Acute Forced Swimming Test Research Articles

Acetate supplementation produces antidepressant-like effect via enhanced histone acetylation

Background: Abnormal energy metabolism is often documented in the brain of patients and rodents with depression. In metabolic stress, acetate serves as an important source of acetyl coenzyme A (Ac-CoA). However, its exact role and underlying mechanism remain to be investigated.Method: We used chronic social failure stress (CSDS) to induce depression-like phenotype of C57BL/6J mice. The drugs were administered by gavage. We evaluated the depressive symptoms by sucrose preference test, social interaction, tail suspension test and forced swimming test. The dendritic branches and spine density were detected by Golgi staining, mRNA level was analyzed by real-time quantitative RT-PCR, protein expression level was detected by western blot, and the content of Ac-CoA was detected by ELISA kit.Result: The present study found that acetate supplementation significantly improved the depression-like behaviors of mice either in acute forced swimming test (FST) or in CSDS model and that acetate administration enhanced the dendritic branches and spine density of the CA1 pyramidal neurons. Moreover, the down-regulated levels of BDNF and TrkB were rescued in the acetate-treated mice. Of note, chronic acetate treatment obviously lowered the transcription level of HDAC2, HDAC5, HDAC7, HDAC8, increased the transcription level of HAT and P300, and boosted the content of Ac-CoA in the nucleus, which facilitated the acetylation levels of histone H3 and H4.Limitations: The effect of acetate supplementation on other brain regions is not further elucidated.Conclusion: These findings indicate that acetate supplementation can produce antidepressant-like effects by increasing histone acetylation and improving synaptic plasticity in hippocampus.

Anti-depressant activity of Erythrina variegata bark extract and regulation of monoamine oxidase activities in mice.

Erythrina variegata, commonly referred to as 'Indian coral tree' belongs to the Fabaceae family. It is a plant native to the coast of India, China and is distributed in tropical and subtropical regions worldwide. In traditional medicine, E.variegata is known to exhibit anxiolytic and anti-convulsant activities and has been used as a nervine sedative. As per the Indian Materia Medica, E.variegata barks have been traditionally known to act on the central nervous system. However, there is a lack of data demonstrating this. Our study focuses on previously unreported anti-depressant activity of E.variegata bark ethanolic extract (EBE) and determination of its mechanism of action possibly through regulation of monoamine oxidase activity in mouse brain homogenates. EBE was characterized using standard protocols for phytochemical analysis, followed by liquid chromatography-mass spectrometry (LC-MS) and gas chromatography-mass spectrometry (GC-MS) analysis. The compounds in EBE (previously reported for anti-depressant activity), were further studied by LC-MS/MS and GC-MS/MS analysis. Anti-depressant activity of EBE (50, 100, 200 and 500 mg/kg) was evaluated in Swiss albino mice using acute and chronic tail suspension test (TST) and forced swim test (FST) models. Furthermore, the possible mechanism of action of EBE was evaluated using the chronic unpredictable mild stress (CUMS) model, wherein inhibitory effects on monoamine oxidase (MAO) A and B were assessed by spectrophotometric-chemical analysis in mouse whole brain homogenates. EBE showed significant reduction in immobility time periods in both TST (acute: 50, 100 and 200 mg/kg and chronic: 100 and 200 mg/kg) and FST (acute: 200 mg/kg and chronic: 100, 200 and 500 mg/kg) models. Moreover, the locomotor activity test confirmed that acute and chronic administration of EBE did not significantly affect the motor activity of mice. In the CUMS model, EBE when administered alone (100 and 200 mg/kg) and in combination (50, 100 and 200 mg/kg) with escitalopram (15 mg/kg), showed significant reductions in immobility time periods compared to the control group, in the acute FST performed on 22nd day of CUMS. Furthermore, when administered alone (50, 100 and 200 mg/kg), EBE showed significant inhibition in MAO-A and B activities compared to the control group. When used in combination, EBE (50, 100 and 200 mg/kg) showed synergistic action with escitalopram (15 mg/kg), resulting in significantly greater inhibition of MAO-A and B activities, compared to both EBE alone and escitalopram alone. Phytochemical analysis of EBE revealed presence of sugars, steroids, glycosides, alkaloids and tannins. LC-MS, LC-MS/MS, GC-MS and GC-MS/MS analysis identified components in EBE, previously reported for their anti-depressant activity. The study thus concluded the anti-depressant like activity of EBE. The study identified components present in EBE that may be responsible for its anti-depressant activity. The possible mechanism of action of EBE was also investigated in the CUMS model, wherein inhibitory effects of EBE on MAO-A and B activities in the mouse brain were demonstrated. Furthermore, the study confirms the traditional use of E.variegata barks in CNS related activities through its anti-depressant like activity.

