| ObjectivesThe prevalence of insomnia is as high as 22%,which is detrimental to the physical and mental health of patients.Sleeping pills can prolong sleep,but there are daytime dysfunctions such as hangover and cognitive impairment.Recent studies suggest that mitochondrial energy metabolism has a significant perihelion rhythm,and its dysfunction is closely related to sleep rhythm and related energy metabolism.In Chinese medicine,"day essence and night rest" is considered to be a good sleep rhythm for the body.When the body loses sleep,it will be accompanied by sleep rhythm disturbances such as difficulty falling asleep,early awakening and daytime dysfunction.The group found that the prescription of Sinisuanzaoren Decoction,which is based on the"liver-based treatment of insomnia",has better efficacy than benzodiazepine sleeping pills such as eszopiclone in improving daytime function.In summary,combining the understanding of "blood returns to the liver when lying down" in the Huangdi’s Canon and Qi Circulation in the theory of Chinese medicine,it is proposed that"the intervention of insomnia based on the regulation of the body’s sleep rhythm by the liver’s main drainage is a characteristic advantage of Chinese medicine to achieve the goal of’diurnal essence and night shutdown’".The modern biological basis is related to the circadian rhythm of the mitochondrial energy regulation mechanism.The present study intends to investigate the biological basis of insomnia and the regulation of sleep rhythm disorders by Sinisuanzaoren Decoction with estazolam as the control drug,taking mitochondrial cycle changes as the core,combining clinical trials and basic experimental studies,and using core body temperature,infrared,CPC cardiopulmonary coupling,gene protein detection and other technologies to pro vide support for Sinisuanzaoren Decoction insomnia.MethodsLiterature study:randomised controlled trials of eszopiclone compared to placebo or blank group for the treatment of insomnia were included by computer search of Cochrane,Pubmed,and China Knowledge Network databases with a search time frame of build to 30 April 2021,and the included studies were assessed using Risk of bias 2,a risk of bias assessment tool recommended by Cochrane Methodological quality assessment was performed,followed by Meta-analysis using Revman 5.4 software,Stata,and descriptive analysis for studies that could not be combined.The primary outcome indicators were daytime function and adverse effects;secondary outcome indicators:sleep latency,sleep efficiency and other sleep factors.Moreover,the use status of eszopiclone tablets among Class Ⅱ psychotropic drugs used in medical institutions nationwide from 2011 to 2021 was retrospectively analyzed by searching the China Knowledge Network,and indicators such as frequency of drug use(DDDs),prescription percentage,and medical institution region were summarized and analyzed.Clinical trial:Through an uncontrolled cross-sectional clinical trial design,insomnia patients were recruited at Beijing University of Chinese Medicine Third Affiliated Hospital,Fangshan Hospital,Beijing University of Chinese Medicine,and Guoyitang Clinic,Beijing University of Chinese Medicine,and the daytime function and nighttime sleep status of insomnia patients were assessed based on the CPC heart-lung coupling technique,PSQI questionnaire and FS-14 scale.Descriptive statistics,correlation analysis and regression analysis were conducted to understand the status of daytime functioning and possible influencing factors of insomnia patients.A case-series clinical trial was designed to control the daytime functioning of patients with insomnia before and after the intervention(0,2 and 4 weeks)and to follow up at 8 weeks.The data were analysed using SPSS 20.0 with independent samples t-test and ANOVA to compare and monitor the improvement in daytime functioning of insomnia patients.Animal experiments:The insomnia rat model was replicated by intraperitoneal injection of PCPA,and the insomnia model was evaluated by the flip-flop test.Thereafter,eszopiclone positive control drug and Sinisuanzaoren Decoction were administered for intervention.The correlation between the sleep condition and energy metabolic rhythm of rats was evaluated by core body temperature and infrared monitoring techniques;the expression of hypothalamic cycle genes Per1,Per2,Bmal1 and whole brain mitochondrial kinetic proteins(Mfn1,Mfn2,Opa1,Drp1,Fis1)were investigated by protein blotting expression method,real-time fluorescence quantitative PCR and luciferase method.The effects of eszopiclone and Sini-Suanzaoren Decoction on prefrontal mitochondrial kinetics and serum LDH,CK and BUN were also investigated by combining with automatic biochemical analyzer.ResultsStudies in the literature(1)Meta-analysis showed that compared to placebo,eszopiclone had an impairing effect on daytime function in insomnia patients with reduced swallowing function and a higher incidence of adverse reactions,but compared to the blank group,eszopiclone was effective in reducing next-day blood pressure,both systolic and diastolic,in elderly patients with sleep disorders,with a beneficial effect on the disease.Eszopiclone had comparable therapeutic effects on sleep duration,number of awakenings,sleep depth,and sleep quality,but data on nocturnal sleep conditions could not be subjected to Meta analysis due to the relative age of the included studies and the lack of raw data.