Antidepressant-like Activity Research Articles

Engeletin alleviates depression-like phenotype by increasing synaptic plasticity via the BDNF-TrkB-mTORC1 signalling pathway.

Major depressive disorder (MDD) is a severe mental disorder associated with high rates of morbidity and mortality. Current first-line pharmacotherapies for MDD are based on enhancement of monoaminergic neurotransmission, but these antidepressants are still insufficient and produce significant side-effects. Consequently, the development of novel antidepressants and therapeutic targets is desired. Engeletin, a natural Smilax glabra rhizomilax derivative, is a compound with proven efficacy in treating ischemic stroke, yet its therapeutic effects and mechanisms for depression remain unexplored. The effects of engeletin were assessed in the forced swimming test (FST) and tail suspension test (TST) in mice. Engeletin was also investigated in the chronic restraint stress (CRS) mouse model of depression with fluoxetine (FLX) as the positive control. Changes in prefrontal cortex (PFC) spine density, synaptic plasticity-linked protein expressions and the brain-derived neurotrophic factor (BDNF)-tyrosine kinase B (TrkB)- mammalian target of rapamycin complex 1 (mTORC1) signalling pathway after chronic stress and engeletin treatment were then investigated. The TrkB and mTORC1 selective inhibitors, ANA-12 and rapamycin, respectively, were utilized to assess the engeletin's antidepressive mechanisms. Our data shows that engeletin exhibited antidepressant-like activity in the FST and TST in mice without affecting locomotor activity. Furthermore, it exhibited efficiency against the depression of CRS model. Moreover, it enhanced the BDNF-TrkB-mTORC1 pathway in the PFC during CRS and altered the reduction in dendritic spine density and levels of synaptic plasticity-linked protein induced by CRS. In conclusion, engeletin has antidepressant activity via activation of the BDNF-TrkB-mTORC1 signalling pathway and upregulation of PFC synaptic plasticity.

Restorative effect of NitroSynapsin on synaptic plasticity in an animal model of depression

In the search for new options for the pharmacological treatment of major depressive disorder, compounds with a rapid onset of action and high efficacy but lacking a psychotomimetic effect are of particular interest. In the present study, we evaluated the antidepressant potential of NitroSynapsin (NS) at behavioural, structural, and functional levels. NS is a memantine derivative and a dual allosteric N-methyl-d-aspartate receptors (NMDAR) antagonist using targeted delivery by the aminoadamantane of a warhead nitro group to inhibitory redox sites on the NMDAR. In a chronic restraint stress (CRS) mouse model of depression, five doses of NS administered on three consecutive days evoked antidepressant-like activity in the chronically stressed male C57BL/6J mice, reversing CRS-induced behavioural disturbances in sucrose preference and tail suspension tests. CRS-induced changes in morphology and density of dendritic spines in cerebrocortical neurons in the medial prefrontal cortex (mPFC) were also reversed by NS. Moreover, CRS-induced reduction in long-term potentiation (LTP) in the mPFC was found to be prevented by NS based on the electrophysiological recordings. Our study showed that NS restores structural and functional synaptic plasticity and reduces depressive behaviour to the level found in naïve animals. These results preliminarily revealed an antidepressant-like potency of NS.

Potential Antidepressant-Like Activity of Rhus coriaria L. (Sumac) Ethanolic Extract: The Mechanism of Action via the Monoaminergic System in a Mouse Model

Background: Studies have reported certain side effects that occur with the use of conventional antidepressants limit their clinical use. Plant derivatives such as Rhus coriaria L. extract can be used as alternatives for depression. Objectives: This study was designed to investigate the antidepressant-like effects of R. coriaria in a mouse model and the role of the monoaminergic system in its mechanism of action. Methods: A total of 174 male NMRI mice were used. Thirty minutes after treating animals with common antidepressants and R. coriaria extract (25 - 200 mg/kg), the tail suspension test (TST) was performed. One hour after treating mice with serotonergic, adrenergic, and dopaminergic antagonists, 100 mg/kg of the extract was administered, and TST was performed after 30 minutes. Potential synergistic interactions between the extract and the sub-doses of fluoxetine (Flx) and imipramine (Imp) were also investigated. Injections were all administered intraperitoneally. Results: Rhus coriaria extract (50 - 200 mg/kg) induced antidepressant-like effects (P < 0.001) without altering animal locomotion in the open field test (OFT; P > 0.05). The tail suspension test showed that the antidepressant-like activity of the extract was blocked by pretreating with the above-mentioned antagonists (P < 0.05 and P < 0.01, respectively). The sub-dose of the extract also increased the efficiency of the sub-doses of common antidepressants (P < 0.001). Conclusions: The extract showed antidepressant-like activity via the monoaminergic system and increased the efficiency of common antidepressants. We suggest adding dried R. coriaria extract powder to the formulation of common antidepressant agents following thorough clinical studies on the substance.

