Tail Suspension Test In Mice Research Articles

Caffeine augments the antidepressant-like activity of mianserin and agomelatine in forced swim and tail suspension tests in mice.

The main goal of this research was an evaluation of the influence of caffeine on the activity of mianserin and agomelatine. The mouse forced swim test and tail suspension test were used to determine the influence of caffeine on the activity of the tested drugs. Drug concentrations in serum and brains were estimated by HPLC. Caffeine increases the anti-immobility action of mianserin and agomelatine. The observed effects were not associated with changes in the level of drugs in serum or brains. The synergistic effect of caffeine and the tested drugs may be associated with their summative actions on monoaminergic neurotransmission. Caffeine-mianserin and caffeine-agomelatine interactions might have been of pharmacodynamic origin.

Evidence for the involvement of NMDA receptors in the antidepressant-like effect of nicotine in mouse forced swimming and tail suspension tests.

The antidepressant action of acute nicotine administration in clinical and animal studies is well recognized. But the underlying mechanism for this effect has not been carefully discovered. We attempted to evaluate the possible role of N-Methyl-D-aspartate (NMDA) receptors in the antidepressant-like effect of nicotine. After the assessment of locomotor activity in the open-field test, forced swimming test (FST) and tail suspension test (TST) were used to evaluate the antidepressant-like effect of nicotine in mice. We performed intraperitoneal administration of nicotine at different doses and periods before the tests. To assess the possible involvement of NMDA receptors, non-effective doses of NMDA antagonists and an NMDA agonist were obtained and were administered simultaneously with the non-effective and effective doses of nicotine, respectively. Nicotine (0.2mg/kg, 30min before FST/TST) significantly reduced the immobility time of mice similar to fluoxetine (20mg/kg). Nicotine did not affect the locomotor behavior of mice in open-field test. Co-administration of non-effective doses of NMDA receptor antagonists, ketamine (1 or 0.3mg/kg), MK-801 (0.05 or 0.005mg/kg), and magnesium sulfate (10 or 5mg/kg) with nicotine (0.1 or 0.03mg/kg) had remarkable synergistic antidepressant effect in both FST and TST. Also, non-effective NMDA (75 or 30mg/kg) reversed the anti-immobility effect of nicotine (0.2mg/kg) on mouse FST and TST. Our study has for the first time confirmed that the antidepressant-like effect of nicotine on mice is NMDA-mediated, and nicotine presumably exerts this effect by antagonizing the glutamatergic NMDA receptors.

Hippocampal BDNF signaling restored with chronic asiaticoside treatment in depression-like mice.

Brain-derived neurotrophic factor (BDNF) plays a key role in the regulation of depression in the brain. Recently, increasing studies have focused on the antidepressant-like mechanism of BDNF and its downstream signaling pathway. A previous study has shown that asiaticoside produced an antidepressant-like action in the mouse tail suspension test and forced swimming test. However, the neurotrophic mechanism that is affected by asiaticoside is unclear. Our present study aimed to verify whether asiaticoside produces an antidepressant-like effect through the activation of BDNF signaling in chronic unpredictable mild stress (CUMS). The results showed that mice treated with asiaticoside for four weeks reversed the decreased sucrose preference and increased immobility time that was observed in CUMS mice. In addition, we found that asiaticoside up-regulated BDNF, PSD-95 and synapsin I expression only in the hippocampus but not in the frontal cortex in both non-stressed and CUMS mice. However, K252a, an inhibitor of BDNF receptor tropomyosin-related kinase receptor B (TrkB), completely abolished the antidepressant-like effect of asiaticoside. Moreover, the expression of hippocampal BDNF, PSD-95 and synapsin I that had increased with asiaticoside also declined with K252a pretreatment. In conclusion, our study implies that it is possible that asiaticoside exerts its antidepressant-like action by activating BDNF signaling in the hippocampus.

