Evaluation of antidepressant activity of methanolic and hydroalcoholic extracts of Acorus calamus L.rhizome through tail suspension test and forced swimming test of mice

Objective:Acorus calamus(AC)L.(Araceae)is an annual semi-aquatic and aromatic plant found in Europe,North America and Asia.Its rhizomes are often used by Native Americans,Americans,and Chinese as well as by other cultures.Ethnobotanical studies and documents have shown their use in various disease treatments,such as insomnia,mental disorders,diabetes mellitus,epilepsy,inflammation,asthma,neuropathic pain,and diarrhea.In this study,the antidepressant activity of methanolic and hydroalcoholic extracts of the AC rhizome part in mice was investigated.Methods:Three doses of methanolic extract of AC rhizome(MEACR)(25,50 and 100 mg/kg b.wt),three doses of hydroalcoholic extract of AC rhizome(HAACR)(100,200 and 400 mg/kg b.wt),and standards(imipramine,15 mg/kg b.wt and fluoxetine,20 mg/kg b.wt)was daily oral administration to the mice for consecutive 14 days.The extract effect on the immobility time was monitored by a tail suspension test(TST)and a forced swimming test(FST).Monoamine oxidase(MAO)levels were also analyzed using standard methods.Results:The optimum antidepressant activity was viewed at 100 mg/kg b.wt of MEACR extract and400 mg/kg b.wt of HAACR extract with 23.82%and 20.59%immobility period reduction,respectively.Besides,the extracts weakened the FST-induced elevation of MAO activity significantly and returned to near-normal levels of neurotransmitters in the brain.100 mg/kg b.wt or above of MEACR extract significantly prevented the MAO-A and MAO-B activities in mice brain at a dose-dependent fashion.But,just 400 mg/kg b.wt of HAACR extract prevented the activity of MAO-A and MAO-B.Fluoxetine and imipramine showed a tendency to prevent the activity of MAO-A and MAO-B.Conclusion:This study suggests that AC rhizome extract mediated antidepressant activity by modulating the central neurochemical and hypothalamic-pituitary-adrenal(HPA)axis in response to FST and TSTinduced stress.Therefore,AC rhizome extract can be used as a valuable plant supplement to treat depressive disorders.

Antidepressant Effect of Shenwei Ningyu Tablets on Rat Chronic Stress Model and Mouse Tail Suspension Model

[Objectives]To explore the antidepressant effect of Shenwei Ningyu Tablet,a new antidepressant traditional Chinese medicine,on rat chronic stress depression model and mouse tail suspension models.[Methods]Rat chronic stress model:except for the normal group,the rats in other groups were given corresponding chronic stress,and administered by gavage 1 h before modeling,for a total of 21 d.The changes of each indicator before and after the experiment were observed through the body weight change,the sugar water test,and open field test.The relevant hormone levels were detected by radioimmunoassay.Mouse tail suspension depression model:after continuous administration for 7 d,the activity times was recorded with the mouse automatic recorder,and the mouse immobility time was recorded after tail suspension,to explore the effects of each administration group on the tail suspension immobility time of mice.[Results]Chronic stress depression model:21 d after modeling,compared with the normal group,rats in the model group exhibited significantly reduced body weight,sucrose preference index,and horizontal and vertical movement scores(P<0.05).Compared with the model group,the low-dose Shenwei Ningyu Tablets group had significant differences in the sugar water test,horizontal and vertical movement scores(P<0.05).In addition,all three dose groups of Shenwei Ningyu Tablets could effectively reduce the content of CRF in chronic stress model rats,and the low dose group could significantly reduce the ACTH level in model rats(P<0.05).Mouse tail suspension depression model:the immobility time after tail suspension in each administration group was significantly different from that in the model group(P<0.05).[Conclusions]Shenwei Ningyu Tablets has a certain anti-depression effect on both the rat chronic stress depression model and the mouse tail suspension depression model.

