| Depression is a kind of mood disorder,which is characterized by a significant and lasting depression as the basic clinical manifestations and associated with a corresponding change in thinking and behavior.And it has a tendency to relapse.Depression can be classified into the category of "deficiency disease" in TCM syndrome differentiation.Traditional Chinese medicine emphasizes "Yang leading dynamic".Yang leading consciousness,emotion,thinking and so on.Furthermore,kidney yang plays an important role in yang of body,and is closely associated with the pathogenesis of depression.The pathogenesis of depression with kidney yang deficiency of is still not completely clear.It is known that a large amount of exogenous glucocorticoid can induce depression with kidney yang deficiency and lead to neuroendocrine disorders,physiological,biochemical and related gene expression changes.Therefore,the kidney yang deficiency depression may lead to the change of CYP450 enzyme activity in the liver,which may cause the therapeutic difference of antidepressant drugs.We investigate the changes of CYP450 activity in kidney yang deficiency depression rats by establishing the kidney yang deficiency depression model,which is induced by injecting hydrocortisone sodium succinate for 21 days.And we adopt the therapy of warming kidney yang to give the rats Sini decoction and then observe the regulation of the change of the activity of losform enzyme,and it may provide reference for clinical medication.A high performance liquid chromatography(HPLC)method was developed for evaluating the quality of Sini decoction granules and the influence of decocting on the contents changes of 6 main components.Results showed that different time of decocting have certain influence on the 6 components such as glycyrrhizin in Sini decoction.And the content of glycyrrhizin,Glycyrrhizic acid,benzoylhypaconine,6-gingero and 6-shogaol are higher,besides the content of mesaconine is lower when it was decocted for 60 min.The LC-MS/MS method was adopted to analyze the content of 5-HT,NE and DA,and to observed the changes of the contents of 5-HT,NE and DA in plasma of depression rats with kidney yang deficiency and the intervention effect of Sini decoction.64 male SD rats were divided into 8 groups:first blank group,first model group,self-healing group,second blank group,second model group,fluoxetine intervention group,the middle dose group of Sini decoction intervention,and the high dose group of Sini decoction intervention.The Blank group were given saline volume,other groups were given hydrocortisone sodium succinate every day,after the modeling,behavioral testings were conducted and biological samples were collected.From the 22ed day,the corresponding experimental drugs were given for 14 days.After that,biological samples were collected again.The results in behavioral test showed that model rats showed obvious symptoms of depression and kidney yang deficiency in weight,open field test,force swimming test and sugar preference test.Results in biochemical test showed that some organ index of model rats decreased significantly,such as kidney,thymus,testis and epididymis index decreased significantly(P<0.05),spleen index significantly decreased(P<0.01),monoamine neurotransmitter disordered,such as the content of 5-HT and NE increased significantly(P<0.05,P<0.01).The contents of 5-HT,NE,DA in the plasma of model rats decreased after 14 days,and the contents of 5-HT and DA were significantly lower than those of the blank group.After the drug treatment,the plasma in the disorder of monoamine neurotransmitter levels were corrected in varying degrees.Compared with model rats without drug intervention,the results showed that fluoxetine could increase or significantly increase 5-HT,NE content of plasma in a rat model.The middle dose Sini decoction could significantly or extremely significantly increased the content of 5-HT,NE and DA in plasma,while the high dose of Sini decoction could significantly increased the content of 5-HT and DA,but significantly decreased the content of NE in plasma.The results showed that the depression model with kidney yang deficiency induced by hydrocortisone was successful,and the Sini decoction had a certain effect on the depression model with kidney yang deficiency and showed a certain antidepressant effect.’Cocktail’ method was used to study the activity of six CYP450 enzymes in depression rats with kidney yang deficiency,and the regulation effect of Sini decoction was studied.Theophylline,chlorzoxazone,tolbutamide,dextromethorphan,omeprazole and midazolam were chosen as probe substrates of CYP1A2,CYP2E1,CYP2C6 respectively,CYP2D2,CYP2D1 and CYP3A2.7 groups