Antidepressant-like effects of rosmarinic acid through mitogen-activated protein kinase phosphatase-1 and brain-derived neurotrophic factor modulation

Rosmarinic acid (RA) is one of the major bioactive compounds of Rosmarinus officinalis, a culinary and edible aromatic plant and was demonstrated to have several neuroprotective properties including anti-depressive-like effect. The current study was designed to contribute to understanding the molecular mechanism of RA beneficial effects in tail suspension test (TST)-induced depression in mice with bupropion as positive control, and mice without TST as negative control. Changes in serum corticosterone (CORT) level and cerebrum level of catecholamines: dopamine (DOP), noradrenaline (NAD), and adrenaline (ADR) were investigated. Moreover, brain-derived neurotrophic factor (Bdnf), mitogen-activated protein kinase phosphatase-1 (Mkp-1), tyrosine hydroxylase (Th) and pyruvate carboxylase (Pc) gene expression in mice cerebrum were investigated using real-time PCR. RA was demonstrated to show anti-depressant-like effect by significant reduction of immobility time in the TST in mice. This effect was accompanied by a downregulation of Mkp-1 to reach the unstressed group level, an upregulation of Bdnf, Th and Pc in the limbic system. Furthermore, RA significantly decreased serum corticosterone level and increased dopamine level in the limbic system in mice brain. Our study provides the first evidence that RA has anti-depressant activity via downregulation of Mkp-1, upregulation of Bdnf and modulation of dopamine and corticosterone synthesis.

Antidepressant-like activity of plumbagin in unstressed and stressed mice.

Plumbagin has been reported to be neuroprotective, so it might possess antidepressant activity. Therefore, the present study was designed to explore the antidepressant potential of plumbagin in unstressed and stressed mice. Depression-like behavior was induced in Swiss male albino mice by subjecting them to unpredictable mild stress daily for 21 successive days. Plumbagin (4, 8 and 16mg/kg, po) and imipramine (15mg/kg, po) were administered for 3 successive weeks to separate groups of unstressed and stressed mice. Tail suspension test and sucrose preference test were used to evaluate antidepressant effect of the drugs. Highest dose (16mg/kg) of plumbagin and imipramine significantly decreased immobility period of unstressed and stressed mice in tail suspension test as compared to their respective controls. These drugs significantly restored the reduced sucrose preference (%) in stressed mice. The drugs did not significantly affect locomotor activity of mice. Antidepressant-like activity of plumbagin was found to be comparable to imipramine. Plumbagin and imipramine significantly inhibited brain MAO-A activity, decreased plasma nitrite, brain malondialdehyde and catalase levels; and increased reduced glutathione levels of unstressed and stressed mice. The drugs significantly reversed stress-induced increase in plasma corticosterone levels. Antidepressant-like activity of plumbagin in unstressed and stressed mice might be through inhibition of brain MAO-A activity and improvement of antioxidant status. Reversal of stress-induced increase in plasma corticosterone levels might also be responsible for antidepressant-like activity of plumbagin in stressed mice.

Synthesis and evaluation of new 1,5-diaryl-3-[4-(methyl-sulfonyl)phenyl]-4,5-dihydro-1H-pyrazole derivatives as potential antidepressant agents.

In an effort to develop potent antidepressant agents, new pyrazoline derivatives 2a–s were synthesized and evaluated for their antidepressant-like activity by tail suspension test (TST) and modified forced swimming test (MFST). The effects of the compounds on spontaneous locomotor activity were also investigated using an activity cage apparatus. Among these derivatives, compounds 2b, 2d, 2f, 2o, and 2r decreased both horizontal and vertical activity number of the mice. On the other hand, compounds 2a, 2h, 2j, 2k, 2l, 2m, and 2n, which did not induce any significant change in the locomotor activity, significantly shortened the immobility time of mice in TST and MFST, representing the presence of the antidepressant-like effect. Additionally, the same compounds increased the swimming time of mice in MFST without any change in climbing duration, similar to the reference drug fluoxetine (10 mg/kg). In the light of previous papers examining the effects of pyrazolines on central nervous system, this study, once more, pointed out remarkable antidepressant activity potential of pyrazoline derivatives.

Evidence for the Involvement of Potassium Channel Inhibition in the Antidepressant-Like Effects of Hesperidin in the Tail Suspension Test in Mice.

