Shandong University of Traditional Chinese Medicine’s Wei Sheng Team Reveals Neurological Mechanism by Which ShuYu Capsule Improves Physical and Emotional Symptoms of Premenstrual Dysphoric Disorder

Premenstrual dysphoric disorder (PMDD) is a severe type of premenstrual syndrome (PMS) (classified as one of the five subtypes of depressive disorders in DSM-5), with clinical manifestations including various physical (e.g., hyperalgesia) and emotional symptoms (e.g., depression and anxiety) that appear synchronously with the estrous cycle. Numerous literature evidences suggest that PMDD symptoms are closely related to abnormal fluctuations in neurosteroid hormones. ShuYu Capsule is a composite Chinese medicine composed of extracts from Radix Paeoniae Alba, Radix Bupleuri, Rhizoma Cyperi, and Radix Glycyrrhizae, which soothes the liver, relieves depression, and regulates qi. Numerous clinical and preclinical studies have confirmed that ShuYu Capsule is highly effective in treating PMDD, but the specific mechanisms remain unclear.

Based on this, on March 19, 2024, Professor Wei Sheng’s research team from Shandong University of Traditional Chinese Medicine published their findings in the journal Phytomedicine titled “ShuYu capsule alleviates emotional and physical symptoms of premenstrual dysphoric disorder: Impact on ALLO decline and GABAA receptor δ subunit in the PAG area”. The study reveals that ShuYu Capsule can alleviate the emotional and physical symptoms of PMDD by affecting the decline of ALLO and the δ subunit of the GABA_A receptor in the PAG area.

Fluoxetine, a typical selective 5-HT reuptake inhibitor, is commonly used as a first-line medication to alleviate emotional disturbances in PMDD in clinical settings, but it has poor efficacy and significant side effects. Traditional Chinese medicine (TCM) formulas are effective but have unclear targets and mechanisms. This study aims to investigate the potential targets and mechanisms of ShuYu Capsule in treating the emotional and physical symptoms of PMDD in rats. Specifically, the focus is on the midbrain periaqueductal gray (PAG) area related to emotional regulation and hyperalgesia susceptibility. Considering the potential mechanisms involving ALLO-GABAA receptor function, the authors conducted a series of experiments to evaluate the efficacy of ShuYu Capsule, revealing the relationship between the drug’s efficacy and ALLO concentration fluctuations on the GABAA receptor function in the PAG area. The results showed that ShuYu Capsule significantly improved estrous cycle-dependent depressive-like behaviors and reduced stress-induced hyperalgesia in PMDD rats. Similar to low-dose fluoxetine, ShuYu Capsule targeted and mitigated the rapid decline of ALLO, rescued the upregulation of GABAAR subunits, and activated PAG neurons. The effects of ShuYu Capsule suggest a central mechanism for PMDD symptoms involving ALLO-GABAA receptor function in the PAG area. This study emphasizes the potential of TMC in treating emotional and physical symptoms associated with PMDD, revealing new therapeutic approaches for this condition.

The study first identified the main components of ShuYu Capsule using g UPLC-Q-Orbitrap MS/MS, identifying 76 compounds. PMDD models were screened in estrous cycle regular rats using Forced swimming test, and it was confirmed that ShuYu Capsule intervention significantly improved estrous cycle-dependent depressive-like and hyperalgesia behaviors in model animals (Figure 1).

Subsequently, the researchers used c-fos staining to understand the functional activation of PAG neurons in the model and drug intervention. Electrical stimulation was applied to the PAG area of each group of rats to record the current threshold that induced freezing and escape behaviors, confirming that ShuYu Capsule intervention could improve hyperalgesia in model animals by activating PAG neurons (Figure 2).

anxiety, and pain, and is the main target of fluoxetine, a first-line treatment for PMDD. Thus, the author’s hypothesis is that ShuYu Capsule might improve depression and pain sensitivity in PMDD rats by regulating the 5-HT system in the PAG. To test this hypothesis, researchers used microdialysis to monitor extracellular 5-HT and its metabolites in the PAG area in real-time for each group of animals. They found that ShuYu Capsule intervention had little effect on 5-HT concentration, excluding the involvement of the 5-HT system in the efficacy of ShuYu Capsule (Figure 3).

Next, researchers measured plasma ALLO levels in different stages of the estrous cycle for each group of rats and used a slow-release pump to simulate rapid ALLO withdrawal. They found that the rapid decline of peripheral ALLO was a possible cause of PMDD symptoms, and ShuYu Capsule intervention could delay the rapid decline of ALLO and improve symptoms (Figure 4).

Since ALLO is an allosteric modulator of the GABAA receptor, researchers measured the expression levels of GABAA receptor subunits in the PAG area of animals in the late estrous stage (when PMDD symptoms appear). They found that ShuYu Capsule intervention could significantly correct the upregulation of the GABAA receptor δ subunit in model animals. Finally, to verify the above mechanism, researchers injected GABAA receptor agonists and antagonists into the PAG area of each group of animals, finding that ShuYu Capsule significantly improved hyperalgesia behavior induced by the agonist in PMDD model rats (Figure 5).

Research Method Highlights

In summary, using Forced swimming test to screen PMDD models, this study confirmed that ShuYu Capsule can improve estrous cycle-dependent depressive-like and hyperalgesia behaviors in model animals. After excluding the involvement of the 5-HT system, researchers found that the effect of TCM intervention is related to the upregulation of GABAA receptor δ subunit in the PAG area caused by the rapid decline of ALLO. Combining slow-release pump simulation and receptor agonist/antagonist experiment results, researchers systematically elucidated for the first time the possible central mechanism of ShuYu Capsule against PMDD: offsetting the rapid physiological decline of ALLO in the late estrous stage, thereby affecting the brain’s response to ALLO withdrawal and subsequent behavioral responses to external stimuli (Figure 6).

This study not only expands the role of PAG area sensitivity in the pathogenesis of PMDD but also reveals the central mechanism of ShuYu Capsule in treating PMDD and its correlation with tetrahydroprogesterone and γ-aminobutyric acid receptors in the PAG area. This provides strong evidence for the treatment of emotional diseases with TCM, further promoting research and interpretation of the modern mechanisms of TCM in treating PMDD. Additionally, this study compares ShuYu Capsule with the first-line Western medicine fluoxetine, conducting research on the characteristics and mechanisms of the two drugs against PMDD, providing scientific evidence from TCM to address challenges and hotspots of international medical concern. More importantly, the TMC syndrome of liver qi stagnation in PMDD will enter the research of clinical subtypes and efficacy relationships of international concern.

In this study, researchers used stereotaxic instruments, electron microscopes, and surgical kits produced by RWD, providing support for the smooth conduct of the experiment. RWD has been deeply involved in the life sciences research field for 22 years, committed to providing reliable solutions and services to customers. To date, RWD products and services cover more than 100 countries and regions worldwide, with clients including over 2300 hospitals, 1000 research institutes, and 6000 higher education institutions, assisting global researchers in publishing over 14,500 SCI articles and gaining widespread industry recognition.