<i>Nardostachys jatamansi</i> Mitigates Radiation-induced Depressive Behaviour: Evidence from Behavioural Assessment and Computational Insights into Multi-target Mechanisms

Antidepressant-like effect of the ethanolic extract from Suanzaorenhehuan Formula in mice models of depression

Anti-migraine and anti-depression activities of Tianshu capsule by mediating Monoamine oxidase

Ludwigia perennis is used in India to treat several ailments in the traditional system of medicine. The chloroform leaf extract of Ludwigia perennis was evaluated for depression and anxiety using in vivo and in silico studies. Wistar albino rats were divided into groups based on parameters like control, standard, 20, and 30 mg/kg b.w. chloroform leaf extract groups for drug administration using gastric intubation. The tail suspension test (TST) and forced swim test (FST) were used to assess the antidepressant activity. Molecular docking against monoamine oxidase A (MAO-A), ADME analysis, toxicity tests, and pass prediction studies were among the in silico investigations. A delayed onset of immobility and lowered immobility time were seen at both the treatment doses (FST: 38.49±2.04 and 35.55±2.95 s; TST: 30.23±1.73 and 26.72±2.26 s) and the standard drug fluoxetine (FST: 31.26±1.76 and TST: 25.54±1.08 s), indicative of its antidepressant ability. While 30 identified phytochemicals were docked with monoamine oxidase A proteins, six compounds mainly showed higher binding affinity. It is stated that γ-sitosterol has a binding affinity of -8.5. The binding affinity of five compounds, namely stigmasterol, ergosterol, dibutyl phthalate, campesterol, 7,9-Di-tert-butyl-1-oxaspiro(4,5)deca-6,9-diene-2,8-dione is -8.2, -8.2, -8.0, -7.8, and -7.4 are like this. The results of the molecular docking studies indicate that the six chemicals that were successfully docked have an anti-depressive impact. Apart from docking, pharmacokinetic and PASS tests validated their drug-likeness, predicted safety after consumption, and predicted pharmacological effects. The chloroform leaf extract of Ludwigia perennis is a rich source of bioactive compounds with strong antidepressant properties.

Introduction Depression has been a global public health issue for a while now. This has prompted many researches to develop safer and more effective treatment of depressive illness. Cytokines are believed to alter neurochemical and neuroendocrine processes that have wide-ranging effects on physiology and behavior including depression. Tapinanthus globiferus has been reported to be used in the management of depression and many other neuro-psychiatric illnesses. Aim The aim of this study is to evaluate the antidepressant activity of the methanol extract of Tapinanthus globiferus in acute inflammatory model of depression in mice. Methods The phytochemicals present in methanol leaves extract of Tapinanthus globiferus were screened for using simple chemical tests. LD50 of the extract was determined using OECD method. Anti-depressant effect of the extract was evaluated using tail suspension test (TST) and forced swim test (FST), while open field test was used to validate the observed activity of the extract. The levels of inflammatory cytokines and BDNF were assayed using ELISA kits Results Saponins, cardiac glycosides, flavonoids, alkaloids, tannins, steroids and triterpenoids, while anthraquinones were absent in the extract. The median lethal dose (LD50) of the extract was greater than 5000 mg/kg. The extractsignificantly (p<0.05) reduced body temperature of the mice (measured rectally), and at the extract at highest dose, it significantly (p<0.05) reduced immobility time that was comparable to fluoxetine in TST. However, in FST, a significant (p<0.05) reduction in immobility was observed only in the fluoxetine group in comparison to the LPS-only group. Correspondingly, in this study, the mice in the LPS-only group had higher levels of pro-inflammatory cytokines; Interleukin-1 (IL-1) and Interleukin-6 (IL-6), and cortisol compared to extract treated groups while BDNF level was much higher in the extract treated group compared to the LPS-only and Normal saline group. Conclusion The methanol extract of Tapinanthus globiferus possesses antidepressant activity which may involve amelioration of inflammatory response and enhancement of neurotrophic factors in mice. This provides scientific basis for the use of the plant in the management of depression in traditional medicine.