Angelica glauca oil exhibits antidepressant-like effect in experimental animals: An in silico, ADMET and in vivo investigation

Angelica glauca is an aromatic plant of the Apiaceae family. Traditionally A. glauca is used to cure several diseases including anxiety and depression. The present investigation is focused on studying the in silico and in-vivo antidepressant potential of A. glauca essential oil (AGEO). The GC-MS analysis was performed on A. glauca root oil to confirm the genuineness of the drug. Compounds viz. alpha phellandrene, limonene, and z-ligustilide obtained through GC-MS analysis were screened for Monoamine oxidase from Aspergillus niger (MAO-N) (PDB: 2vvl) binding through molecular docking studies by using autoDock/Mcule tool. Prediction of ADME and physicochemical properties of above-detected compounds was done by using preADMET tool version 2.0. The antidepressant activity was investigated by the forced swimming method and tail suspension method. The docking studies exhibits that limonene has a maximum affinity for MAO-N, followed by alpha phellandrene and z-ligustilide. It has been observed that upon oral administration of A. glauca oil (250 & 500 µl/kg b.w.) and reference drug selegiline at the dose of (0.2 mg/kg) shows significant (p<0.01) reduction in immobility in rats in both the behavioral models. All the results were compared with the control group and justified by histopathological analysis of the brain. The data obtained from the study suggests the antidepressant-like action of A. glauca root oil and its phytocompounds in the behavioral models of FST and TST in a dose-dependent manner.

Ginsenoside Rb1 protects hippocampal neurons in depressed rats based on mitophagy-regulated astrocytic pyroptosis

BackgroundAstrocytes play a vital role in offering functional support for neurons, which are related to the pathogenic mechanism of depression. Ginsenoside Rb1 (GRb1) is demonstrated with antidepressant-like activities. PurposeWe aimed to investigate whether GRb1 can inhibit mitophagy-mediated astrocytic pyroptosis to protect neurons in depression. Study DesignModel rats were subjected to chronic unpredictable mild stress (CUMS) for determining the in vivo antidepressant activity of GRb1. MethodsThe mitophagy-mediated antipyroptosis role of GRb1 was assessed in lipopolysaccharide (LPS) + ATP-stimulated astrocytes. The mechanism by which GRb1 protects synaptic plasticity was investigated using hippocampal neurons incubated in an astrocyte medium. The rat depressive-like behaviors were determined through sucrose preference, forced swimming, and the open-field tests. Escitalopram was used in the anti-depression control of GRb1. Cyclosporin A (CsA), a mitophagy inhibitor, and interleukin (IL)-1β were used to reverse the role of GRb1 in mitophagy and pyroptosis, respectively. ResultsGRb1 inhibited LPS-induced inflammation and activation in the astrocytes and repressed nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway. Also, GRb1 repressed LPS + ATP-promoted astrocytic pyroptosis. During GRb1 treatment, the activation of mitophagy with a decrease in ROS was observed in LPS + ATPs-stimulated astrocytes. CsA enhanced GRb1-decreased ROS and promoted astrocytic pyroptosis. The GRb1-treated astrocyte medium suppressed neuron death and increased neuron viability and synaptic density. Escitalopram and GRb1 improved the depressive-like behaviors of the rats. GRb1 activated mitophagy and inhibited astrocytic activation and pyroptosis in rats with depression. It also reduced impairments in synaptic structures and increased synaptic density in depressive-like rats. IL-1β increased astrocytic pyroptosis and reversed GRb1-enhanced synaptic plasticity in the rats exposed to CUMS. There were no statistical changes in depressive-like behaviors between GRb1 and Escitalopram groups. ConclusionGRb1 modulates mitophagy and the NF-κB pathway to inhibit astrocytic pyroptosis, thereby maintaining neurological homeostasis by repressing inflammation and enhancing synaptic plasticity.

