Antidepressant-like Effects In Mice Research Articles

Psilocybin promotes neuroplasticity and induces rapid and sustained antidepressant-like effects in mice.

Psilocybin offers new hope for treating mood disorders due to its rapid and sustained antidepressant effects, as standard medications require weeks or months to exert their effects. However, the mechanisms underlying this action of psilocybin have not been identified. To investigate whether psilocybin has rapid and sustained antidepressant-like effects in mice and investigate whether its potential mechanisms of action are related to promoted neuroplasticity. We first examined the antidepressant-like effects of psilocybin in normal mice by the forced swimming test and in chronic corticosterone (CORT)-exposed mice by the sucrose preference test and novelty-suppressed feeding test. Furthermore, to explore the role of neuroplasticity in mediating the antidepressant-like effects of psilocybin, we measured structural neuroplasticity and neuroplasticity-associated protein levels in the prefrontal cortex (PFC) and hippocampus. We observed that a single dose of psilocybin had rapid and sustained antidepressant-like effects in both healthy mice and chronic CORT-exposed mice. Moreover, psilocybin ameliorated chronic CORT exposure-induced inhibition of neuroplasticity in the PFC and hippocampus, including by increasing neuroplasticity (total number of dendritic branches and dendritic spine density), synaptic protein (p-GluA1, PSD95 and synapsin-1) levels, BDNF-mTOR signalling pathway activation (BDNF, TrkB and mTOR levels), and promoting neurogenesis (number of DCX-positive cells). Our results demonstrate that psilocybin elicits robust, rapid and sustained antidepressant-like effects which is accompanied by the promotion of neuroplasticity in the PFC and hippocampus.

NSC689857, an inhibitor of Skp2, produces antidepressant-like effects in mice.

We have previously reported that two inhibitors of an E3 ligase S-phase kinase-associated protein 2 (Skp2), SMIP004 and C1, have an antidepressant-like effect in non-stressed and chronically stressed mice. This prompted us to ask whether other Skp2 inhibitors could also have an antidepressant effect. Here, we used NSC689857, another Skp2 inhibitor, to investigate this hypothesis. The results showed that administration of NSC689857 (5 mg/kg) produced an antidepressant-like effect in a time-dependent manner in non-stressed male mice, which started 8 days after drug administration. Dose-dependent analysis showed that administration of 5 and 10 mg/kg, but not 1 mg/kg, of NSC689857 produced antidepressant-like effects in both non-stressed male and female mice. Administration of NSC689857 (5 mg/kg) also induced antidepressant-like effects in non-stressed male mice when administered three times within 24 h (24, 5, and 1 h before testing) but not when administered acutely (1 h before testing). In addition, NSC689857 and fluoxetine coadministration produced additive antidepressant-like effects in non-stressed male mice. These effects of NSC689857 were not associated with the changes in locomotor activity. Administration of NSC689857 (5 mg/kg) also attenuated depression-like behaviors in male mice induced by chronic social defeat stress, suggesting therapeutic potential of NSC689857 in depression. Overall, these results suggest that NSC689857 is capable of exerting antidepressant-like effects in both non-stressed and chronically stressed mice.

Dopaminergic Modulation and Computational ADMET Insights for the Antidepressant-like Effect of N-(3-(Phenylselanyl)prop-2-yn-1-yl)benzamide.

The compound N-(3-(phenylselanyl)prop-2-yn-1-yl)benzamide (SePB), which combines a selenium atom and a benzamide nucleus in an organic structure, has demonstrated a fast antidepressant-like effect in mice. This action is influenced by the serotonergic system and represents a promising development in the search for novel antidepressant drugs to treat major depressive disorder (MDD), which often resists conventional treatments. This study aimed to further explore the mechanism underlying the antidepressant-like effect of SePB by investigating the involvement of the dopaminergic and noradrenergic systems in the tail suspension test (TST) in mice and evaluating its pharmacokinetic profile in silico. Preadministration of the dopaminergic antagonists haloperidol (0.05 mg/kg, intraperitoneally (i.p.)), a nonselective antagonist of dopamine (DA) receptors, SCH23390 (0.01 mg/kg, subcutaneously (s.c.)), a D1 receptor antagonist, and sulpiride (50 mg/kg, i.p.), a D2/3 receptor antagonist, before SePB (10 mg/kg, intragastrically (i.g.)) prevented the anti-immobility effect of SePB in the TST, demonstrating that these receptors are involved in the antidepressant-like effect of SePB. Administration of the noradrenergic antagonists prazosin (1 mg/kg, i.p.), an α1-adrenergic antagonist, yohimbine (1 mg/kg, i.p.), an α2-adrenergic antagonist, and propranolol (2 mg/kg, i.p.), a β-adrenergic antagonist, did not block the antidepressant-like effect of SePB on TST, indicating that noradrenergic receptors are not involved in this effect. Additionally, the coadministration of SePB and bupropion (a noradrenaline/dopamine reuptake inhibitor) at subeffective doses (0.1 and 3 mg/kg, respectively) produced antidepressant-like effects. SePB also demonstrated good oral bioavailability and low toxicity in computational absorption, distribution, metabolism, excretion, and toxicity (ADMET) analyses. These findings suggest that SePB has potential as a new antidepressant drug candidate with a particular focus on the dopaminergic system.