The objective of the study was to determine the effect of nifedipine, imipramine and sertraline on the acute and long-term antidepressant-like responses of furosemide in the forced swim (FST) and tail suspension (TST) tests in mice. Groups of mice of six in each group were treated for 30 days with Tween 80, furosemide (10 mg/kg) + nifedipine (5 mg/kg), furosemide (10 mg/kg) + imipramine (10 mg/kg) and furosemide (10 mg/kg) + sertraline (5 mg/kg), respectively. Experiments were done on day 1, 15 and 31 in the FST and TST. In the FST and TST, results showed that in the test groups, sertraline, imipramine and nifedipine enhanced the reduction of immobility of furosemide significantly when 15-days values were compared with acute values (F(3, 20) = 14.21, P &lt; 0.05, &lt; 0.01) and when 30-days values were compared with 15-days values (F(3, 20) = 24.26, P &lt; 0.05, &lt; 0.01).&nbsp;Duncan multiple range (DMR)&nbsp;post-hoc test showed that the furosemide + sertraline combination gave the most significant response. In conclusion, results show that the antidepressant-like action of furosemide is enhanced in the FST and TST models of depression in mice by co-administration of imipramine, sertraline and nifedipine. &nbsp; Key words: Furosemide, nifedipine, imipramine, sertraline, forced swim test (FST), tail suspension test (TST), antidepressant.

Background and Objective: Depression is a common disorder, especially in developed countries. Functional changes of cholinesterase are involved in pathogenesis of some brain disorders. Until now, exact association of these changes with depression has not been determined. This study was conducted to evaluate the changes of serum cholinesterase in lipopolysaccharide (LPS)-induced model of depression in male mice. Materials and Methods: Male mice (n = 48) were divided into 2 groups of control and LPS. For induction of depression, LPS (0.5 mg/kg; i.p.) was injected 24 h before the experiments. Open field, forced swimming, and tail suspension tests were used for behavioral assessment. Finally, serum cholinesterase activity was determined using biochemical method. Results: LPS injection significantly decreased travelled distance in open field test (p<0.05) and increased immobility duration in forced swimming and tail suspension tests (p<0.01). In addition, serum cholinesterase showed a significant decrease in LPS subgroups versus control (p<0.05). Conclusion: Our data showed that LPS could induce a valid model of depression and changes of cholinesterase are in part involved in development of its complications.

Antidepressant-like effect of mitragynine isolated from Mitragyna speciosa Korth in mice model of depression

L-Arginine (L-Arg), a substrate for nitric oxide synthase (NOS) at a dose of 250-500 mg/kg, i.p., significantly reduced the duration of immobility both in the forced swimming test (FST) and in the tail suspension test (TST), two models of depression in mice, without changing locomotion in an open field. Paradoxically, a similar effect was observed with the administration of N(G)-nitro-L-arginine (L-NNA) (0.3-10 mg/kg, i.p.), an inhibitor of NOS. However, higher doses of L-Arg (750-1000 mg/kg) and L-NNA (30 mg/kg) did not produce any anti-immobility effect in FST and TST. The inactive isomers D-Arg (100-1000 mg/kg, i.p.) and D-NNA (0.3-30 mg/kg, i.p.) did not affect immobility duration in either the FST and TST. Preadministration of L-NNA (30 mg/kg, i.p.), but not of D-NNA completely blocked the anti-immobility effect of L-Arg (500 mg/kg, i.p.) in the FST. Similarly, L-Arg (750 mg/kg, i.p.), but not D-Arg blocked the anti-immobility effect of L-NNA (3 mg/kg, i.p.) in the FST. The results indicate that either the synthesis of NO or the inhibition of its synthesis may produce antidepressant-like effects when assessed in the FST and TST. The physiological meaning of this finding is still obscure, but it could indicate that NO has a dual role in the modulation of depression.

