestinal Permeability in Rats with Chronic Unpredictable Mild Stress | Chapter 2 | Insights into the Prevention and Treatment of Depression with Famous TCM Prescription Xiaoyaosan

 Purpose: In our present study, a rat depression model induced by 6 weeks of chronic unpredictable mild stress (CUMS) was established, and we investigated how Xiaoyaosan affects the intestinal permeability of depressed rats and alterations in tight-junction proteins (TJs) involved in this process.

Methods: The rat depression model was established using CUMS for 6 consecutive weeks. A total of 40 healthy male Sprague-Dawley rats were randomly sorted into four groups: the control group, CUMS group, Xiaoyaosan group, and fluoxetine group. All groups, excluding the control group, were subjected to the 6-week CUMS program to generate the depression model. Body weight, food intake, and behaviors were observed during the modeling period. Histopathological alterations of colon tissue were evaluated by hematoxylin-eosin staining (H&E), and mucus-containing goblet cells were detected by periodic acid-Schiff (PAS) staining. The ultrastructural morphology of colonic mucosa  was observed by transmission electron microscopy. Furthermore, immunohistochemistry (IHC) and quantitative reverse transcription polymerase chain reaction (qRT-PCR) were used to determine the expression of TJs. The concentrations of 5-hydroxytryptamine (5-HT) in the hypothalamus and colon were also assessed using enzyme-linked immunosorbent assay (ELISA).

Results: Treatment of depressed rats with Xiaoyaosan alleviated depression-like behaviors as demonstrated by increases in the total distance traveled, the number of entries into the central area in the open field test, the duration spent in the central area, and sucrose preference. Xiaoyaosan treatment also increased body weight gain and food intake in depressed rats. Moreover, Xiaoyaosan treatment effectively improved the colonic pathological and ultrastructural changes, upregulated the expression of ZO-1, occludin, and claudin-1 in the colon, and increased 5-HT levels in the hypothalamus and colonic mucosa.

Conclusions: Xiaoyaosan treatment attenuates depression-like behaviors caused by CUMS and ameliorates CUMS-induced abnormal intestinal permeability, which may be associated with the expression of TJs. These results suggest that Xiaoyaosan exerts an antidepressant effect that may be related to an improvement of intestinal barrier function via the brain-gut axis.

Author(s) Details:

Fengmin Ding,
Formula-pattern Research Center, School of Traditional Chinese Medicine, Jinan University, Guangzhou-510632, Guangdong, China.

Jiajia Wu,
School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, No. 11 North Third Ring Road Chaoyang District, Beijing-100029, China.

Chenyue Liu,
School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, No. 11 North Third Ring Road Chaoyang District, Beijing-100029, China.

Qinglai Bian,
School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, No. 11 North Third Ring Road Chaoyang District, Beijing-100029, China.

Wenqi Qiu,
School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, No. 11 North Third Ring Road Chaoyang District, Beijing-100029, China.

Qingyu Ma,
Formula-pattern Research Center, School of Traditional Chinese Medicine, Jinan University, Guangzhou-510632, Guangdong, China.

Xiaojuan Li,
Formula-pattern Research Center, School of Traditional Chinese Medicine, Jinan University, Guangzhou-510632, Guangdong, China.

Man Long,
Formula-pattern Research Center, School of Traditional Chinese Medicine, Jinan University, Guangzhou-510632, Guangdong, China.

 
Xiaojuan Zou,
Formula-pattern Research Center, School of Traditional Chinese Medicine, Jinan University, Guangzhou-510632, Guangdong, China.

 
Jiaxu Chen,
Formula-pattern Research Center, School of Traditional Chinese Medicine, Jinan University, Guangzhou-510632, Guangdong, China and School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, No. 11 North Third Ring Road Chaoyang District, Beijing-100029, China.

Please see the link here: https://stm.bookpi.org/IPTDFTPX/article/view/11263

Effects of Xiaoyaosan on Depressive-Like Behaviors in Rats with Chronic Unpredictable Mild Stress through HPA Axis Induced Astrocytic Activities | Chapter 1 | Insights into the Prevention and Treatment of Depression with Famous TCM Prescription Xiaoyaosan

 Astrocytes in the hippocampus are immediately relevant to depressive-like behavior. By regulating their activities, Xiaoyaosan (XYS), a traditional Chinese medicine compound, works in the treatment of depression.

Objective: Chronic unpredictable mild stress (CUMS) rat model was established to observe the regulation of XYS. We investigated the behavioral changes of CUMS, the expression of corticosterone (CORT) of the hypothalamo–pituitary–adrenal (HPA) axis, the expression of Glu-NMDA receptor and astrocytes glial fibrillary acidic protein (GFAP) in the hippocampus. We also investigated whether these changes were linked to XYS.

Methods: 80 adult SD rats were randomly divided into four groups, control group, CUMS group, XYS group, and fluoxetine group. The rats in the control group and the CUMS group received 0.5 ml of deionized water once a day by intragastrically administration. Rats in the two treatment groups received XYS (2.224g/kg/d) and fluoxetine (2.0mg/kg/d) once a day, respectively. Rat hippocampus GFAP and Glu-NMDA receptor were respectively detected by real-time fluorescent quantitative PCR and western blot. The CORT of HPA axis was detected by Elisa. Body weight, food intake, and behavioral tests, such as open field tests, the sucrose preference test, and exhaustive swimming test, were used to assess depressive-like behavior in rats.

Results: In this work, significant behavioral changes and differences in expression of the CORT of HPA axis and hippocampal GFAP and Glu-NMDA receptor were presented in CUMS-exposed rats. Like fluoxetine, XYS improved CUMS-induced rat’s body weight, food intake, and depressive-like behavior. The study also proved that XYS could reverse the CUMS-induced changes of the CORT of HPA axis and affect the astrocytic activities and down-regulate the NR2B subunit of NMDA receptor (NR2B) level in the hippocampus.

Conclusion: Changes in the hippocampus GFAP and Glu-NMDA receptor may be an essential mechanism of depression. Besides, XYS may be critical to the treatment of depression by intervention the HPA axis, GFAP and Glu-NMDA receptor.

Author(s) Details:

Ming Song,
Formula-pattern Research Center, School of Traditional Chinese Medicine, Jinan University, Guangzhou-510632, Guangdong, China.

Jianjun Zhang,
Formula-pattern Research Center, School of Traditional Chinese Medicine, Jinan University, Guangzhou-510632, Guangdong, China.

Xiaojuan Li,
Formula-pattern Research Center, School of Traditional Chinese Medicine, Jinan University, Guangzhou-510632, Guangdong, China and School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, No. 11 North Third Ring Road Chaoyang District, Beijing-100029, China.

Yueyun Liu,
Formula-pattern Research Center, School of Traditional Chinese Medicine, Jinan University, Guangzhou-510632, Guangdong, China.

Tingye Wang,
Formula-pattern Research Center, School of Traditional Chinese Medicine, Jinan University, Guangzhou-510632, Guangdong, China.

Zhiyi Yan,
Formula-pattern Research Center, School of Traditional Chinese Medicine, Jinan University, Guangzhou-510632, Guangdong, China.

Jiaxu Chen,
Formula-pattern Research Center, School of Traditional Chinese Medicine, Jinan University, Guangzhou-510632, Guangdong, China and School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, No. 11 North Third Ring Road Chaoyang District, Beijing-100029, China.

Please see the link here: https://stm.bookpi.org/IPTDFTPX/article/view/11262