The administration of hesperidin elicits an antidepressant-like effect in mice by a mechanism dependent on an interaction with the L-arginine-nitric oxide (NO)-cyclic guanosine monophosphate (cGMP) pathway, whose stimulation is associated with the activation of potassium (K(+)) channels. Thus, this study investigated the involvement of different types of K(+) channels in the antidepressant-like effect of hesperidin in the mice tail suspension test (TST). The intracerebroventricular administration of tetraethylammonium (TEA, a nonspecific blocker of K(+) channels), glibenclamide (an ATP-sensitive K(+) channel blocker), charybdotoxin (a large- and intermediate-conductance calcium-activated K(+) channel blocker) or apamin (a small-conductance calcium-activated K(+) channel blocker) combined with a subeffective dose of hesperidin (0.01 mg/kg, intraperitoneally [i.p.]) was able to produce a synergistic antidepressant-like effect in the mice TST. Moreover, the antidepressant-like effect elicited by an effective dose of hesperidin (0.3 mg/kg, i.p.) in TST was abolished by the treatment of mice with pharmacological compounds K(+) channel openers (cromakalim and minoxidil). Results showed that the antidepressant-like effect of hesperidin in TST may involve, at least in part, the modulation of neuronal excitability through inhibition of K(+) channels and may act through a mechanism dependent on the inhibition of L-arginine-NO pathway.

Involvement of α1B-adrenoceptors in the anti-immobility effect of imipramine in the tail suspension test

Imipramine is a tricyclic antidepressant inhibitor of norepinephrine and serotonin neuronal reuptake. The roles of specific α1-adrenoceptor subtypes that might be targeted by the increased synaptic levels of noradrenaline induced by imipramine are not well understood. This study investigates the α1-adrenoceptor subtypes involved in the anti-immobility effect of imipramine in the mouse tail suspension test. The anti-immobility effect of imipramine (32mg/kg, i.p.) was significantly antagonised by the non-subtype-selective α1-adrenoceptor antagonist prazosin (0.5 and 1.0mg/kg, i.p.). Neither the selective α1A-adrenoceptor antagonist 5-methyl-3-[3-[3-[4-[2-(2,2,2,-trifluroethoxy)phenyl]-1-piperazinyl]propyl]-2,4-(1H,3H)-pyrimidinedione (RS-100329, 0.5 and 1.0mg/kg) nor the selective α1D-adrenoceptor antagonist 8-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-8-azaspiro[4.5]decane-7,9-dione dihydrochloride, (BMY-7378, up to 1.0mg/kg, i.p.) affected the anti-immobility effect of imipramine. However, the anti-immobility effect of imipramine was significantly antagonised by the selective α1B-adrenoceptor antagonist (2S)-4-(4-amino-6,7-dimethoxy-2-quinazolinyl)-2-[[(1,1-dimethylethyl)amino]carbonyl]-1-piperazinecarboxylate (L-765,314). In addition, mice treated only with RS-100329 or BMY-7378, but not with L-765,314, showed reduced immobility times in comparison to mice treated with vehicle. These results indicate that the selective antagonism of α1A- and α1D-adrenoceptors results in antidepressant-like effects and that the α1B-subtype is the main target for the increased levels of noradrenaline caused by imipramine.

Differential role of AMPA receptors in mouse tests of antidepressant and anxiolytic action

Depression and anxiety often co-occur, and conventional monoamine-facilitating antidepressants show efficacy against symptoms in both disorders. Rodent studies indicate that antidepressant effects of monoamine-based antidepressants involve increased α-amino-3-hydroxy-5- methyl-4-isoxazolepropionic acid glutamate receptor (AMPAR) neurotransmission, and positive allosteric modulators (PAMs) at AMPARs produced antidepressant-like effects in rodents. While this suggests that increased AMPAR-mediated neurotransmission is beneficial in depression management, preclinical studies addressing AMPARs in relation to anxiety have given ambiguous results with both anxiolytic-like and anxiogenic-like effects observed after AMPAR blockade. This study systematically compared the effects of the AMPAR potentiator LY451646 and the AMPAR antagonist GYKI-53655 on depression-related behaviour using the mouse forced swim (FST) and tail suspension tests (TST), and anxiety-related behaviour using the elevated zero maze (EZM), marble burying (MB) and novelty-induced hypophagia (NIH) tests. The serotonin-selective antidepressant citalopram was included for comparison. Due to the importance of AMPARs in learning and memory we also tested if GYKI-53655 disrupted performance in the V-maze test for attention-dependent behaviour, and the social transmission of food preference (STFP) test of long-term memory. LY451646 (3 mg/kg) showed an antidepressant-like profile in the FST and TST, and GYKI-53655 (≥5 mg/kg) had a depressogenic-like effect in the TST but no effect in the FST. Conversely, GYKI-53655 produced marked anxiolytic-like effects in the EZM (≥2.5 mg/kg), MBT (≥2.5 mg/kg), and NIH tests (≥5 mg/kg), while LY451646 (≥3 mg/kg) increased anxiety-like behaviour in the EZM. Citalopram showed an antidepressant-like effect in the FST (≥10 mg/kg), but not TST, an anxiolytic-like effect in the EZM (≥3 mg/kg) and MB test (≥2.5 mg/kg), and an anxiogenic-like effect in the NIH test (≥30 mg/kg). GYKI-53655 did not affect cognitive performance in the V-maze or STFP tests. Collectively, these findings suggest a differential role of AMPARs in depression and anxiety, with AMPAR activation promoting antidepressant responses and AMPAR inhibition promoting anxiolytic responses. The potential of AMPARs as a novel target in depression and anxiety pharmacotherapy is discussed.

