Study On The Clinical Efficacy And Mechanism Of Qinggan Jieyu Optimized Decoction In The Treatment Of Premenstrual Syndrom

Premenstrual syndrome is an endocrine disorder disease with high prevalence and complex symptoms.It may affect patients’ daily life and social function,reduce their life quality,and even increase the risk of suicide.Its specific pathogenesis is not clear,and the diagnostic criteria are subjective.It only depends on the patients’ self-reported mental and physical symptoms and the decline of social ability.There is no reliable potential objective biological markers or imaging changes to assist the diagnosis.Although there are many treatment methods,each has its own limitations.In recent years,traditional Chinese medicine has achieved remarkable.results in improving PMS symptoms.Among them,Optimizing Qingganjieyu Decoction has a significant effect on PMS liver depression and heat syndrome,but its effect is still lack of evidence-based medical evidence,and its specific mechanism is not clear.Therefore,first of all,our study discussed the clinical effect of Optimizing Qingg anjieyu Decoction on PMS patients with liver depression and heat syndrome;Secondly,our study discussed the potential serum biological markers of PMS and potential mechanism of Optimizing Qingganjieyu Decoction on PMS liver depression and heat syndrome based on metabolomics;Finally,our study further discussed the mechanism of Optimizing Qingganjieyu Decoction on PMS,based on the cAMP-PKA-CREB pathway mediated by 5-HT1AR.Objectives:1 To review relevant literatures at home and abroad on premenstrual syndrome,collate and summarize the progress of premenstrual syndrome,and conduct a Meta-analysis on the efficacy of TCM for the treatment of PMS to provide evidence-based med ical evidence for clinical use.2 To observe the effects of Optimizing Qingganjieyu Decoction on the clinical symptoms,TCM syndrome,luteal phase sex hormone and 5-HT in patients with PMS liver depression and heat syndrome.Thus to investigate the clinical effects of Optimizing Qingganjieyu Decoction on patients with PMS liver depression and heat syndrome.3 To explore the potential serum biological markers of PMS and potential mechanism of Optimizing Qingganjieyu Decoction on PMS liver depression and heat syndrome based on metabolomics.4 To further explore the mechanism of Optimizing Qingganjieyu Decoction on PMS,based on the cAMP-PKA-CREB pathway mediated by 5-HT1AR.Methods:1 Clinical efficacy observationA total of 31 patients with PMS liver depression and heat syndrome who met the criteria were collected by self-contrast test.The patients were required to complete the basal body temperature chart to observe ovulation.The patients were treated with Optimizing Qingganjieyu Decoction during luteal phase for 3 consecutive treatment courses.The general condition,safety observation indicators,DRSP score,liver depression and heat syndrome evaluation score,HAMA score,E2,P,PRL and 5-HT in the late luteal phase were observed and compared before and after treatment.2 MetabonomicsAccording to the case selection criteria,30 patients with PMS liver depression and heat syndrome,30 patients with PMS non liver depression and heat syndrome,and healthy people were detected.Subjects were instructed to complete the basal body tern perature chart to observe ovulation,and serums were remained in the late luteal phas e.Potential serum biomarkers for PMS,liver depression and heat syndrome,and PMS liver depression and heat syndrome were analyzed by conducting different comparison s;30 patients with PMS liver depression and heat syndrome were treated by Optimizing Qingganjieyu Decoction,and the potential mechanism of Optimizing Qingganjieyu Decoction on PMS liver depression and heat syndrome was analyzed by comparison between before and after treatment groups.3 Experimental researchProgesterone withdrawal model was used to build PMS rat model,and the rats were divided into blank group,model group,high-dose,medium-dose and low-dose of Optimizing Qingganjieyu Decoction groups.After drug intervention and drug sampling,the open field test was performed,serum sex hormone were measured by ELISA,mRNA and protein expression of 5-HT1AR,PKA,CREB,as well as p-CREB were measured by Western blot and Real-Time PCR.Results:1 Clinical efficacy observation of Optimizing Qingganjieyu Decoction on PMS liver depression and heat syndrome1.1 DRSP score:After the treatment with Optimizing Qingganjieyu Decoction,the total score of luteal phase,follicular phase,and the difference between the total score of luteal and follicular phase of DRSP decreased significantly(P<0.05);The score of the three dimensions of mood change,symptom,and affect level all decreased significantly(P<0.01).1.2 Liver depression and heat syndrome evaluation score:After the treatment with Optimizing Qingganjieyu Decoction,liver depression and heat syndrome evaluation score decreased significantly(P<0.01).1.3 HAMA score:After the treatment with Optimizing Qingganjieyu Decoction,HAMA score decreased significantly(P<0.01).1.4 E2,P and