Methylene Blue Analogues with Marginal Monoamine Oxidase Inhibition Retain Antidepressant-like Activity.

Methylene blue (MB) possesses diverse medical applications. Among these, MB presents with antidepressant-like effects in animals and has shown promise in clinical trials for the treatment of mood disorders. As an antidepressant, MB may act via various mechanisms which include modulation of the nitric oxide cyclic guanosine monophosphate (NO-cGMP) cascade, enhancement of mitochondrial respiration and antioxidant effects. MB is also, however, a high potency inhibitor of monoamine oxidase (MAO) A, which most likely contributes to its antidepressant effect, but also to its adverse effects profile (e.g., serotonin toxicity). The latter has raised the question whether it is possible to design out the MAO inhibition properties of MB yet retaining its clinically useful attributes. This study explores this idea further by characterizing five newly synthesized low MAO-A active MB analogues and examining their antidepressant-like properties in the acute forced swim test (FST) in rats, with comparison to imipramine and MB. The results show that all five analogues exhibit antidepressant-like properties in the FST without confounding effects on locomotor activity. The magnitude of these effects is comparable to those of imipramine and MB. Moreover, these newly synthesized MB analogues are markedly less potent MAO-A inhibitors (IC50 = 0.518-4.73 μM) than MB (IC50 = 0.07 μM). We postulate that such lower potency MAO-A inhibitors may present with a reduced risk of adverse effects associated with MAO-A inhibition. While low level MAO-A inhibition still may produce an antidepressant effect, we posit that other MB-related mechanisms may underlie their antidepressant effects, thereby representing a novel group of antidepressant compounds.

Identification of a novel, fast-acting GABAergic antidepressant.

Current pharmacotherapies for depression exhibit slow onset, side effects and limited efficacy. Therefore, identification of novel fast-onset antidepressants is desirable. GLO1 is a ubiquitous cellular enzyme responsible for the detoxification of the glycolytic byproduct methylglyoxal (MG). We have previously shown that MG is a competitive partial agonist at GABA-A receptors. We examined the effects of genetic and pharmacological inhibition of GLO1 in two antidepressant assay models: the tail suspension test (TST) and the forced swim test (FST). We also examined the effects of GLO1 inhibition in three models of antidepressant onset: the chronic FST (cFST), chronic mild stress (CMS) paradigm, and olfactory bulbectomy (OBX). Genetic knockdown of Glo1 or pharmacological inhibition using two structurally distinct GLO1 inhibitors (S-bromobenzylglutathione cyclopentyl diester (pBBG) or methyl gerfelin (MeGFN)) reduced immobility in the TST and acute FST. Both GLO1 inhibitors also reduced immobility in the cFST after 5 days of treatment. In contrast, the serotonin reuptake inhibitor fluoxetine (FLX) reduced immobility after 14, but not 5 days of treatment. Furthermore, 5 days of treatment with either GLO1 inhibitor blocked the depression-like effects induced by CMS on the FST and coat state, and attenuated OBX-induced locomotor hyperactivity. Finally, 5 days of treatment with a GLO1 inhibitor (pBBG), but not FLX, induced molecular markers of the antidepressant response including brain-derived neurotrophic factor (BDNF) induction and increased phosphorylated cyclic-AMP response binding protein (pCREB) to CREB ratio in the hippocampus and medial prefrontal cortex (mPFC). Our findings indicate that GLO1 inhibitors may provide a novel and fast-acting pharmacotherapy for depression.