The modulation of NMDA receptors and L-arginine/nitric oxide pathway is implicated in the anti-immobility effect of creatine in the tail suspension test.

The modulation of N-methyl-D-aspartate receptor (NMDAR) and L-arginine/nitric oxide (NO) pathway is a therapeutic strategy for treating depression and neurologic disorders that involves excitotoxicity. Literature data have reported that creatine exhibits antidepressant and neuroprotective effects, but the implication of NMDAR and L-arginine/nitric oxide (NO) pathway in these effects is not established. This study evaluated the influence of pharmacological agents that modulate NMDAR/L-arginine-NO pathway in the anti-immobility effect of creatine in the tail suspension test (TST) in mice. The NOx levels and cellular viability in hippocampal and cerebrocortical slices of creatine-treated mice were also evaluated. The anti-immobility effect of creatine (10mg/kg, po) in the TST was abolished by NMDA (0.1pmol/mouse, icv), D-serine (30µg/mouse, icv, glycine-site NMDAR agonist), arcaine (1mg/kg, ip, polyamine site NMDAR antagonist), L-arginine (750mg/kg, ip, NO precursor), SNAP (25μg/mouse, icv, NO donor), L-NAME (175mg/kg, ip, non-selective NOS inhibitor) or 7-nitroindazole (50mg/kg, ip, neuronal NOS inhibitor), but not by DNQX (2.5µg/mouse, icv, AMPA receptor antagonist). The combined administration of sub-effective doses of creatine (0.01mg/kg, po) and NMDAR antagonists MK-801 (0.001mg/kg, po) or ketamine (0.1mg/kg, ip) reduced immobility time in the TST. Creatine (10mg/kg, po) increased cellular viability in hippocampal and cerebrocortical slices and enhanced hippocampal and cerebrocortical NO x levels, an effect potentiated by L-arginine or SNAP and abolished by 7-nitroindazole or L-NAME. In conclusion, the anti-immobility effect of creatine in the TST involves NMDAR inhibition and enhancement of NO levels accompanied by an increase in neural viability.

Antidepressant-Like Effect of the Leaves of Pseudospondias microcarpa in Mice: Evidence for the Involvement of the Serotoninergic System, NMDA Receptor Complex, and Nitric Oxide Pathway.

Depression continues to be a major global health problem. Although antidepressants are used for its treatment, efficacy is often inconsistent. Thus, the search for alternative therapeutic medicines for its treatment is still important. In this study, the antidepressant-like effect of Pseudospondias microcarpa extract (30–300 mg kg−1, p.o.) was investigated in two predictive models of depression—forced swimming test and tail suspension test in mice. Additionally, the mechanism(s) of action involved were assessed. Acute treatment with the extract dose dependently reduced immobility of mice in both models. The antidepressant-like effect of the extract (100 mg kg−1, p.o.) was blocked by p-chlorophenylalanine and cyproheptadine but not prazosin, propranolol, or yohimbine. Concomitant administration of d-cycloserine and the extract potentiated the anti-immobility effect. In contrast, d-serine, a full agonist of glycine/NMDA receptors, abolished the effects. Anti-immobility effects of PME were prevented by pretreatment of mice with L-arginine (750 mg kg−1, i.p.) and sildenafil (5 mg kg−1, i.p.). On the contrary, pretreatment of mice with L-NAME (30 mg kg−1, i.p.) or methylene blue (10 mg kg−1, i.p.) potentiated its effects. The extract produces an antidepressant-like effect in the FST and TST that is dependent on the serotoninergic system, NMDA receptor complex, and the nitric oxide pathway.