Antidepressant-like effects of tomatidine and tomatine, steroidal alkaloids from unripe tomatoes, via activation of mTORC1 in the medial prefrontal cortex in lipopolysaccharide-induced depression model mice

ABSTRACT Ketamine, an N-methyl-D-aspartate receptor antagonist, produces rapid antidepressant effects in patients with treatment-resistant depression. However, owing to the undesirable adverse effects of ketamine, there is an urgent need for developing safer and more effective prophylactic and therapeutic interventions for depression. Preclinical studies have demonstrated that activation of the mechanistic target of rapamycin complex 1 (mTORC1) in the medial prefrontal cortex (mPFC) mediates the rapid antidepressant effects of ketamine. The steroidal alkaloid tomatidine and its glycoside α-tomatine (tomatine) can activate mTORC1 signaling in peripheral tissues/cells. We examined whether tomatidine and tomatine exerted prophylactic and therapeutic antidepressant-like actions via mPFC mTORC1 activation using a mouse model of lipopolysaccharide (LPS)-induced depression. Male mice were intraperitoneally (i.p.) administered tomatidine/tomatine before and after the LPS challenge to test their prophylactic and therapeutic effects, respectively. LPS-induced depression-like behaviors in the tail suspension test (TST) and forced swim test (FST) were significantly reversed by prophylactic and therapeutic tomatidine/tomatine administration. LPS-induced anhedonia in the female urine sniffing test was reversed by prophylactic, but not therapeutic, injection of tomatidine, and by prophylactic and therapeutic administration of tomatine. Intra-mPFC infusion of rapamycin, an mTORC1 inhibitor, blocked the prophylactic and therapeutic antidepressant-like effects of tomatidine/tomatine in TST and FST. Moreover, both tomatidine and tomatine produced antidepressant-like effects in ovariectomized female mice, a model of menopause-associated depression. These results indicate that tomatidine and tomatine exert prophylactic and therapeutic antidepressant-like effects via mTORC1 activation in the mPFC and suggest these compounds as promising candidates for novel prophylactic and therapeutic agents for depression.

Sceletium tortuosum-derived mesembrine significantly contributes to the anxiolytic effect of Zembrin®, but its anti-depressant effect may require synergy of multiple plant constituents

Ethnopharmacology relevanceSceletium tortuosum (L.) N.E.Br. (ST) is an alkaloid-rich succulent plant with various mechanisms of action that infer psychotropic effects. These actions correlate with clinical evidence suggesting efficacy in the treatment of depression and anxiety, in line with its use by indigenous populations. Its low side effect profile suggests potential of ST to improve the overall wellbeing and compliance of millions of patients that experience severe side effects and/or do not respond to current prescription medication. However, to elucidate specific physiological effects of ST extracts, it is necessary to first understand which of its constituents are the major contributors to beneficial effects demonstrated for ST in this context. Aim of the studyTo determine an anxiolytic- and antidepressant-like effective concentration of a ST extract by means of a dose response in zebrafish (ZF) larvae, and to assess relative contributions of equivalent concentrations of isolated alkaloids contained in the effective concentration(s). Materials and methodsA dose response study employing a light-dark transition test (LDTT) was done in ZF larvae (<5 days post fertilization) to track locomotor activity in terms of anxiety-like (hyperlocomotion) and depression-like (hypolocomotion) behaviour. Larvae were treated for 1 h directly before the LDTT with escalating concentrations of a ST extract commercially known as Zembrin® (Zem) ranging from 0.25 to 500 μg/mL and compared to an untreated control group (n = 12 per treatment concentration). LDTT was repeated after 24 h to evaluate long-term exposure toxicity. The concentration that best attenuated hyperlocomotion during the dark phase following light-dark transition was identified as the anxiolytic-like concentration. This concentration, plus one higher and one lower concentration, were used for subsequent tests. The percentage content of each alkaloid (mesembrine, mesembrenone, mesembrenol, and mesembranol) in these concentrations were calculated and applied to additional larvae to identify the most effective anxiolytic-like alkaloid in the LDTT. To identify antidepressant-like therapeutic concentration and equivalent alkaloid concentration, the same treatment concentrations were tested in larvae (n = 12 per treatment concentration) pre-exposed to reserpine for 24 h. Depending on normality of data distribution, Brown-Forsythe and Welch, or Kruskal-Wallis ANOVA were used, with Dunnett or Dunn's multiple comparisons tests. ResultsOnly the extreme concentration of Zem (500 μg/mL) elicited toxicity after treatment for 24 h. Zem 12.5 μg/mL was the most effective anxiolytic-like concentration as it significantly decreased locomotor activity (P = 0.05) in the LDTT. Low (5 μg/mL), optimal (12.5 μg/mL) and high (25 μg/mL) Zem concentrations, as well as treatment solutions of single alkaloids (mesembrine, mesembrenone, mesembranol and mesembrenol), prepared to contain equivalent concentrations of each major alkaloid contained within these three concentrations of Zem, were tested further. Only mesembrine concentrations equal to that contained within the optimal and high dose of Zem (12.5 and 25 μg/mL) showed significant anxiolytic-like effects (P < 0.05). Only the highest Zem concentration (25 μg/mL) reversed the effects of reserpine - indicating antidepressant-like properties (P < 0.05) - while isolated alkaloids failed to induce such effects when administered in isolation. ConclusionsCurrent data provide evidence of both anxiolytic- and antidepressant-like effect of whole extract of Zem, with relatively higher concentrations required to achieve antidepressant-like effect. Of all alkaloids assessed, only mesembrine contributed significantly to the anxiolytic-like effects of Zem. No alkaloid alone could be pinpointed as a contributor to the antidepressant-like activity observed for higher concentration Zem. This may be due to synergistic effects of the alkaloids or may be due to other components not tested here. Current data warrants further investigation into mechanisms of action, as well as potential synergy, of ST alkaloids in suitable mammalian in vivo models.