Evaluation of Costus speciosus in Experimental Models of Depression in Albino Mice

Introduction: Despite theavailability of numerous antidepressant drugs the therapy of depression is far from satisfactory. Two of the many reasons for this are the delay in onset of effect and the adverse effects associated with most of the antidepressants. Costus speciosus rhizome has shown adaptogenic activity. Objective: To evaluate the antidepressant activity of50% aqueous-ethanol extract of Costus speciosus (CS) leaves in experimental models of depression. Materials and Methods: Male albino mice were randomly assigned to five groups of six each. We studied three doses of the leaf extract (100, 200 and 400 mg/kg) on two models of depression – forced swim test and tail suspension test. Imipramine was used as the standard control. Both acute and chronic effects were studied. Drugs (test drug, standard control and vehicle) were administeredorally, one hour before the experiment in the acute study and daily for 14 days for the chronic study. Results: Imipramine showed significant antidepressant activity as demonstrated by a reduction in duration of immobility in both acute and chronic studies of forced swim test and tail suspension test. CS showed a dose dependent antidepressant activity. CS_100 demonstrated an antidepressant effect only in the acute forced swim test. CS_200 demonstrated an antidepressant activity in both acute and chronic forced swim test but not in tail suspension test. CS_400 showed maximum antidepressant activity in both acute and chronic studies, which was comparable to that of the standard drug imipramine. Conclusion: CS showed dose dependent antidepressant activity with CS_400 mg/kg showing maximum effect.

The antidepressant like action of ethanolic extract of areca catechu on behavioral models of depression in rats

Background: The objective was to investigate the anti-depressant like activity of areca catechu nut ethanolic extract (ACEE) using behavioural tests in rats.Methods: Forced swim test (FST) and tail suspension test (TST) were used to assess the anti-depressant like effect of ACEE rats. Motor coordination was also assessing using rota-rod test in rats to see generalised CNS depression. Fluoxetine was the reference standard drug. Rats were divided into four groups with six rats in each group namely control group, fluoxetine 10 mg/kg group, ACEE 50 mg/kg group and fluoxetine 5 mg/kg plus ACEE 25 mg/kg. All treatments were administered orally.Results: The areca nut ethanolic extract (ACEE) (50mg/kg oral) exhibited anti-depressant like activity i.e. decrease the duration of immobility time (sec) in acute forced swim test (FST) and in acute tail suspension test (TST) in rats (104±1.7, 95%CI 99.65 to 108.4, p <0.01) Vs control and (136.3±1.94, 95%CI 131.3 to 141.3, p<0.01) Vs control respectively. ACEE in low dose of 25 mg potentiated the anti-depressant activity of low dose fluoxetine 5 mg/kg in both the test 102.3±2.60, CI 95.64 to 109.0 p<0.01) Vs control. The ACEE did not produce motor incoordination in rats.Conclusions: The results of present study suggest that the areca catechu nut ethanolic extract 50mg/kg possess potential anti-depression like effect without generalized CNS depression. Further studies are needed to confirm this.

Azure B and a synthetic structural analogue of methylene blue, ethylthioninium chloride, present with antidepressant-like properties

AimsThe phenothiazinium compound, methylene blue (MB), possesses diverse pharmacological actions and is attracting attention for the treatment of bipolar disorder and Alzheimer's disease. MB acts on both monoamine oxidase (MAO) and the nitric oxide (NO)-cGMP pathway, and possesses antidepressant activity in rodents. The goal of this study was to synthesise a structural analogue of MB, ethylthioninium chloride (ETC), and to evaluate the effects of the structural changes on the MAO inhibitory and antidepressant properties of MB. This study also investigated the antidepressant properties of azure B, the major metabolite of MB, versus MB and imipramine as active comparators. Main methodsETC and azure B were firstly evaluated as inhibitors of human MAO, and secondly for antidepressant-like activity in the acute forced swim test (FST) in rats, and compared to saline, imipramine and MB. Key findingsThe results document that ETC is a reversible inhibitor of MAO-A and MAO-B with IC50 values of 0.510μM and 0.592μM, respectively, and that it is a weaker MAO-A inhibitor than MB and azure B. ETC and azure B were more effective than imipramine and MB in reversing immobility in the FST without inducing locomotor effects, with evidence supporting a serotonergic action. Of interest is the finding that ETC is more toxic for cultured cells than MB. ConclusionAzure B may therefore be a contributor to the antidepressant effect of MB. Small structural changes made to MB retain its antidepressant effect, even though the resulting phenothiazinium compound possesses reduced MAO-A inhibitory potency.

