Synthesis of Sedative-hypnotic Zopiclone Analogues

Eight new cyclopyrrolone compounds were synthesized according to the structure activity relationship and action mechanism of Zopiclone, a cyclopyrrolone hypnotic. Their preliminary pharmacodynamics are under investigation.

Effect of Suan Zao Ren (Semen Ziziphi Spinosae) Extract on the TXNIP/NLRP3 Pathway in Insomniac Rats

Objectives This study aimed to investigate the therapeutic effects of Suan Zao Ren(Semen Ziziphi Spinosae,SZS)extract on insomnia induced by p-chlorophenylalanine(PCPA)in rats and its influence on the thioredoxin-interacting protein(TXNIP)/nucleotide-binding domain Leucine-rich repeat and pyrin domain-containing receptor 3(NLRP3)inflammasome pathway,and to preliminarily explore themechanism by which SZS extract improves insomnia.Methods Fifty male Sprague–Dawley(SD)rats were used,with 8 rats in the blank group and 42 rats in the modeling group.The modeling group was induced by intraperitoneal injection of PCPA at a dose of 500mg·kg^(-1) for six consecutive days,with daily cage exchange.After 6 days,40 successfully modeled rats were randomly divided into five groups:themodel group(equal volume of distilled water),the positive group(0.75 mg·kg^(-1)),and low-,medium-,and high-dose SZS extract groups(1.5,3,and 6 g·kg^(-1),respectively),with 8 rats in each group.Treatments were administered for seven consecutive days.Enzyme-linked immunosorbent assay was used to measure levels of 5-hydroxytryptamine(5-HT)and gamma-aminobutyric acid(GABA)in the rat cerebral cortex.The thiobarbituric acid(TBA)method was used to determine malondialdehyde(MDA)levels,and the hydroxylamine method was used to determine superoxide dismutase(SOD)levels.The 2,2′-azino-bis(3-ethylbenzthiazoline-6-sulfonic acid)method was used to measure total antioxidant capacity(TAOC)in the cerebral cortex.Pathological changes in the cerebral cortex were observed,and Western blot was used to detect the protein expressions of TXNIP,NLRP3,apoptosis-associated speck-like protein containing a Caspase activation and recruitment domain(CARD),and cysteine–aspartate-specific protease 1(Caspase-1)in the cerebral cortex.Results Compared with the blank group,the model group showed a significantly prolonged sleep latency(p<0.001)and a significantly shortened sleep duration(p<0.001).There were no changes in serum MDA and SOD levels.MDA levels in the cerebral cortex were significantly increased(p<0.001),while SOD and TAOC levels were significantly decreased(p<0.001).The 5-HT level was increased(p<0.05),and the GABA level was significantly decreased(p<0.001).SZS extract improved these conditions to varying degrees.Light microscopy showed no significant changes in cortical neurons but transmission electron microscopy revealed intact mitochondrial structures in the blank group,while the model group showed swollen and unclear mitochondria with reduced organelles.After 7 days of treatment,these conditions improved in the SZS extract groups.Compared with the blank group,the expressions of the four proteins in the model group were increased,and the expressions of these proteins were decreased in the SZS extract groups compared with the model group.Conclusion SZS extract may exert an antioxidant effect to treat insomnia by downregulating the expression of TXNIP/NLRP3 proteins and regulating oxidative stress levels in the cerebral cortex.

Advances in Researches on Chemical Composition and Functions of Hemerocallis Plants

The genus Hemerocallis is a kind of perennial herbaceous plants of Liliaceae and consists of about 15 species in the world,11 of which can be found in China. Some species of Hemerocallis are widely cultivated for medicinal,edible and ornamental application. Considerable progress had been made in researches on chemical composition and functions of Hemerocallis plants. Previous phytochemical studies on Hemerocallis plants have demonstrated the presence of flavonoids,anthraquinones,alkaloids,terpenoids,triterpenes and triterpenoid saponins,caffeoylquinic acid derivatives,naphthalene glycosides,steroid and steroidal saponins,phenylethanoid glycosides,and lignans. Functional activities of Hemerocallis plants are mainly manifested in sedative hypnotic,antidepressant,antioxidant,anti-tumor,hepatoprotective,antibacterial and insecticidal activities. Chemical composition of Hemerocallis plants is various,and structural type is rich,and has a variety of significant functional activities,so it is worth further study.