Design and synthesis of novel PDE4 inhibitors as potential candidates for antidepressant agents

PDE4 inhibitors exhibit anti-stress and antidepressant-like abilities by catalyzing the hydrolysis of cAMP, a primary regulator for intracellular communication in the brain. Herein, novel diarylpyrazole derivatives are synthesized and investigated for their ability to inhibit PDE4. In vitro studies indicate that most of the synthesized compounds show significant potency for the inhibition of PDE4. Specifically, N-(4-(3-(3,5-dimethoxyphenyl)-1 H-pyrazol-5-yl)benzyl)-2-morpholinoethan-1-amine exhibits the most potent PDE4 inhibition, with an IC50 value of ca. 0.09 μM. It also produces antidepressant-like activities in sugar water consumption and in forced swimming tests in vivo.

The study of the spectrum of pharmacological activity of the new original NT-3 mimetic dipeptide GTS-302

BACKGROUND: The association of the pathogenesis of neurodegenerative diseases, depression, anxiety, and cognitive disorders with the deficit of neurotrophin-3 determines the prospect of creating drugs with a similar mechanism of action. Since the use of full-size neurotrophin-3 is limited by unsatisfactory pharmacokinetic properties, it is relevant to create low-molecular-weight mimetics of neurotrophin-3 that are active when administered systemically. A dimeric dipeptide mimetic of the 4th loop of neurotrophin-3, hexamethylenediamide bis(N--oxibutyryl-L-glutamyl-L-asparagine) GTS-302, which activates TrkC and TrkB receptors, has been developed at the V.V. Zakusov Research Institute of Pharmacology.&#x0D; AIM: The aim of this study was to investigate the spectrum of pharmacological activity of GTS-302.&#x0D; MATERIALS AND МETHODS: The pharmacological effects of GTS-302 were investigated following its intraperitoneal administration. The antidepressant-like activity of GTS-302 was studied in the forced swim test in mice after acute and 7-day administration. The anxiolytic and cognitive activity of the dipeptide were studied in the elevated plus maze test in mice and the novel object recognition test in rats after acute administration, respectively. The effect of GTS-302 on pain sensitivity was studied in the hot plate test in mice after acute administration.&#x0D; RESULTS: It was found that GTS-302 exhibits antidepressant-like activity after acute administration at doses of 0.5, 1.0, 5.0 and 10 mg/kg. After 7-day administration, the antidepressant-like activity of GTS-302 was more pronounced in terms of effect size and statistical significance. The dipeptide GTS-302 at doses of 1.0, 5.0 and 10.0 mg/kg showed anxiolytic and cognitive activity and did not affect pain sensitivity.&#x0D; CONCLUSIONS: The pharmacological spectrum of the low-molecular-weight mimetic of neurotrophin-3, dipeptide GTS-302, revealed upon systemic administration includes a number of neuropsychotropic effects characteristic of the full-sized neurotrophin. This allows us to consider GTS-302 as a potential neuropsychotropic drug.