THE ROLE OF MUSCLE SPINDLE IN MUSCLE ATROPHY INDUCED BY SIMULATED MICROGRAVITY

Objective To compare the cross section area (CSA) and the immunoreactivity of conjugated ubiquitin in soleus extrafusal and intrafusal fibers after simulated microgravity and to demonstrate the role of muscle spindle in muscle atrophy induced by simulated microgravity. Methods The immunohistochemical technique (ABC) and image analysis were used to assess the conjugated ubiquitin immunostaining and the cross sectional area of intrafusal and extrafusal fibers of soleus in simulated microgravity rats. Results ①Tail suspension caused a progressive loss of soleus mass. Mean fiber CSA of extrafusal fibers were (7±2)%, (21±4)% and (32±7)% smaller after 3 days, 7 days and 14 days suspension, respectively. While the CAS of intrafusal fibers (bag + chain fibers) were (14±3)% ( P < 0.05 ), (30±7)% ( P < 0.01 ) and (44±10)% ( P < 0.01 ) smaller after 3 days, 7 days and 14 days suspension. ② The immunoreactivity of conjugated ubiquitin both in extrafusal and intrafusal fibers increased after tail suspension. The immunoreactivity of intrafusal fibers increased 1 day after suspension and reached the hightest level at 3 days after tail suspension. The immunoreactivity of extrafusal fibers increased after 3 days suspension and reached the highest level after 7 days tail suspension, which was lower than that in intrafusal fibers after 3 days tail suspension. Conclusion These results suggest that soleus atrophy of intrafusal fibers caused by tail suspension is earlier and more severe than that in extrafusal fibers.

Neuronal protein-tyrosine phosphatase 1B hinders sensory-motor functional recovery and causes affective disorders in two different focal ischemic stroke models

Ischemic brain injury causes neuronal death and inflammation.Inflammation activates protein-tyrosine phosphatase 1B(PTP1B).Here,we tested the significance of PTP1B activation in glutamatergic projection neurons on functional recovery in two models of stroke:by photothrombosis,focal ischemic lesions were induced in the sensorimotor cortex(SM stroke)or in the peri-prefrontal cortex(peri-PFC stroke).Elevated PTP1B expression was detected at 4 days and up to 6 weeks after stroke.While ablation of PTP1B in neurons of neuronal knockout(NKO)mice had no effect on the volume or resorption of ischemic lesions,markedly different effects on functional recovery were observed.SM stroke caused severe sensory and motor deficits(adhesive removal test)in wild type and NKO mice at 4 days,but NKO mice showed drastically improved sensory and motor functional recovery at 8 days.In addition,peri-PFC stroke caused anxiety-like behaviors(elevated plus maze and open field tests),and depression-like behaviors(forced swimming and tail suspension tests)in wild type mice 9 and 28 days after stroke,respectively,with minimal effect on sensory and motor function.Peri-PFC stroke-induced affective disorders were associated with fewer active(FosB+)neurons in the PFC and nucleus accumbens but more FosB+neurons in the basolateral amygdala,compared to sham-operated mice.In contrast,mice with neuronal ablation of PTP1B were protected from anxiety-like and depression-like behaviors and showed no change in FosB+neurons after peri-PFC stroke.Taken together,our study identifies neuronal PTP1B as a key component that hinders sensory and motor functional recovery and also contributes to the development of anxiety-like and depression-like behaviors after stroke.Thus,PTP1B may represent a novel therapeutic target to improve stroke recovery.All procedures for animal use were approved by the Animal Care and Use Committee of the University of Ottawa Animal Care and Veterinary Service(protocol 1806)on July 27,2018.

