A Preliminary Study On The Mechanism Of Antidepressant-Like Effects Of Schisandrae Chinensis Fructus

In the present study,the antidepressant-like effect of Schisandrae Chinensis Fructus(SCF)was investigated based on the techniques of behavioral pharmacology and endogenous biomarkers assay.With neural signaling pathways as the breakthrough point,combined with the network of neural pathways,the pharmacological mechanisms of antidepressant-like effect of SCF were explored from behavioral,neural biochemical and protein levels in a variety of animal models of depression.The main contents of this study are as follows:1.The depression model of chronic unpredictable mild stress(CUMS)in mice was established.The relationships between dose and time effect of SCF on antidepressant activity were evaluated by the sucrose preference test(SPT),locomotor activity test and forced swimming test(FST).The results showed that SCF(600 mg/kg)could significantly increase the sucrose consumption and short the immobility time of FST in CUMS-induced mice after 3 weeks of administration,which indicating that SCF has an antidepressant-like effect on the CUMS model in mice.Besides,SCF did not affect the locomotor activity,showing that the antidepressant-like effect was not linked to the neural excitatory effect.To further corroborate the antidepressant-like effect of SCF,the behavioral despair model,learned helplessness model,reserpine-induced model and chronic unpredictable stress model were established in mice,respectively.SCF all showed excellent antidepressant-like effect in the above mentioned models.The results suggested that the antidepressant-like effect of SCF is a multi-target mechanism and is related to maintaining the homeostasis of neurotransmitters in the brain.2.The antidepressant mechanism of SCF in CUMS-induced model was studied by using the combination of monoamine neurotransmitter receptor agonists/antagonists.The results showed that co-administration with 5-hydroxytryptamine(5-HT)synthesis inhibitor,norepinephrine(NE)inhibitor and dopamine(DA)inhibitor could antagonize the antidepressant-like effect of SCF.Additionally,SCF could greatly increase the number of headtwitches induced by 5-HTP and the number of death induced by yohimbine in mice,indicating that SCF has an antidepressant-like mechanism associated with monoaminergic neurotransmitter receptors.It was found that SCF had antidepressant-like effect by stimulating 5-HT1A receptor,α1 receptor,α2 receptor and D1 receptor,and antagonizing 5-HT3 receptor and 5-HT2A receptor by combining each receptor subtype agonists/antagonists.Further,SCF significantly increased the levels of 5-HT,NE and DA in the hippocampus of CUMS-induced mice,and decreased the ratios of 5-HT/5-HIAA,NE/MHPG,DA/HVA and DA/DOPAC,demonstrating that the antidepressant-like effect of SCF in CUMS model was related to the level of monoamine neurotransmitters and inhibited their metabolism.3.The antidepressant-like mechanism of SCF in CUMS model was investigated by using co-administration amino acid neurotransmitter receptor agonists/antagonists.The results showed that both y-aminobutyric acid(GABA)antagonist and glutamate(Glu)agonist could antagonize the antidepressant-like effect of SCF,which indicated that the antidepressant mechanism of SCF was related to the amino acid neurotransmitter receptors.It was found that SCF has an antidepressant effect by stimulating GABAA receptor and antagonizing NMDA receptor by the combined use of various receptor subtypes agonists/antagonists.Moreover,SCF significantly increased the level of GABA,decreased the level of Glu and restored the balance of Glu/GABA in the hippocampus of mice,illustrating that the antidepressant-like effect of SCF in CUMS model was related to the content of amino acid neurotransmitters and the excitatory/inhibitory balance in brain.4.Using CUMS-induced mice to explore the mechanisms of antidepressant-like effect and cognitive dysfunction improvement of SCF.The results showed that SCF could significantly reverse the decrease of BDNF and its receptor TrkB expression,and activate the PI3K/Akt/GSK3β signaling pathway,glutamate GluRl receptor,and increase the amount of PSD95.Meanwhile,K252a,a specific antagonist of TrkB receptor,could antagonize the antidepressant-like effect of SCF and down-regulate the expression of BDNF and other proteins in related signal pathway,indicating that the effect might be related to the regulation of neurotrophic factor,activation of neurotrophic factor receptor downstream pathway and protection of neuronal function.The results of Y-maze and Morris water maze showed that CUMS procedure could induce the impairment of learning and memory in mice,while SCF could improve cognitive dysfunction and decrease the level of CORT in serum,the levels of AChE and oxidative stress in hippocampus.Suggesting that SCF could improve the cognitive dysfunction induced by CUMS,which may be related to relieving the hyperfunction of HPA axis,the dysfunction of acetylcholinergic system and the oxidative stress injury.5.To explore the antidepressant-like mechanism of SCF on neuroendocrine pathway in chronic CORT-stressed mice model.The results showed that SCF could significantly reduce the adrenal index and the levels of CORT,CRH and ACTH in serum of CORT-induced mice,suggesting that the antidepressant-like mechanism of SCF might be related to regulating the function of the HPA axis.After combined administration of K252a,the antidepressant effect was antagonized,the expression of BDNF,TrkB,CREB was decreased,declaring that BDNF and its downstream signaling pathway were also involved in the regulation mechanism of SCF on neuroendocrine pathway.6.To study the antidepressant-like mechanism of SCF on neuroinflammatory pathway in lipopolysaccharide(LPS)-stressed mice.The results showed that SCF could remarkably alleviate the depressive symtoms in LPS-induced mice,and decrease the expression of proinflammatory cytokines,such as TNF-α,IL-6 and IL-1β,regulate the activation state of NFκB and reduce the level of the inflammasome(NLRP3)in hippocampus,illuminating that neuroinflammatory was involved in the antidepressant-like mechanism of SCF.In addition,the anti-inflammation mechanism of SCF may be related to the neuroprotective effect based on the up-regualted BDNF level.7.To investigate the relationship of antidepressant-like effect between sleep deprivation and SCF,the model of sleep deprivation was established by platform over water protocol and combined with CUMS to establish the complex model of depression and sleep deprivation.The results showed that sleep deprivation for 12 hours significantly improved depressive-like behavior in mice,while sleep deprivation for 72 hours aggravated depression-like behavior,indicating that short-term sleep deprivation has antidepressant-like effect.SCF combined with sleep deprivation for 12 hours had a synergistic antidepressant-like effect,which could significantly increase the level of BDNF in the hippocampus,and activate the downstream TrkB/CREB/ERK signaling pathway,PI3K/Akt/GSK3β signaling pathway and mTOR/p70S6K/PSD95 signaling pathway.The synergistic antidepressant-like effect of shortterm sleep deprivation and SCF may be related to regulation of neurotrophic factor,activation of downstream pathway of neurotrophic factor receptor and increase of synaptic plasticity.