Neuropharmacological Effects of the Dichloromethane Extract from the Stems of Argemone ochroleuca Sweet (Papaveraceae) and Its Active Compound Dihydrosanguinarine.

Argemone ochroleuca Sweet (Papaveraceae) is used in folk medicine as a sedative and hypnotic agent. This study aimed to evaluate the anxiolytic-like, sedative, antidepressant-like, and anticonvulsant activities of a dichloromethane extract of A. ochroleuca stems (AOE), chemically standardized using gas chromatography-mass spectrometry (GC-MS), and its active compound dihydrosanguinarine (DHS). The anxiolytic-like, sedative, antidepressant-like, and anticonvulsant activities of the AOE (0.1-50 mg/kg p.o.) and DHS (0.1-10 mg/kg p.o.) were evaluated using murine models. A possible mechanism for the neurological actions induced by the AOE or DHS was assessed using inhibitors of neurotransmission pathways and molecular docking. Effective dose 50 (ED50) values were calculated by a linear regression analysis. The AOE showed anxiolytic-like activity in the cylinder exploratory test (ED50 = 33 mg/kg), and antidepressant-like effects in the forced swimming test (ED50 = 3 mg/kg) and the tail suspension test (ED50 = 23 mg/kg), whereas DHS showed anxiolytic-like activity (ED50 = 2 mg/kg) in the hole board test. The AOE (1-50 mg/kg) showed no locomotive affectations or sedation in mice. A docking study revealed the affinity of DHS for α2-adrenoreceptors and GABAA receptors. The anxiolytic-like and anticonvulsant effects of the AOE are due to GABAergic participation, whereas the antidepressant-like effects of the AOE are due to the noradrenergic system. The noradrenergic and GABAergic systems are involved in the anxiolytic-like actions of DHS.

Nanoemulsion-based piperine to enhance bioavailability for the treatment of LPS-induced depression-like behaviour in mice

In the present study, the objective was to encapsulate piperine in nanoform by solvent evaporation method and to investigate the antidepressant-like activity of nanopiperine in lipopolysaccharide (LPS) induced depression in mice. LPS-induced depression in mice was reversed by repeated treatment of nanopiperine at dosages of 5 and 10 mg/kg body weight for 14 days. After 24 h of LPS injection, the animals were exposed to a (TST) tail suspension test and (FST) forced swim test. A sequence of behaviours was measured on days 0, 7, and 14. On day 14, the animals were euthanized, and the blood was collected; biochemical analysis was performed for the measurement of inflammatory and oxidative stress markers. Within the same period, nanopiperine improved hippocampal progenitor cell proliferation and increased brain-derived neurotrophic factor (BDNF) levels in the hippocampus of mice subjected to LPS-induced stress. In addition, the neurotransmitter estimation by the HPLC method showed that nanopiperine increased the levels of neurotransmitters. In summary, the nanopiperine showed potent neuroprotective and antidepressant activity, and stability relating to the elevated level of hippocampal BDNF level and as compared to pure piperine, the nanopiperine showed better oral bioavailability and stability.

(S)-Ketamine but Not (R)-Ketamine Shows Acute Effects on Depression-Like Behavior and Sleep-Wake Architecture in Rats.

Racemic ketamine consists of two enantiomers, namely (R)-ketamine and (S)-ketamine, with distinguishable pharmacological properties. Both enantiomers have been reported to show rapid antidepressant effects in rodents. Currently, the (S)-enantiomer has been approved for the treatment of major depression, whereas (R)-ketamine failed to show antidepressant effect in recent clinical studies. Major depressive disorder is frequently characterized by disinhibition of rapid eye movement (REM) sleep and disruption of non-REM (NREM) sleep. Racemic ketamine and most conventional antidepressants affect these parameters. However, it remains largely unknown which enantiomer is responsible for these effects. Here, we compared acute effects of the two ketamine enantiomers (15 mg/kg i.p.) on different sleep-wake stages in freely moving, EEG-equipped rats. We also evaluated the antidepressant-like activity of the enantiomers in a chronic restraint stress model of depression. (S)-ketamine but not (R)-ketamine increased REM sleep latency and decreased REM sleep time at 2 and 3 hours, and increased electroencephalogram delta power during NREM sleep. In addition, only (S)-ketamine increased wakefulness and decreased NREM sleep in the first 2 hours. In the forced swimming test, only (S)-ketamine decreased the immobility time of chronically stressed rats. Effects of the two ketamine enantiomers on rat sleep-wake architecture and behavior are markedly different when administered in the same dose. (S)-ketamine remarkably affects the sleep-wake cycle and very likely sleep-related neuroplasticity, which may be relevant for its antidepressant efficacy. Our results regarding (R)-ketamine's lack of effect on vigilance and behavior are in line with recent clinical studies.