Depression is a neuropsychological disorder with a complex pathophysiology and its pharmacotherapy is compromised by adverse side effects. Addressing the need for effective treatment for depression, the current study aims to characterize the antidepressant activity of oil extract derived from Aethoscytus foveolus, bugs that are widely available in India, in a mice model of stress-induced depression. Chemical moieties characterized by GC-MS of A. foveolus oil extract have shown good affinity for monoamine oxidase A (MAO-A) in-silico. In-vitro MAO-inhibitory assay using mouse brain homogenates also showed similar results at IC50 1.363 nM (R2 = 0.981, SD ± 0.05, n = 3) of it. These results encouraged us to investigate the antidepressant potential of this oil extract in vivo. Stress-exposed mice (Swiss Albino, either sex, 25-30 gm) were administered 5 and 10 mg/kg doses of oil extract and classified as separate groups (N = 6 per group). Behavioral tests like the forced-swim test, tail-suspension test, and open-field test demonstrated significant attenuation of stress-induced depressive-like behavior of mice by both doses (p < 0.0001 with positive control group i.e., stress group), while biochemical tests on mice brain tissues showed amelioration of stress-induced hyperactivation of MAO (p < 0.0001) and oxidative stress (by increasing Superoxide dismutase and catalase, while reducing lipid peroxidase and nitric oxide) (p < 0.0001). The altered mRNA expression of proinflammatory cytokines (NF-κB, IL-6, IL-12, and TNF-α) (p < 0.015) was also improved by this oil extract. In addition, histopathology of hippocampus tissues of mice supports that this oil recovers stress-mediated structural changes of the brain. In conclusion our findings suggest that oil derived from A. foveolus could be beneficial in the alleviation of stress-mediated depressive-like behavior of mice, and in our knowledge, this is the first report identifying anti-neurodegenerative potential of A. foveolus.

IntroductionDepression is one of the common comorbidities seen in chronic alcohol use disorder. Also, alcohol withdrawal induces depression and anxiety, which is associated with relapse in alcohol consumption. Minocycline, a tetracycline derivative, has shown an antidepressant effect in preclinical models. However, their effect on alcohol withdrawal-induced depression has not been studied. Therefore, the current study has been undertaken to evaluate the effect of minocycline on alcohol abstinence-induced depression models in mice.MethodWe conducted the study in two models. C57bl/6 mice were given a two-bottle choice (alcohol + water) for 28 days. During alcohol abstinence of 14 days, mice were treated with 10 mg/kg, 30 mg/kg, and 50 mg/kg of minocycline and were evaluated for behavioral changes using the forced swim test (FST) and tail suspension test (TST). A sucrose preference test was carried out where mice were exposed to binge alcohol drinking protocol for 12 days, where a two-bottle choice (alcohol or water) was given. This was followed by exposing the mice to a two-bottle choice paradigm (alcohol + sucrose) and they were divided into groups - no treatment group, vehicle-treated, minocycline 30 mg/kg or minocycline 50 mg/kg treated - and consumption of sucrose was assessed.ResultIn the forced swim test, a significant decrease in immobility time (p<0.05) was observed in the high-dose minocycline group (82.75±19.09) as compared to the vehicle control group (128.12±35.44). In the tail suspension test also, a significant decrease in immobility time (p<0.05) was seen in the high-dose minocycline group (83.75±18.61) as compared to the vehicle control group (122.25±18.51). The water and alcohol intake were comparable among all groups. In the sucrose preference test, it was found that the minocycline 50 mg/kg group had the highest sucrose preference (55%) followed by the minocycline 30 mg/kg group (50%) as compared to 42% in the vehicle control group. Significant reduction in brain-derived neurotrophic factor (BDNF) levels was seen with minocycline 50 mg/kg (p<0.05) and minocycline 30 mg/kg group (p<0.05) in BDNF levels when compared to the normal control group.ConclusionMinocycline in a higher dose (50 mg/kg) has shown an effect in alcohol withdrawal-induced depression in the abstinence-induced two-bottle choice model in mice. Both doses of minocycline have shown an effect in the sucrose preference test in the alcohol withdrawal-induced depression model.