Long lasting preventive effects of piperlongumine and a Piper longum extract against stress triggered pathologies in mice

Aim:To compare doxycycline (DOX) such as oral efficacies of piperlongumine (PL) and a Piper longum fruits extract (PLE) as stress resistance inducers.Materials and Methods:Efficacies of oral pretreatments with 5 mg/kg PL or PLE or of 50 mg/kg DOX for 10 consecutive days against stress resistance were compared. Mice in treated groups were subjected to a stress induced hyperthermia on the 1st, 5th, 7th, and 10thday. Treated mice were then subjected to tail suspension test on the 11thday. Alteration in body weights, core temperatures, and gastric ulcers triggered by occasional exposures to foot shocks were determined.Results:DOX like long-lasting protective effects of PL and PLE against gradual alterations in body weights, basal temperatures and transient hyperthermic responses triggered by foot shocks during the post-treatment days were observed. Altered responses of stressed mice in tail suspension test observed 1 day after the last foot-shock exposures and gastric ulcers and other pathologies quantified 1 day after the test were also suppressed in PL or PLE or DOX pretreated groups.Conclusion:PL and crude PLE are DOX like long-acting desensitizers of stress triggered co-morbidities. Reported observations add further experimental evidences justifying traditionally known medicinal uses of P. longum and other plants of the Piperaceae family, and reveal that PL is also another very long acting and orally active inducer of stress resistance. Efforts to confirm stress preventive potentials of low dose plant-derived products enriched in PL or piperine like amide alkaloids in volunteers and patients can be warranted.

Antidepressant-Like and Antioxidant Effects of Plinia trunciflora in Mice.

The jaboticaba tree, Plinia trunciflora (O. Berg) Kausel, is popularly named “jabuticabeira” in Brazil and is used in folk medicine to treat diabetes and chronic inflammation of the tonsils, but studies evaluating the central effects of this species are limited. This study evaluated the antidepressant-like and antioxidant effects of P. trunciflora (PT) aqueous extract, in which five different anthocyanins were identified. PT showed significant ferric-reduction power and DPPH radical scavenging activity in vitro and reduced lipid peroxidation both in vitro and ex vivo. At the behavioural level, PT (400 and 800 mg/kg, i.p.) dose-dependently reduced immobility time in the tail suspension test in Swiss male mice. The identification of bioactive compounds accompanied by the in vitro and ex vivo antioxidant activity of PT suggests that these activities might be related to the antidepressant-like activity of P. trunciflora.

Synthesis and evaluation of neuropharmacological profile of isatin-3-[ N 2-(2-benzalaminothiazol-4-yl)] hydrazones

Background and objective Isatin and its derivatives are versatile lead molecule for potential bioactive agents and are reported to possess a wide spectrum of activities such as central nervous system (CNS), antibacterial, antifungal, anticonvulsant, anti-HIV, antidepressant, anti-inflammatory, etc. In this study, we evaluated neuropharmacological profile of isatin-3-[N2 -(2-benzalaminothiazol-4-yl)] hydrazone derivatives using well-defined preclinical models. Materials and methods The isatin-3-[N2 -(2-benzalaminothiazol-4-yl)] hydrazone derivatives ( Va-Vj ) were synthesized and characterized using spectral data. Neuropharmacological profile of Va-Vj (10 and 100 mg/kg, orally) was investigated by gross behavioural profile, hole board, locomotor activity, hypnotic activity, forced swim test, tail suspension test and rota rod test in mice. Imipramine (10 mg/kg) and diazepam (2 mg/kg) were used as standard for antidepressant and sedative as well as a hypnotic drug, respectively. Results and conclusion Isatin derivatives showed dose-dependent neuropharmacological action on the CNS, such as anxiolytic, sedative, hypnotic and depressant action. Among all the derivatives, halogen-substituted compounds ( Vh and Vi ) at 100 mg/kg showed significant (P < 0.001) action when compared with the control group (0.1% sodium carboxy methylcellulose (CMC)), and other substituted isatin derivatives Va, Vb, Vc, Vd, Ve, Vf, Vg and Vj also proved to possess a significant (P < 0.05) action at 100 mg/kg compared with the control group. From these results, we concluded that Va-Vj compounds possessed a wide range of CNS activities.