Role of BDNF-TrkB signaling in the antidepressant-like actions of loganin, the main active compound of Corni Fructus.

Corni Fructus (CF) and some CF-contained prescriptions are commonly used in clinical treatment of depression. This investigation aims to evaluate the main active compound of CF in antidepressant properties and its key target. Firstly, this study established a behavioral despair model and used high-performance liquid chromatography method to evaluate the antidepressant-like effects of water extract, 20%, 50%, and 80% ethanol extracts of CF, and its main active compound. Then, this study created chronic unpredictable mild stress (CUMS) model to assess loganin's antidepressant-like properties, and its target was evaluated by quantitative real-time polymerase chain reaction, Western blot, Immunofluorescence, enzyme-linked immunosorbent assay, and tyrosine receptor kinase B (TrkB) inhibitor. Results showed that the different extracts of CF significantly shortened the immobility time in forced swimming and tail suspension tests. Moreover, loganin alleviated CUMS-induced depression-like behavior, promoted neurotrophy and neurogenesis, and inhibited neuroinflammation. Furthermore, K252a blocked the improvement of loganin on depression-like behavior, and eliminated the enhancement of neurotrophy and neurogenesis and the inhibition of neuroinflammation. Overall, these results indicated that loganin could be used as a major active compound of CF for the antidepressant-like properties and exerted antidepressant-like actions by regulating brain derived neurotrophic factor (BDNF)-TrkB signaling, and TrkB could be used as key target for itsantidepressant-like actions.

Antidepressant effects of novel positive allosteric modulators of Trk-receptor mediated signaling – a potential therapeutic concept?

BackgroundMajor depressive disorder (MDD) is defined as a complex mental disorder which is characterized by a pervasive low mood and aversion to activity. Several types of neurotransmitter systems e.g. serotonergic, glutamatergic and noradrenergic systems have been suggested to play an important role in the origination of depression, but neurotrophins such as brain derived neurotrophic factor (BDNF) have also been implicated in the disease process.ObjectivesThe purpose of this study was to examine the effects of a newly developed class of molecules, characterized as positive allosteric modulators of neurotrophin/Trk receptor mediated signaling (Trk-PAM), on neurotransmitter release and depression-like behavior in vivo.MethodsThe effect of and possible interaction of neurotrophin/Trk signaling pathways with serotonergic and glutamatergic systems in the modulation of depression-related responses was studied using newly developed Trk-PAM compounds (ACD855, ACD856 and AC26845), as well as ketamine and fluoxetine in the forced swim test (FST) in rodents. Moreover, in vivo microdialysis in freely moving rats was used to assess changes in neurotransmitter levels in the rat.ResultsThe results from the study show that several different compounds, which all potentiate Trk-receptor mediated signaling, display antidepressant-like activity in the FST. Moreover, the data also indicate that the effects of both fluoxetine and ketamine in the FST, both used in clinical practice, aremediated via BDNF/TrkB signaling, which could have implications for novel therapies in MDD.ConclusionsTrk-PAMs could provide an interesting avenue for the development of novel therapeutics in this area.