Objective: To evaluate the antidepressant activity of methanolic extract of Dolichos Biflorus seeds in Swiss albino mice. Methodology: A total of 72(n=72) Swiss albino male mice were used in the study. They were divided into 12 groups of six mice in each. First six groups were evaluated by Tail Suspension Test (TST) and remaining by Forced Swim Test (FST). First group of mice (control) received normal saline 10mg/kg, second group (standard) received Imipramine 10mg/kg and third, fourth, fifth and sixth groups (test) respectively received methanolic extract of Dolichos Biflorus seeds (MEDB) 100mg/kg, 200mg/kg, 300mg/kg and 400mg/kg dose orally for 30 days. They were evaluated for antidepressant activity using TST after 60 minutes of drug administration on 30^th day. Duration of immobility was noted for six minutes for each mouse in all groups. Similarly, remaining six groups (7^th to 12^th) received the same drugs and evaluated for antidepressant activity using FST after 60 minutes of drug administration. Results: Results were analyzed by Kruskal-Wallis non-parametric test followed by Dunnet's test for comparison between groups. The immobility periods were expressed in mean±SD. The immobility period in TST were 245±9.7, 80±7.8, 216.4±4.9, 225.3±2.3, 198.4±3.2 and 185.4±2.7 seconds respectively for control, standard and four test groups (100/200/300/400mg/kg). Similarly, immobility periods of 139.33±7.9, 71.66±4.9, 54.7±2.9, 58±5.2, 126.2±7.9 and 113.4±2.8 seconds were noted for FST for remaining six groups of mice. In TST, test drug MEDB in all the doses (50/100/200/300/400mg/day) failed to show statistically significant antidepressant action when compared to control group (p>0.05). Whereas, in FST, MEDB in a dose of 200mg/kg has shown statistically significant (p<0.05) antidepressant action when compared to control. Conclusion: Present study shown methanolic extract of Dolichos Biflorus seeds (MEDB) has significant antidepressant activity at the dose of 200mg/kg in FST model of depression in mice.

Exploring the contribution of the dopaminergic and noradrenergic systems in the antidepressant-like action of 1-(2-(4-(4-ethylphenyl)-1H-1,2,3-triazol-1-yl)phenyl)ethanone in mice.

Depression is declared the second leading cause of disability worldwide. Recently, cases of depression have increased significantly in adolescents, young adults as well as in elder population. Monoamine oxidase‐A (MAO‐A) is considered one of the major targets for the treatment of depression. In the current study, we have designed and synthesized various indole functionalized piperazinyl derivatives and evaluated them for in vitro MAO‐A inhibitory activity and in vivo antidepressant‐like activity. Most of the compounds were found to possess potent MAO‐A inhibitory activity with IC 50 values in the sub‐micromolar range along with significant selectivity over MAO‐B. Compounds RP1 and RP9 emerged as the most promising reversible MAO‐A inhibitors with IC 50 values of 0.11±0.03 μM and 0.14±0.02 μM and displayed selectivity of 193 folds and 178 folds over Monoamine oxidase‐B (MAO‐B), respectively. In the series, RP1 showed good intracellular ROS inhibitory activity along with neuroprotective properties. These compounds were found nontoxic against SH‐SY5Y cells and explored antidepressant activities. In the in vivo Forced swimming test (FST) and Tail suspension test (TST) studies, RP1 exhibited potential antidepressant‐like behavior similar to standard drug fluoxetine while compound RP9 showed antidepressant‐like activity only in the TST studies. The molecular docking and dynamics studies further supported the results obtained in the in vitro and in vivo studies. Thus, the indole functionalized piperazinyl derivatives were found to be promising ligands and can be developed as new antidepressant molecules.