Experimental Evaluation of Antidepressant activity of Aqueous and Chloroform Leaf and Shoot Extracts ofEicchornia crassipesLinn in Mice

The main objective of the study to evaluate the Anti-depressant activity of aqueous and chloroform extract of Eicchornia crassipes in Forced swim test (FST), Tail Suspension test (TST) in mice. Phytochemical screening showed presence of carbohydrates, alkaloids, flavanoids, steroids, saponins, amino acids, gums and mucilage. AEEC and CEEC did not produce any lethal effect even upto 2000mg/kg, p.o during Acute Oral Toxicity study. In FST and TST, CEEC showed diminution of duration of immobility time in 200mg/kg but not in 100mg/kg. From the above finding concluding that, shortening of immobility time in the FST and TST indicating, CEEC showed more antidepressant activity acting either by the enhancement of central 5-HT or catecholamine neurotransmission compared to AEEC in mice.

Rapid Antidepressant Activity of Ethanol Extract of Gardenia jasminoides Ellis Is Associated with Upregulation of BDNF Expression in the Hippocampus.

Ethanol extract of Yueju pill, a Traditional Chinese Medicine herbal formula widely used to treat mood disorders, demonstrates rapid antidepressant effects similar to ketamine, likely via instant enhancement of brain-derived neurotrophic factor (BDNF) expression in the hippocampus. Here we investigated ethanol extracts of the constituent herbs of Yueju responsible for rapid antidepressant effects. Screening with tail suspension test in Kunming mice at 24 hours after a single administration of five individual constituent herbs of Yueju, we found that only Gardenia jasminoides Ellis (GJ) showed a significant effect. The antidepressant response started at 2 hours after GJ administration. Similar to Yueju and ketamine, a single administration of GJ significantly reduced the number of escape failures in the learned helplessness test. Furthermore, GJ decreased latency of food consumption in the novelty suppressed-feeding test. Additionally, starting from 2 hours and continuing for over 20 hours after GJ administration, BDNF expression in the hippocampus was upregulated, temporally linked with the antidepressant response. These findings suggest that GJ has rapid antidepressant effects, which are associated with the elevated expression of BDNF in the hippocampus. In Yueju formula, Yue represents GJ, as thus our study demonstrates the primary role of GJ in rapid antidepressant efficacy of Yueju.

To Investigate the Role of Memantine as Anxiolytic in Elevated Plus Maze Test and as Antidepressant in Tail Suspension Test in Swiss Albino Mice

Background: The magnitude of improvement seen with present conventional medicines for anxiety and depression remain disappointing thereby providing a scope for the study of newer drugs. In the literature, there is evidence demonstrating the modulation of N-methyl-D-aspartate (NMDA)receptors in anxiety and depression. The present study is undertaken to evaluate the antianxiety effect of memantine in elevated plus maze (EPZ) test and its antidepressant effect in tail suspension test (TST)in Swiss albino mice.Methods: Animals were divided into six groups (n=6). First group mice were given normal saline (10 ml/kg), second group were administered lorazepam (0.5 mg/kg), third group with memantine (3 mg/kg) and fourth group with memantine plus lorazepam, fifth group was administered amitriptyline (10 mg/kg)and sixth group received memantine plus amitriptyline. All drugs were administered by intraperitoneal route daily for 7 consecutive days. Results were analyzed by one-way ANOVA followed by post-hoc Tukey’s test.Results: Memantine treated mice showed significant increase (p&lt;0.001)in time spent and number of entries in open arm and significant decrease in time spent and number of entries in closed arm in EPZ when compared to control group. Duration of immobility was significantly (p&lt;0.001)reduced in animals treated with memantine when compared to the control group in TST.Conclusions: NMDA antagonist, memantine has showed significant antianxiety effect in EPZ test and antidepressant effect in TST.

Agmatine enhances antidepressant potency of MK-801 and conventional antidepressants in mice

Agmatine, an endogenous guanidine amine, has been shown to produce antidepressant-like effects in animal studies. This study investigated the effects of the combined administration of agmatine with either conventional monoaminergic antidepressants or the N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 in the tail suspension test (TST) in mice. The aim was to evaluate the extent of the antidepressant synergism by examining the ability of a fixed dose of agmatine to shift the antidepressant potency of fluoxetine, imipramine, bupropion and MK-801. A sub-effective dose of agmatine (0.0001mg/kg, p.o.) significantly increased the potency by which fluoxetine, imipramine, bupropion and MK-801 decreased immobility time in the TST by 2-fold (fluoxetine), 10-fold (imipramine and bupropion) and 100-fold (MK-801). Combined with previous evidence indicating a role of monoaminergic systems in the effect of agmatine, the current data suggest that agmatine may modulate monoaminergic neurotransmission and augment the activity of conventional antidepressants. Moreover, this study found that agmatine substantially augmented the antidepressant-like effect of MK-801, reinforcing the notion that this compound modulates NMDA receptor activation. These preclinical data may stimulate future clinical studies testing the effects of augmentation therapy with agmatine for the management of depressive disorders.