Anti-depressant Potentials of Some Bioactive Components of Basella alba Leaves in Chronic Unpredictable Stress Rat Model

Bioactive components of Basella alba leaves are responsible for their antidepressant-like activity. However, the component with the greatest anti-depressant activity is unknown. This study investigated the antidepressant-like activities of the bioactive components (phenols, flavonoids, and glycosides) in Basella alba leaves. Forty-two male Wistar rats weighing 50–200 g were randomly divided into six groups (n=7). All the groups, except for the control, were subjected to chronic unpredictable stress (CUS) for five weeks. The rats in the CUS groups were treated with normal saline (1 mL/kg), escitalopram (5 mg/kg), and each of the phenol-, flavonoid-, and glycoside-rich Basella alba extracts (200 mg/kg) orally for twenty-one days. The tail suspension, sucrose preference, light-dark box, and hole-board tests were carried out before and after the induction of depression. In the CUS groups, reduced mobility time on tail suspension, increased percentage sucrose consumption, frequency of head dips on the hole board, and line-cross frequency in the light-dark box were observed. The latency on the hole board was reduced with Basella alba components, while there was a significant (p&lt;0.05) decrease in serum brain-derived neurotrophic factor and an increase in serum IL-6 in the CUS animals not treated with extracts. The phenol-rich Basella alba extract showed the most potent antidepressant-like activity, followed by the flavonoid-rich extract. The bioactive components of Basella alba, particularly phenols, were effective in ameliorating the depressive features of CUS and should be further studied for use as an adjunct or stand-alone antidepressant.

Neuropharmacological study of Moringa olifera

Objective: Moringa olifera is a medicinal plant widely used in many parts of the world for hypertension, pain and epilepsy. The aim of this study was to determine the effect of M. olifera aqueous leaf, root and steam extract on neurobehavioral activities of healthy mice. Method: Male mice were randomly divided into a control group (given 0.9% NaCl orally) and three groups treated with the extract at doses of 100, 200, and 400 mg/kg/day for 14 consecutive days. Neuropharmacological activity were evaluated by neuro-muscular coordination (rota rod treadmill), pain (hot plate and acetic acid-induced abdominal constriction). Administration of M. olifera extract had a significant and dose dependent antinociceptive action in both thermal and chemical tests (p &lt; 0.05). The extract (400 mg/kg) caused a reduction in exploration activity and neuromuscular coordination, and decreased the mobility time in the FST, suggesting an antidepressant-like action. Motor activity was not significantly affected by any of the doses used. Conclusion: The results suggest that the plant aqueous extract may have a dose-dependent central nervous system (CNS) depressant action.

Changes in social, sexual, and hedonic behaviors in rats in response to stress and restoration by a negative allosteric modulator of α5-subunit containing GABA receptor

Major depressive disorder (MDD) is a debilitating and costly human condition. Treatment for MDD relies heavily on the use of antidepressants that are slow to produce mood-related changes and are not effective in all patients, such as selective serotonin reuptake inhibitors (SSRIs). Several novel compounds, including negative allosteric modulators of GABA-A receptors containing the α5-subunit (GABA-NAMs), are under investigation for potential fast acting therapeutic use in MDD. Preclinical evidence that these compounds produce a rapid antidepressant-like response comes primarily from simple tests of escape behavior and preference for rewarding stimuli after chronic stress. To increase the ethological relevance of these compounds, we tested the hypothesis that the GABA-NAM, L-655,708, would produce an antidepressant-like response in more complex stress-sensitive social and sex behaviors, which are of relevance to the symptoms of human depression. In male rats subjected to chronic restraint stress, injection of L-655,708 increased reward in a sexual conditioned place preference task, increased male sexual activity with a receptive female, and re-established male social dominance hierarchies within 24 h. We also report increased sucrose preference in the social defeat stress (SDS) model of depression following GABA-NAM administration, demonstrating that its antidepressant-like actions are independent of the type of chronic stress administered. This work extends the impact of GABA-NAMs beyond traditional tests of anhedonia and further supports the development of alpha5 subunit-selective GABA-NAMs as a potential fast-acting therapeutic approach for treating human MDD.

BTRX-246040 Acts Through the Ventrolateral Periaqueductal Gray to Exert Antidepressant-Relevant Actions in Mice.