Evaluation of antidepressant activity of ropinirole coadministered with fluoxetine in acute and chronic behavioral models of depression in rats

Certain unknown aspects of ropinirole action, such as its antidepressant effect after chronic administration and on cotreatment with fluoxetine, remain to be evaluated, which formed the rationale for this study. Wistar rats of either sex (weighing 150-200 g) were used. In the dose-finding study, oral dose of ropinirole (20 mg/kg) was selected. This was combined with two different doses of fluoxetine (10 and 20 mg/kg). Their antidepressant-like effects were compared in acute and chronic forced-swim test (FST). Acute FST was conducted in two sessions after administration of three doses within 24 h. Chronic FST was conducted over 14 days. Drugs were administered each day for 14 days. Effect on locomotor activity was tested in OFT. ANOVA with post hoc Tukey test was used. Dose-finding study of ropinirole showed that out of three doses, 20 mg/kg produced maximum reduction in immobility in acute FST (137±8 s). Coadministration of ropinirole with fluoxetine in acute FST further reduced immobility (107±8 s). This effect was more prominent in chronic forced-swim-stressed rats (74±2 s). Neither ropinirole nor its coadministration with fluoxetine increased locomotor activity in open-field test. The potential of ropinirole to act as an antidepressant agent is proven by the reduction in immobility time in FST. Further, there is an augmentation of the effect of fluoxetine by ropinirole, suggesting synergistic interaction of dopamine and serotonin pathway in brain.

Role of monoamine oxidase, nitric oxide synthase and regional brain monoamines in the antidepressant-like effects of methylene blue and selected structural analogues

Dual action antidepressants have important therapeutic implications. Methylene blue (MB), a charged compound structurally related to tricyclic antidepressants, acts on both monoamine oxidase (MAO) and the nitric oxide (NO)-cGMP pathway, and has demonstrated antidepressant activity in rodents. We investigated the antidepressant properties of MB and selected structural analogues and whether their actions involve MAO, NO synthase (NOS) and regional brain monoamines.Acute imipramine (IMI, 15mg/kg), saline, MB, acriflavine (ACR), methylene green (MG), methylene violet (MV), thionine (THI) and tacrine (TAC) (1-60mg/kg i.p.) were tested for antidepressant activity in the forced swim test (FST), as well as MAO-A/B inhibitory activity. Active antidepressant compounds were subsequently studied at their most effective dose during sub-chronic treatment, followed by behavioural sampling in the FST and assay of cortico-limbic monoamines and hippocampal nitrate (for NOS activity).Only IMI, MB (15, 30, 60mg/kg) and MG (7.5, 25, 40mg/kg) reduced immobility in the acute FST. MB, MG and ACR were potent inhibitors of especially MAO-A. Following sub-chronic treatment, IMI (15mg/kg) increased noradrenergic behaviour in the FST, while MB (15mg/kg) and MG (15mg/kg) enhanced serotonergic behaviour. MB and MG bolstered cortico-limbic serotonin (5HT) levels and to a lesser extent l-norepinephrine (l-NE), but did not significantly alter regional dopamine (DA) levels. MB, and to lesser degree MG, reduced hippocampal nitrate levels.MB and MG present with structure-specific antidepressant-like effects following acute and sub-chronic treatment, possibly involving NOS and MAO-A inhibition and cortico-limbic 5HT and l-NE release. A role for MAO-B and DA appears minimal.