Study On The Antidepressant Effect And Pharmacokinetics Of Curculigoside C

Curculigoside C is a natural phenolic glycoside isolated from Curculigo orchioides Gaertn.In this thesis,the evaluation of anti-depressant activity,mechanism discussion and pharmacokinetics of Curculigoside C were studied.And the following innovative achievements have been achieved:1.Antidepressant activity of Curculigoside C was screened for the first timePreventive intragastric administration of CC?20.0,40.0,80.0 mg/kg?for 7 days before establishing LPS-induced depression model in mice.The behaviors of LPS-induced depression mice were evaluated by forced swimming and tail suspension experiments.The serum levels of interleukin-6?IL-6?,tumor necrosis factor-??TNF-??and superoxide dismutase?SOD?were measured.The data showed that CC can increase the body weight of depressed mice,increase their preference rate for sugar and water,shorten the immobility time in forced swimming and tail suspension experiments,increase the levels of SOD in serum,and decrease the expressions of IL-6 and TNF-? in serum.The results indicated that CC had a good antidepressant effect.2.Metabonomic study of CC with antidepressant was carried out for the first timeThe differential metabolites in serum and hippocampus of mice were identified by UPLC-MS/MS,and a multivariate covariate analysis model was constructed to clarify all intra-group differences.A total of four OPLS-DA models had been established,all showing reliable prediction results.Based on a robust and reliable discriminant pattern,25 differentmetabolites and 8 perturbed metabolic pathways were identified.The results showed that CC can could play an antidepressant role by regulating linoleic acid metabolism,steroid hormone biosynthesis,arachidonic acid metabolism,sphingolipid metabolism,retinol metabolism,glutathione metabolism,glycerophospholipid metabolism and tryptophan metabolism pathway.3.Pharmacokinetics of CC by intragastric administration in rats was studied for the first time?1?The absorption of CC by intragastric administration was studiedThe UPLC-MS/MS method for the determination of CC in plasma was established.The absorption of CC in vivo after intragastric administration?15.0,30.0,60.0 mg/kg?and intravenous injection?2.0 mg/kg?were determined,and the pharmaco-kinetic parameters were calculated.Methodological validation indicated that the quantitative method satisfied the analytical requirements.The pharmacokinetic parameters such as t_1/2,AUC,CL and Vz were obtained.The results showed that CC was absorbed rapidly by oral administration with high elimination rate and low absolute bioavailability.After gastrointestinal administration,CC was widely distributed outside blood vessels.?2?The tissue distribution of CC in rats was completedA UPLC-MS/MS analysis method was established to determine the CC contents in 13 tissues,such as heart,liver,spleen,lung,kidney,large intestine,small intestine,brain,stomach,fat,muscle,testis and uterus,at different time points.The results showed that the drug concentrations in tissues were significantly higher than that in plasma,which furtherly confirmed the wide distribution of CC in vivo.The contents of CC in all tissues decreased with the prolongation of time at 7 h after administration,which indicated that CC was not easy to accumulate in vivo.On the other hand,the content of CC was lower in testis,but higher in uterus,whichshowed the difference between male and female rat.?3?The study on excretion of CC by intragastric administration in rats was completed.CC?30.0 mg/kg?was administered intragastrically to rats,and and the excretion of CC in bile,urine and feces was determined.The results showed that the amount of CC excreted by bile was less,the cumulative excretion at 48 h was 2.03%,and the maximum excretion was reached at6¹0 h;The most CC were excreted by feces,the cumulative excretion was 35.4%,and the maximum excretion was reached at 2⁶ h;The CC excretion in urinary was11.75% and reached the maximum at 12 h²4 h.The total cumulative excretion of the prototype drug CC was less than 50%,which furtherly confirmed the biotransformation of CC in rats and the extensive metabolism.?4?The metabolic study of CC was completed.Rats were given 60.0 mg/kg CC by gavage,and UPLC-QTOF-MS was used to measure the metabolism of CC in bile,urine and feces.Combined with UNIFI metabolite analysis platform,12 metabolites were identified,including 7 Phase I metabolites and 5 Phase II metabolites.Phase I metabolic reactions of CC included dehydration,hydrolysis,deglycosylation,desaturation,and phase II metabolic reactions included sulfation,glucosylation,cysteine conjugation,formylation,and demethylation.The results showed that CC was mainly metabolized in liver,and all metabolites could be found in bile,urine and feces.It was concluded that the oral bioavailability of CC might be related to liver microsomes.In summary,this study showed that CC had the good antidepressant effect by regulating multiple signaling pathways such as linoleic acid metabolism,arachidonic acid metabolism and sphingolipid metabolism.After intragastric administration,CChas the characteristics of rapid absorption,high elimination rate,low bioavailability,extensive distribution and metabolism,and difficulty in accumulation.This paper provides theoretical basis and data supports for the further development and utilization of CC,and also provides new ideas and methods for PK-PD research of similar substances.