BTRX-246040, a nociceptin/orphanin FQ peptide receptor antagonist, is being developed for the treatment of depressive patients. However, the underlying mechanism of this potential antidepressant is still largely unclear. Here, we studied the antidepressant-related actions of BTRX-246040 in the ventrolateral periaqueductal gray (vlPAG). The tail suspension test, forced swim test, female urine sniffing test, sucrose preference test, and learned helplessness (LH) combined with pharmacological approaches were employed to examine the antidepressant-like effects and drug effects on LH-induced depressive-like behavior in C57BL/6J mice. Electrophysiological recordings in vlPAG neurons were used to study synaptic activity. Intraperitoneal administration of BTRX-246040 produced antidepressant-like behavioral effects in a dose-dependent manner. Systemic BTRX-246040 (10 mg/kg) resulted in an increased frequency and amplitude of miniature excitatory postsynaptic currents (EPSCs) in the vlPAG. Moreover, slice perfusion of BTRX-246040 directly elevated the frequency and amplitude of miniature EPSCs and enhanced the evoked EPSCs in the vlPAG, which were blocked by pretreatment with the nociceptin/orphanin FQ peptide receptor agonist Ro 64-6198. In addition, intra-vlPAG application of BTRX-246040 produced antidepressant-like behavioral effects in a dose-dependent manner. Moreover, intra-vlPAG pretreatment with 6-cyano-7-nitroquinoxaline-2,3-dione reversed both systemic and local BTRX-246040-mediated antidepressant-like behavioral effects. Furthermore, both systemic and local BTRX-246040 decreased the LH phenotype and reduced LH-induced depressive-like behavior. The results suggested that BTRX-246040 may act through the vlPAG to exert antidepressant-relevant actions. The present study provides new insight into a vlPAG-dependent mechanism underlying the antidepressant-like actions of BTRX-246040.

Effect of Gabapentin-Fluoxetine Derivative GBP1F in a Murine Model of Depression, Anxiety and Cognition.

Gabapentin is a commonly prescribed antiepileptic agent for seizures, which is also used for pain and addiction management. Due to growing evidence of its abuse liability, there has been an incentive to synthesise potentially useful gabapentin derivatives devoid of adverse effects. A gabapentin adduct with a fluoxetine moiety, GBP1F, was assessed for any sedative, cognitive, anxiolytic, or antidepressant-like actions in murine behavioral models. Selected groups of mice were used for each behavioral paradigm, and the effect of GBP1F (5, 10, and 15 mg/kg) was assessed using spontaneous locomotor activity, the tail suspension test, elevated plus maze test, and the Y maze test models. Immediately following behavioral experiments, postmortem striatal and hippocampal tissues were evaluated for the effect of GBP1F on concentrations of dopamine, DOPAC, HVA, serotonin, 5-HIAA, vitamin C, and noradrenaline using high performance liquid chromatography with electrochemical detection. GBP1F induced a mild suppression of locomotor activity, ameliorated anxiety and depression-like behavior, did not alter cognitive behavior, and raised serotonin and 5-HIAA concentrations in the hippocampus and striatum. GBP1F also positively enhanced dopamine and vitamin C tissue levels in the striatum. Thus, GBP1F represents a compound with anxiolytic- and antidepressant-like effects though further studies are warranted at the molecular level to focus on the precise mechanism(s) of action.

Antidepressant-like activity of a brain penetrant HCN channel inhibitor in mice.

Changes in Hyperpolarization-Activated Cyclic Nucleotide-Gated (HCN) channel function have been linked to depressive-like traits, making them potential drug targets. However, there is currently no peer-reviewed data supporting the use of a small molecule modulator of HCN channels in depression treatment. Org 34167, a benzisoxazole derivative, has been patented for the treatment of depression and progressed to Phase I trials. In the current study, we analysed the biophysical effects of Org 34167 on HCN channels in stably transfected human embryonic kidney 293 (HEK293) cells and mouse layer V neurons using patch-clamp electrophysiology, and we utilised three high-throughput screens for depressive-like behaviour to assess the activity of Org 34167 in mice. The impact of Org 34167 on locomotion and coordination were measured by performing rotarod and ledged beam tests. Org 34167 is a broad-spectrum inhibitor of HCN channels, slowing activation and causing a hyperpolarising shift in voltage-dependence of activation. It also reduced I h-mediated sag in mouse neurons. Org 34167 (0.5mg/kg) reduced marble burying and increased the time spent mobile in the Porsolt swim and tail suspension tests in both male and female BALB/c mice, suggesting reduced depressive-like behaviour. Although no adverse effects were seen at 0.5mg/kg, an increase in dose to 1mg/kg resulted in visible tremors and impaired locomotion and coordination. These data support the premise that HCN channels are valid targets for anti-depressive drugs albeit with a narrow therapeutic index. Drugs with higher HCN subtype selectivity are needed to establish if a wider therapeutic window can be obtained.