Antidepressant Effects of Ginsenosides from Panax notoginseng

Ginsenosides Rg 1,Rb 1,R 1,Rd,and Re are major constituents of Panax notoginseng,a famous traditional Chinese medicinal herb,which has both stimulative and inhibitory effects on the central nervous system (CNS).The monoamine hypothesis proposes that depression is a result of the depletion of 5-hydroxytryptamine (5-HT),norepinephrine (NE) and dopamine (DA) in addition to the activation of monoamine oxidase in the CNS.The purpose of this study was to determine whether P.notoginseng Saponin (PNS) has an antidepressant activity.We investigated the antidepressant-like activities of Rg 1,Rb 1,R 1,Rd,and Re in mice,using two animal models of depression.In addition,we analyzed the neurochemicals by the chronic unpredictable mild stress test.Our results showed that Rb 1,Rd,and Re treatment at 10 mg kg-1 significantly reduced the duration of immobility in both the tail suspension and forced swimming tests.Rb 1,Rd,and Re increases in 5HT and NE levels at 10 mg kg-1 in both the frontal cortex and hippocampus.Dopamine levels increased in the hippocampus and the striatum.Moreover,5-hydroxyindoleacetic acid (5-HIAA) levels were found increased in the hippocampus.These findings suggest that the antidepressant effects of Rb 1,Rd,and Re may be related to the increase in 5-HT and NE in the CNS,and through the alterations in the synthesis or metabolism of dopamine.

Assessment of commonly used tests in experimental depression studies according to behavioral patterns of rodents

Considering the main factor that causes or triggers depression in humans is stress.Several stress factors are applied to form depression-like symptoms in rodents.Depression tests are used to analyze the nature and patterns of depression.Well-founded modeling and versatile evaluation of tests are necessary to investigate a hypothesis that is related to depression.It is impossible to model or test all aspects of depression in humans by using experimental animals.As a result,the aims of the study should be determined specifically in depression models.The correct interpretation of the tests that are suitable for these aims is indispensable for the reliability of the data.To achieve this goal,the biological basis of the depression-related behaviors of animals should be well known.In this review,model and test concepts related to depression are discussed and behavioral patterns of rodents are explained with several examples.

Behavioral animal models of depression

Depression is a chronic,recurring and potentially life-threatening illness that affects up to 20%of the population across the world.Despite its prevalence and considerable impact on human,little is known about its pathogenesis.One of the major reasons is the restricted availability of validated animal models due to the absence of consensus on the pathology and etiology of depression.Besides,some core symptoms such as depressed mood,feeling of worthlessness,and recurring thoughts of death or suicide,are impossible to be modeled on laboratory animals.Currently,the criteria for identifying animal models of depression rely on either of the 2 principles：actions of known antidepressants and responses to stress.This review mainly focuses on the most widely used animal models of depression,including learned helplessness,chronic mild stress,and social defeat paradigms.Also,the behavioral tests for screening antidepressants,such as forced swimming test and tail suspension test,are also discussed.The advantages and major drawbacks of each model are evaluated.In prospective,new techniques that will be beneficial for developing novel animal models or detecting depression are discussed.

Antidepressant-like effects of the ethanolic extract of XiaobuxinTang,a traditional Chinese herbal prescription in animal models of depression

Background Xiaobuxin-Tang, a traditional Chinese herbal prescription recorded in a silk scroll unearthed from Mogao Caves of Dunhuang has been indicated that it can remit depressive disorder. The present study was designed to investigate its antidepressant effects in various animal depression models.Methods Xiaobuxin-Tang was extracted by 70% alcohol, and then three behavioral despair models and 5-Hydroxytryptophan （HTP）-induced head twitch response model were adopted to assess the antidepressant effects of the ethanolic extract of Xiaobuxin-Tang with the study on spontaneous motor activity. Groups of mice and rats received oral treatment with Xiaobuxin-Tang （150-1200 mg/kg） only once acutely in all tests. The duration of immobility was measured during the last 4 minutes of the 6-minutes test period in mice forced swimming test, rats forced swimming test and mice tail suspension test. In 5-HTP-induced head twitch response, the mice were intraperitoneally administered with 120 mg/kg of L-5-HTP, and then the cumulative number of head twitches was counted in 20 minutes. Spontaneous motor activities of mice were recorded automatically in 10 minutes by VIDEOMEX-V image analytic system.Results The extract at doses of 300 mg/kg （p.o.） and 600 mg/kg （p.o.） significantly decreased the duration of immobility time in a dose dependent manner in mice forced swimming test; also, the extract at dose of 1200 mg/kg （p.o.） significantly decreased the duration of immobility time in rat forced swimming test. Furthermore, the extract at a dose of 600 mg/kg had the same effect in mice tail suspension test. Meanwhile, the extract at the effective doses for behavioral despair models, had no effect on spontaneous motor activity in mice. The extract （300-1200 mg/kg, p.o.） also increased the accumulative number of the 5-HTP-induced head twitch response in mice in 20 minutes.Conclusion Our results suggested that the ethanolic extract of Xiaobuxin-Tang exerts antidepressant-like effect.

