Anti-Depressant Effect And Mechanism Of Stevia Extracts And Steviol Glycosides

Background Major depressive disorder（MDD）is one of the most common psychiatric diseases and it significantly undermines human health.It has the characteristics of high incidence and high mortality.Moreover,MDD is difficult to heal completely and has a risk of recurrent attack.It has been indicated by a large number of researches that MAPK^ERKpathway plays a critical role on the pathogenic process of MDD by participating in neuromodulation,and may be a potential target of antidepressant.Stevia is a common plant,and is easy and inexpensive to cultivate.Up to now,the chemical composition of Stevia has been studied intensively.Some studies have shown that the extracts of Stevia have broad effects,including anti-oxidative,controlling blood sugar level,lowering blood pressure,and promoting metabolism.In addition,it is used for the treatment of depression in folk of some countries.However,there is a lack of studies on the antidepressant effects of Steviaextracts and Steviol glycosides.Objective To investigate the anti-depressant effects of Stevia extracts and Steviol glycosides,and their effects on the expressions of D site albumin promoter binding protein（DBP）,gamma-aminobutyric acid（GABA）B receptor,2（Gabbr2）and Substance P（SP）which are closely related to MAPK^ERKpathway in brain and spleen tissues.Method First,mice were randomly divided into control group（C）,model group（M）,positive control group（P）,Stevia extracts low dose group（SEL）,Stevia extracts high dose group（SEH）,Steviol glycosides low dose group（SGL）,Steviol glycosides high dose group（SGH）.Second,MDD model mice were induced by injecting corticosterone into abdominal cavity for 21 consecutive days,during which open-field test,sucrose consumption and forced swimming testwere used to evaluate the depressive-behavior.Third,contents of Glutamic acid（Glu）,GABA,serotonin（5-HT）and dopamine（DA）in the brain were assessed using HPLC-fluorometric method.Finally,the expressions of DBP,Gabbr2 and SP protein were determined using Western Blot.Result1.The mobile scores and the number of rearing of mice in model group significantly decreased;consumption of sweet water was reduced;the swimming immobility timewas increased;the contents of 5-HT,DA,Glu,and GABA decreased;the content of Glu was elevated;significant difference was identified compared with the control group.These results indicated that the MDD model was established successfully.2.Observations on the groups given with Stevia extractsand Steviol glycosides,showed that the mobile scores,the number of rearing,and sweet water consumption greatly increased compared with the model group,the swimming immobility timewas decreased significantly,there was statistical difference compared with the model group.3.The contents of DA,5-HT and GABA significantly increased after given with low dose of Stevia extracts,high dose of Stevia extracts and low dose of Steviol glycosides,meanwhile the content of Glu decreased.It had significant statistical difference compared with the model group;high dose of Steviol glycosidescould not improve the neurotransmitter content,and there was no significant difference compared with the model group.4.Low dose of Stevia extractsand high dose of Stevia extractstreatment upregulated the levels of DBPand SP expressions in the MDD mice brains with a dose-dependent,there was significant difference compared with the model group,but they didn’t affect the expression of Gabbr2;After Stevia extracts administration,the expression of SP which in mice spleen tissue was elevated in a dose-dependent,but it didn’t affect on the expression of SP.5.After Steviol glycosidestreatment,only low dose of Steviol glycosides effectively improved the expressions of Gabbr2 and SP of brain tissues of MDD mice.High dose of Steviol glycosides had no effect on expressions of DBP、Gabbr2 and SP,or reduced them;Low dose of Steviol glycosidesincreased the expressions of DBP and SP in the spleen of MDD mice,it had significance difference compared with model group.While high dose of Steviol glycosides didn’t affect on the expressions of DBP and SP of spleen tissues of MDD mice.Conclusion1.Stevia extracts and Steviol glycosides can improve depressive symptoms via increase the mobile scores,the number of rearing,and sweet water consumption,and reducedthe swimming immobility time.Meanwhile reduce the content of Glu and increase the contents of DA,5-HT and GABA.2.Stevia extracts can effectively improve depressive symptoms,probably via regulating the expressions of DBP,Gabbr2 and SP,which are related to MAPK^ERKpathway.3.Steviaextracts has anti-depression effectwith a dose-dependent.But the anti-depression effectof high dose of Steviol glycosides is under low dose of Steviol glycosides in molecular level,even has no effect.One possible explanation is that Steviol glycosides is chemical substance with high purity,so it is likely to producecytotoxicity effect.The dose design of Steviol glycosides needs to be further investigated.Maybe reduce a dose in follow-up study.