Enhanced antidepressant-like effects of the macromolecule trefoil factor 3 by loading into negatively charged liposomes

Immunocytes, mainly neutrophils and monocytes, exhibit an intrinsic homing property, enabling them to migrate to sites of injury and inflammation. They can thus act as Trojan horses carrying concealed drug cargoes while migrating across impermeable barriers to sites of disease, especially the blood–brain barrier (BBB). In this study, to target circulating phagocytic cells, we formulated negatively charged nanosize liposomes and loaded trefoil factor 3 (TFF3) into liposomes by the pH-gradient method. According to the optimized formulation (5:1.5 of lipid to cholesterol, 10:1 of lipid to drug, 10 mg/mL of lipid concentration, and 10 mmol/L of phosphate-buffered saline), 44.47% entrapment efficiency was obtained for TFF3 liposomes with 129.6 nm particle size and −36.6 mV zeta potential. Compared with neutrally charged liposomes, the negatively charged liposomes showed a strong binding capacity with monocytes and were effectively carried by monocytes to cross the BBB in vitro. Furthermore, enhanced antidepressant-like effects were found in the tail-suspension and forced-swim tests in mice, as measured by decreased immobility time, as well as increased swimming time and reduced immobility in rats. These results suggested that negatively charged liposomes could improve the behavioral responses of TFF3, and our study opens up a new way for the development of effective therapies for brain disease by increasing the permeability of the BBB.

Potential of novel phytoecdysteroids isolated from Vitex doniana in the treatment depression: Involvement of monoaminergic systems

Vitex doniana Sweet (Verbanaceae) is used in traditional African medicine for the treatment of neurological disorders including depression. In our previous studies, three new phytoecdysteroids were isolated from methanol stem bark extract of V. doniana (VD) (11β-hydroxy-20-deoxyshidasterone, 21-hydroxyshidasterone, and 2,3-acetonide-24-hydroxyecdysone) along with known ecdysteroids. This study was designed to investigate antidepressant-like effect of VD and the isolated phytoecdysteroids in behavioral models of despair, forced-swim test (FST) and tail-suspension test (TST) in mice. VD (100 and 200mg/kg, p.o.) treatment reduced (P<0.05) the duration of immobility in both tests without affecting the locomotor activity and exploratory behavior as observed in the open field test. Similarly, 21-hydroxyshidasterone, 11β-hydroxy-20-deoxyshidasterone, ajugasterone and 24-hydroxyecdysone acute oral treatments significantly reduced immobility time with peak effect at 10mg/kg, which was similar to the effect of conventional antidepressants (imipramine and fluoxetine) in the FST. Conversely, pretreatment of mice with yohimbine (1mg/kg, i.p., α2-adrenoceptor antagonist), ketanserin (5mg/kg, i.p., 5-HT2A/2C receptor antagonist) or sulpiride (dopamine D2 receptor antagonist) prevented the antidepressant-like effect of 21-hydroxyshidasterone while the effects of 11β-hydroxy-20-deoxyshidasterone and 24-hydroxyecdysone were blocked by yohimbine or ketanserin in the FST. Moreover, the anti-immobility effect elicited by ajugasterone was prevented by prazosin (62.5μg/kg, i.p., α1-adrenoceptor antagonist) pretreatment. Our findings demonstrated that V. doniana and its phytoecdysteroids constituents elicited antidepressant-like effect in behavioral paradigm of despair. Furthermore, 21-hydroxyshidasterone produces its antidepressant-like effect through interaction with α2-adrenoceptor, 5-HT2A/2C receptor and dopamine D2-receptors but 11β-hydroxy-20-deoxyshidasterone and 24-hydroxyecdysone effects depend on interaction with α2-adrenoceptor and 5-HT2A/2C receptors while ajugasterone produces its action through interaction with post-synaptic α1-adrenoceptors. Thus, phytoecdysteroids could play a pivotal role in the treatment of major depression.