A Network Pharmacology-Based Study on Antidepressant Effect of Salicornia europaea L.Extract with Experimental Support in Chronic Unpredictable Mild Stress Model Mice

Objective:To investigate the pharmacodynamic material basis,mechanism of actions and targeted diseases of Salicornia europaea L.(SE)based on the network pharmacology method,and to verify the antidepressant-like effect of the SE extract by pharmacological experiments.Methods:Retrieval tools including Chinese medicine(CM),PubMed,PharmMapper,MAS 3.0 and Cytoscape were used to search the components of SE,predict its targets and related therapeutic diseases,and construct the"Component-TargetPathway"network of SE for central nervous system(CNS)diseases.Further,protein-protein interaction(PPI)network,Kyoto Encyclopedia of Genes and Genomes(KEGG)and Gene Ontology(GO)function annotation of depression-related targets were analyzed to predict the antidepressant mechanism of SE.Chronic unpredictable mild stress(CUMS)model was used to construct a mouse model with depression-like symptoms.And the animals were randomly divided into 6 groups(n=10)including the normal group(nonstressed mice administered with distilled water),the CUMS group(CUMS mice administered with distilled water),the venlafaxine group(CUMS mice administered with venlafaxine 9.38 mg/kg),SE high-,medium-,and low-dose groups(CUMS mice administered with SE 1.8,1.35 and 0.9 g/kg,respectively).Then some relevant indicators were determined for experimental verification by the forced swim test(FST),the tail suspension test(TST)and open-field test(OFT).Dopamine(DA)concentration in hippocampus and cerebral cortex,IL-2 and corticosterone(CORT)levels in blood,and nuclear factor E2 related factor 2(Nrf2),kelch-like epichlorohydrin related protein 1(Keap1),NAD(P)H dehydrogenase[quinone]1(NQO1)and heme oxygenase-1(HO-1)levels in mice were measured by enzyme linked immunosorbent assay(ELISA)and Western blot respectively to explore the possible mechanisms.Results:The"target-disease"network diagram predicted by network pharmacology,showed that the potential target of SE involves a variety of CNS diseases,among which depression accounts for the majority.The experimental results showed that SE(1.8,1.35 g/kg)significantly decreased the immobility period,compared with the CUMS group in FST and TST in mice after 3-week treatment,while SE exhibited no significant effect on exploratory behavior in OFT in mice.Compared with CUMS group,the SE group(0.9 g/kg)showed significant differences(P<0.05)in DA levels in the hippocampus and cerebral cortex.In addition,compared with CUMS control group,SE(1.8 g/kg)group showed a significant effect on decreasing the activities of CORT(P<0.05),and serum IL-2level with no statistical significance.Finally,Western blot results showed that compared with the model group,Nrf2,Keap1,NQO1 and HO-1 protein expressions in SE group(1.8 g/kg)were up-regulated(all P<0.01).Conclusion:The SE extract may have an antidepressant effect,which appeared to regulate Nrf2-ARE pathway and increased levels of DA and CORT in the hippocampus and cortex.