PRL in the late luteal phase:After the treatment with Optimizing Qingganjieyu Decoction,PRL in the late luteal phase decreased significantly(P<0.05);E2 and P also decreased,but the differences were not statistically significant(P>0.05).1.5 5-HT in the late luteal phase:After the treatment with Optimizing Qingganjie yu Decoction,5-HT in the late luteal phase increased significantly(P<0.05).2 Metabonomics analysis on the potential serum biomarkers of PMS and potential mechanism of Optimizing Qingganjieyu Decoction on PMS liver depression and heat syndrome.2.1 Metabolic pathways of PMS:Phenylalanine metabolism,nicotinate and nicotin amide metabolism,histidine metabolism,tryptophan metabolism,glycerophospholipid metabolism.2.2 Metabolic pathways of PMS liver depression and heat syndrome:Phenylalanine metabolism,nicotinate and nicotinamide metabolism,histidine metabolism,glyceropho spholipid metabolism.2.3 Metabolic pathways of liver depression and heat syndrome in PMS:Phenylala nine metabolism,phenylalanine,tyrosine and tryptophan biosynthesis,histidine metabolism,nicotinate and nicotinamide metabolism,arginine and proline metabolism,glycerop hospholipid metabolism,terpenoid backbone biosynthesis,alanine,aspartate and glutam ate metabolism,cysteine and methionine metabolism.2.4 Potential mechanism of Optimizing Qingganjieyu Decoction:Linoleic acid met abolism,nicotinate and nicotinamide metabolism,sphingolipid metabolism,tryptophan metabolism,glycerophospholipid metabolism,arginine and proline metabolism,alanine,aspartate and glutamate metabolism.3 Experimental research of the potential mechanism of Optimizing Qingganjieyu Decoction on PMS rats model3.1 Effects on behavior:After 21 d of modeling,PMS rats showed behavioral changes to various degrees as well as reduced body mass(P<0.05).The open field test showed a decrease in total distance,less central distance,less time and decrease in the number of central entries(P<0.05),while the change of vertical movement was not statistically significant(P>0.05).Different degrees of symptom reduction were seen in high-dose group and medium-dose group(P<0.05).The open field test showed a increase in total distance,more central distance,much time and increase in the number of central entries(P<0.05),while the change of vertical movement was not statistically significant(P>0.05).3.2 Effects on sex hormones:After the treatment with Optimizing Qingganjieyu Decoction,serum P of PMS rats increased significantly(P<0.05),the ratio of E2/P decreased significantly(P<0.05),the change of serum PRL,E2 were not statistically significant(P>0.05).3.3 Effects on the cAMP-PKA-CREB pathway mediated by 5-HT1AR:The protein and mRNA expression of 5-HT1AR in the hippocampal of model group increased significantly compared with blank group(P<0.01),high-dose,medium-dose and lowdose of Optimizing Qingganjieyu Decoction groups decreased significantly compared with model group(P<0.05).The protein expression of PKA and p-CREB and the phosphorylation level of CREB of model group decreased significantly compared with blank group(P<0.01),high-dose of Optimizing Qingganjieyu Decoction group increased significantly compared with model group(P<0.05).Conclusions:1 According to literature review,PMS is an endocrine disordered disease with extremely high prevalence and complex and diverse symptoms,and TCM has accumulated considerable experience in the treatment of PMS based on syndrome differentiation.A Meta-analysis found that TCM treatment based on syndrome differentiation was superior to hormonal agents and nutritional supplements and non-inferior to antidepressants in terms of clinical efficiency.In terms of hormone levels in the late luteal phase,TCM was superior to the improvement of P and PRL in the positive control group except hormonal agents,and was non-inferior to the improvement of E2 in positive control group.2 Clinical efficacy observation showed that Optimizing Qingganjieyu Decoction could significantly improve both psychosomatic symptoms and liver depression and heat syndromes,and the effects were significant in three dimensions of mood change,symptom,and affect level.Regulating serum PRL and 5-HT in the late luteal phase might be its potential mechanism.3 Metabonomics analysis showed that multiple metabolic pathways were involved in the findings.Taken together with the current studies on the pathogenesis of PMS,it is believed that the tryptophan metabolism pathway and the glutamate metabolism pathway are two most important pathways,and three neurotransmitters were involved:5HT,glutamate and GABA.4 The experimental research showed that high-dose,medium-dose of Optimizing Qingganjieyu Decoction could improve the emotional symptoms such as anxiety,depression and irritability as well as related behavioral changes in PMS rats,and the effects were more prominent in the high dosage group.It may regulate progesterone level,and downregulating 5-HT1AR expression,promoting cAMP-PKA-CREB signaling pathway,and may act on the central nervous system through factors such as BDNF,and ultimately improving PMS.