The present study investigated a possible antidepressant-like effect of ((4-tert-butylcyclohexylidene)methyl) (4-methoxystyryl) sulfide (BMMS) by using the forced swimming test (FST) and the tail suspension test (TST) in Swiss mice. The contribution of serotoninergic, glutamatergic and nitrergic systems in the antidepressant-like activity of BMMS was evaluated. We also examined the involvement of monoamine oxidase (MAO)-A, MAO-B and Na+, K+-ATPase activities in prefrontal cortex of mice. BMMS, (0.1-10mg/kg, intragastrically (i.g.)) and fluoxetine (32mg/kg, i.g.) decreased the immobility time in the FST and TST. The anti-immobility effect of BMMS (10mg/kg, i.g.) in the TST was prevented by the pretreatment of mice with WAY100635 (0.1mg/kg, subcutaneously (s.c.), a 5-HT1A receptor antagonist), ketanserin (5mg/kg, intraperitoneal (i.p.), a 5-HT2A/2C receptor antagonist), and partially blocked by ondansetron (1mg/kg, i.p., a 5-HT3 receptor antagonist). The anti-immobility effect of BMMS (10mg / kg, i.g.) was not avoided by pretreatment with MK-801 (0.01mg/kg, s.c. a non-competitive N-methyl D-Aspartate (NMDA) receptor) in the TST. Pretreatment with L-arginine (500mg/kg, i.p., a nitric oxide precursor) reversed partially the reduction in the immobility time elicited by BMMS (10mg/kg, i.g.) in TST. BMMS altered Na+,K+-ATPase and MAO-A activities in prefrontal cortex of mice, but was not able to change the MAO-B activity. In conclusion, BMMS exerted an antidepressant-like effect in mice and serotonergic and nitrergic systems are involved in the antidepressant-like action of compound. BMMS modulated MAO-A and Na+, K+- ATPase activities in prefrontal cortex of mice.

Asiaticoside is one of the triterpenoid components found in Centella asiatica that has promising neuroprotective properties. The present study aimed to evaluate the antidepressant-like properties of asiaticoside and to investigate the possible mechanisms underlying its mode of action using a mouse model of chronic unpredictable mild stress (CMS). Behavioral tests, including sucrose preference test, forced swimming test and tail suspension test, were performed to evaluate symptoms of depression. The expression levels of neurotransmitters, 5-hydroxytryptamine (5-HT) and norepinephrine (NE), in the hippocampus were measured by high-performance liquid chromatography. ELISA and western blotting were used to detect protein expression. It was demonstrated that asiaticoside treatment (20 and 40 mg/kg; intragastric) significantly reversed the decrease in sucrose consumption, and reduced the immobility time in tail suspension tests and forced swimming tests in CMS mice. Furthermore, asiaticoside treatment upregulated the expression of 5-HT and NE in the CMS mouse model. Asiaticoside administration also downregulated the levels of interleukin (IL)-1β, IL-6 and tumor necrosis factor-α in the hippocampus, and reduced the phosphorylation of nuclear factor (NF)-κBp65 and the expression of nod-like receptor protein 3 (NLRP3), thus decreasing the expression of mature caspase-1. Furthermore, asiaticoside significantly increased the levels of cAMP and protein kinase A (PKA), and enhanced phosphorylation of the cAMP-related specific marker vasodilator-stimulated phosphoprotein at serine 157. Therefore, asiaticoside may activate the cAMP/PKA signaling pathway to inhibit NF-κB- and NLRP3-related inflammation. Moreover, phosphorylation of the cAMP-responsive element-binding protein at serine 133 and the expression of brain-derived neurotrophic factor were increased after asiaticoside administration. Collectively, the present results suggested that asiaticoside may play a vital role as an antidepressant and anti-inflammatory agent in the CMS mouse model by regulating the cAMP/PKA signaling pathway.