(2)The current use of eszopiclone in China remains high,with a large number of prescriptions and a high proportion of prescriptions,and remains at the top of the list over time migration in the last decade.The gradual use of third-generation sleeping pills in eastern China,such as Fujian,Zhejiang and Shandong,has led to a decline in the proportion of second-generation sleeping pills,such as eszopiclone,in use.Clinical trials(1)Research data suggest that approximately 90%of patients with insomnia have varying degrees of daytime functional impairment,but the assessment of daytime functioning in insomnia is particularly crude and sketchy.In this study,the fatigue in daytime functional impairment in insomnia was classified into mental fatigue and physical fatigue based on previous fatigue studies,and a joint assessment of daytime function was conducted with the aid of the FS-14 scale.The results of the correlation analysis of sleep staging obtained from the cardiopulmonary coupled sleep quality assessment system showed that the time to mature sleep(i.e.stable sleep period,corresponding to the high frequency part of CPC analysis)was closely related to daytime function.(2)Sinisuanzaoren Decoction intervention for insomnia for 4 weeks,with follow-up at 8 weeks:daytime function factor scores decreased at 2 weeks,were significantly different at 4 weeks,and increased slightly at 8 weeks,but remained statistically different from baseline and were not statistically different from 4 weeks.FS-14 and brain and physical fatigue factors both decreased significantly at 4 weeks,and were stable at 8 weeks.Animal experiments(1)There was a trend of low core body temperature during the day and high core body temperature during the night in the normal group,which was consistent with the pattern of previous studies,i.e.a decrease in core body temperature induced sleep and an increase in core body temperature induced wakefulness.After replicating the insomnia model,the core body temperature of the rats was significantly higher during the daytime(sleep period)and lower at night(awakening period)compared to the normal group.Moreover,the infrared thermography of the tail surface of rats showed that when the tail surface temperature of the normal group was higher than that of the model group,the core body temperature decreased and the rats fell asleep;when the tail surface temperature of the normal group was lower than that of the model group,the core body temperature increased and the rats woke up.(2)The expression of Perl,Per2 and Bmall in the normal group showed a trend of low day(sleeping period)and high night(waking period),while the expression of Perl,Per2 and Bmal1 mRNA in the insomnia model rats showed rhythm disorder,and the rhythm was restored after drug intervention.The normal group of rats showed a trend of high protein expression of Mfn1,Mfn2,Opal,Drpl and Fis1 during the day(sleep period)and low night(wake period),while the mitochondrial Mfn2,Opal,Drpl and Fis1 protein expression increased at 24:00 in the insomnia model rats,and the protein expression of Mfn2 and Fis1 was significantly higher than that of the normal group.At 24:00(waking period),the whole brain ATP content of the rats in the model group was lower than that of the normal group,while the content increased after the western drug intervention and was lower than that of the normal group,and the ATP content increased after the Chinese medicine intervention and was significantly higher than that of the normal group.The ATP content in the model group was lower and lower than that in the normal group.(3)The expression of Opal,Fis1,Mfn1,Mfn2 and Drpl tended to increase in the PCPA replicated insomnia rat model,and the content of Opal,Fis1,Mfn1,Mfn2 and Drp1 in the prefrontal lobe of rats was higher than that in the model group after the administration of western drug eszopiclone at 24:00,while the expression of the above indicators decreased and was lower than that in the model group after the administration of Chinese herbal medicine Sini-Suanzaoren Decoction.After replicating the rat model of PCPA,the contents of LDH,CK and BUN increased,and the contents were higher in the Western medicine intervention than in the model group,and lower in the Chinese medicine intervention than in the model group.Conclusion(1)Eszopiclone has shown improvement in nighttime sleep,but has higher adverse effects than placebo and impairs patients’ swallowing function.However,the use in China remains high and is regionally related.(2)The validity and feasibility of "treating insomnia from the liver" has been proven by the practice of TCM practitioners and many researchers over the ages.Patients with insomnia often have impaired daytime functions,and the effect of "daytime essence and nighttime darkness" can be achieved after the intervention of Sinisuanzaoren Decoction,which is based on the idea of "treating from the liver",probably due to the relationship between the liver and circadian rhythms and energy metabolism in modern Tibetan theory.This multi-targeted and multi-level treatment of insomnia through the "liver theory of insomnia" not only significantly improves the sleeping condition but also the daytime function of patients.(3)After the intervention of PCPA insomnia rats with Sinisuanzaoren Decoction,the circadian rhythm of mitochondrial dynamics may be restored by regulating the circadian expression of rhythm genes,so that the ATP supply can be brought back to balance and the daytime mental and physical fatigue of prefrontal and muscle tissues can be eliminated. |
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