of male SD rats,including first blank group,first model group,second blank group,second model group,fluoxetine intervention group,middle dose intervention group of Sini decoction and high dose intervention group of Sini decoction.After 21 days modeling,6 probe drugs were given to the first blank rats and the first model rats.Blood samples were collected from orbit according to the pre design point of time.Plasma concentration of six kinds of probe drugs were determinated by LC-MS/MS and computed pharmacokinetic parameters.The results showed that compared with the first blank group,the metabolism of theophylline,chlorzoxazone and tolbutamide in the first model group rats was accelerated significantly(P<0.01),the metabolism of dextromethorphan,omeprazole,midazolam had no significant difference.The results showed that CYP2E1,CYP1A2 and CYP2C9 were induced in depression rats with kidney yang deficiency.From 22ed day,corresponding experimental drugs were given to intervention for 14 days.After that theophylline,chlorzoxazone and tolbutamide were given.LC-MS/MS was used to determinate plasma concentration of three kinds probe.Substrates and pharmacokinetic parameters were calculated and compared between each groups.The results show that compared with the model group,the enzyme activity of CYP1A2,CYP2E1 and CYP2C6 gradually return to normal in each treatment group,which indicated that Sini decoction and fluoxetine have a certain regulating effect on enzyme activity of CYP1A2,CYP2E1 and CYP2C6 in depression rats with kidney yang deficiency.A LC-MS/MS method was established to determinate the content of taurine(Tau),glutamic acid(Glu),glycine(Gly),kynerenine(Kyn),kynurenic acid(KA)and alanine(Ala)in rat plasma,and observed the changes of Tau,Glu,Gly,Kyn,KA and Ala in the plasma of depression rats with kidney yang deficiency,and the effect of Sini decoction on it.48 male SD rats were divided into second control group,second model group,fluoxetine group,medium dose of Sini decoction group,high dose of Sini decoction group.The model of kidney yang deficiency was established by hydrocortisone.After the model was completed,the corresponding experimental drugs were given for 14 days,and plasma was collected after the treatment.The results showed that the content of Ala,Glu,Gly and the ratio of Kyn/KA in the plasma of model rats were significantly lower than that of the blank group.Compared with the 2ed model group,the levels of Ala,Glu,Gly in the plasma of the self-healing group were decreased and the Kyn/KA ratio was significantly increased.After 14 days of antidepressant western medicine fluoxetine or middle and high dose of Sini decoction intervention treatment,the medium and high dose of Sini decoction can increase or signigicantly increase the content of Ala,Glu and Gly in the plasma.The high dose of Sini decoction can significantly increase the ratio of Kyn/KA in plasma.Meanwhile high dose Sini decoction can significantly increase the content of Tau in plasma.Fluoxetine can increase of significantly increase the content of Ala,Glu and Gly in plasma,but decrease the value of Kyn/KA.The results showed that the levels of Glu,Gly,Ala,Kyn and KA in the plasma of kidney yang deficiency depression rats were abnormal,and antidepressant western medicine fluoxetine and traditional Chinese medicine prescription Sini Decoction can effectively regulate the content of five amino acid neurotransmitters,and return to normal levels.It is speculated that the antidepressant mechanism of fluoxetine and Sini decoction may involve the regulation of metabolism of amino acid neurotransmitters.The expression of brain-derived neurotrophic factor(BDNF)in hippocampus and prefrontal cortex of depression rats with kidney yang deficiency was investigated by Western blot,and the effect of Sini decoction on BDNF was observed.40 male SD rats were divided into 5 groups,including blank group,model group,fluoxetine group,middle and high dose group of Sini decoction.At the beginning of the twenty-second day,the corresponding experimental drugs were given for 14 days.Hippocampus and prefrontal cortex were collected after treatment.The results showed that compared with the blank group,the expression of BDNF in hippocampus and prefrontal cortex of rat model were significantly decreased(P<0.05),antidepressant fluoxetine and medium and high dose of Sini decoction can improve the expression of BDNF in hippocampus and prefrontal cortex in different degrees.It is suggested that fluoxetine and Sini decoction may play an important role in the protection of the nervous system by improving the expression of BDNF in depression. |
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