Sedative and Hypnotic Effects and Transcriptome Analysis of Polygala tenuifolia in Aged Insomnia Rats

Objective:To study the sedative and hypnotic effects and underlying mechanisms of Polygala tenuifolia(PT)on treating aged insomnia rats.Methods:Sixty Sprague-Dawley male rats were divided into 6 groups by a random number table,including control group,model group,diazepam group(0.92 mg/kg),as well as PT low-,medium-and high-dose groups(0.0875,0.175,0.35 g/kg,respectively),10 rats in each group.Aged insomnia rat model was established with subcutaneous injection of D-galactose for 42 days and then intraperitoneal injection of para-chlorophenylalanine for 3 days.PT and diazepam were respectively given to aged insomnia rats by intragastric administration for 7 days after model establishment.Then the rats were investigated by body weight,Morris water maze test,pentobarbital test,enzyme-linked immunosorbent assay,and transcriptome sequencing.Results:Compared with the model group,PT increased the body weight,improved memory ability,and prolonged pentobarbital-induced sleep time of aged insomnia rats(P<0.01 or P<0.05).The medium dose of PT also increased the neurotransmitter levels of 5-hydroxytryptamine(5-HT)and gamma-aminobutyric acid(GABA),and decreased the level of Glu in the hippocampus of aged insomnia rats(P<0.05 or P<0.01).Twenty-four differentially expressed genes(DEGs)were overlapped among model group,medium-dose PT group,and diazepam group in transcriptome analysis.Fuom and Pcp2 were down-regulated by the treatment of medium-dose PT(P<0.01 or P<0.05).The metabolic pathways of PT were relatively less than diazepam(91 vs.104).Conclusions:The sedative and hypnotic effects of PT in aged insomnia rats might be related to neuro,metabolism pathways,especially through GABAergic signaling pathway.It provided more effective herb choice for the treatment of senile insomnia.

Sedative–hypnotic effect of YZG-330 and its effect on chloride influx in mouse brain cortical cells

This study was to examine the sedative–hypnotic effect of YZG-330 and its influence on Cl−influx in mouse cortical cells.In a sleep time-prolongation test in which mice were administered a threshold dosage of sodium pentobarbital(ip),YZG-330(0.125,0.5 and 2 mg/kg,po)prolonged the sleep time by 25%(P40.05),64%(Po0.01)and 506%(Po0.001),respectively.Thereafter,treatment with YZG-330 permitted mice that had woken up after the threshold dose of sodium pentobarbital(ip)to fall asleep again.A Cl−-sensitive fluorescent probe,N-(ethoxycarbonylmethyl)-methoxyquinolinium bromide(MQAE),was used to determine the effect of YZG-330 on Cl−influx.YZG-330(0.3,0.6 and 1.5 mM)increased Cl−influx in mouse cortical cells in a concentration-dependent manner.These data suggest that YZG-330 has a hypnotic effect in mice,and the effect may be related to an increase in Cl−influx in cortical cells.

Research on Hypnotic and Anticonvulsant Activities of Total Alkaloids in Leaves of Eucommia ulmoides

Objective To study the hypnotic and anticonvulsant activities of the leaves of Eucommia ulmoides（LEU）,the total alkaloids were extracted from LEU using water-acid method.Methods Mice were divided into five groups,including groups contained total alkaloids in three different doses,negative and positive control groups.Direct hypnotic experiment in mice,pentobarbital sodium synergistic experiment,and anticonvulsant experiment were used.The numbers of spontaneous activities,sleep rate,sleep latency,sleep time,convulsion rate,and convulsion latency of the mice were recorded and analyzed.Results The total alkaloids from LEU could increase the sleep rate,significantly lengthen the sleep time,and shorten the sleep latency of mice.Even the low dose of total alkaloids（0.33 g/kg）showed significantly different activities with negative control group（physiological saline）with the synergistic effect of the superthreshold dose of pentobarbital sodium.Furthermore,the total alkaloids efficiently inhibited the convulsion caused by nikethamide.Conclusion The total alkaloids from LEU have the excellent sedative,hypnotic,and anticonvulsant activities in mice,with high safety and little drug side effects.Therefore,they have the protential development prospects in sedative-hypnotic drugs.