N-(3-((3-(trifluoromethyl)phenyl)selanyl)prop-2-yn-1-yl) benzamide induces antidepressant-like effect in mice: involvement of the serotonergic system.

Major Depressive Disorder (MDD) significantly impairs the quality of life for those affected. While the exact causes of MDD are not fully understood, the deficit of monoamines, especially serotonin and noradrenaline, is widely accepted. Resistance to long-term treatments and adverse effects are often observed, highlighting the need for new pharmacological therapies. Synthetic organic compounds containing selenium have exhibited pharmacological properties, including potential antidepressant effects. To evaluate the antidepressant-like effect of N-(3-((3-(trifluoromethyl)phenyl)selenyl)prop-2-yn-1-yl) benzamide (CF3SePB) in mice and the involvement of the serotonergic and noradrenergic systems. Male Swiss mice were treated with CF3SePB (1-50mg/kg, i.g.) and 30min later the forced swimming test (FST) or tail suspension test (TST) was performed. To investigate the involvement of the serotonergic and noradrenergic systems in the antidepressant-like effect of CF3SePB, mice were pre-treated with p-CPA (a 5-HT depletor, 100mg/kg, i.p.) or the receptor antagonists WAY100635 (0.1mg/kg, s.c., a 5-HT1A receptor antagonist), ketanserin (1mg/kg, i.p., a 5-HT2A/2C receptor antagonist), ondansetron (1mg/kg, i.p., a 5-HT3 receptor antagonist), GR110838 (0.1mg/kg, i.p., a 5-HT4 receptor antagonist), prazosin (1mg/kg, i.p., an α1-adrenergic receptor antagonist), yohimbine (1mg/kg, i.p., an α2-adrenergic receptor antagonist) and propranolol (2mg/kg, i.p., a non-selective beta-adrenergic receptor antagonist) at specific times before CF3SePB (50mg/kg, i.g.), and after 30min of CF3SePB administration the FST was performed. CF3SePB showed an antidepressant-like effect in both FST and TST and this effect was related to the modulation of the serotonergic system, specially the 5-HT1A and 5-HT3 receptors. None of the noradrenergic antagonists prevented the antidepressant-like effect of CF3SePB. The compound exhibited a low potential for inducing acute toxicity in adult female Swiss mice. This study pointed a new compound with antidepressant-like effect, and it could be considered for the development of new antidepressants.

1-(Phenylselanyl)-2-(p-tolyl)indolizine: A selenoindolizine with potential antidepressant-like activity in mice mediated by the modulation of dopaminergic and noradrenergic systems

1-(Phenylselanyl)-2-(p-tolyl)indolizine (MeSeI) is a selenoindolizine with an antidepressant-like effect in mice by regulation of the serotonergic system. This study investigated the involvement of dopaminergic and noradrenergic systems in the antidepressant-like action of MeSeI. For this purpose, Swiss male mice were pretreated with different antagonists, after 15 min, the MeSeI was administrated by intragastric (i.g.) via; after 30 min, the mouse behavior was assessed in the forced swimming test (FST). The action of MeSeI on the activity of monoamine oxidase (MAO) was determined. The pretreatment of mice with haloperidol (0.05 mg/kg, intraperitoneally, i.p.; non-selective dopamine receptor antagonist), sulpiride (50 mg/kg, i.p.; D2 receptor antagonist), yohimbine (1 mg/kg, i.p.; α2 receptor antagonist), and propranolol (2 mg/kg, i.p.; non-selective β receptor antagonist), inhibited the anti-immobility action of MeSeI (50 mg/kg, i.g.) in the FST. This blocking effect was not observed when SCH23390 (0.01 mg/kg, i.p.; D1 receptor antagonist), and prazosin (1 mg/kg, i.p.; α1 receptor antagonist) were administered. The coadministration of subeffective doses of bupropion (3 mg/kg. i.g.; dopamine and noradrenaline reuptake inhibitor) and MeSeI (0.5 mg/kg. i.g.) reduced the immobility time in the FST. Furthermore, MeSeI inhibited MAO-A and B activities in vitro and ex vivo tests. These results suggest that MeSeI exerts its antidepressant-like effect via regulation of the D2, α2, and β1 receptors and the inhibition of MAO-A and B activities. Molecular docking investigations corroborated these results. This study provides comprehensive insights into the antidepressant-like mechanism of MeSeI in mice, suggesting its potential as a novel antidepressant candidate.

Psychobiotics Lactiplantibacillus plantarum JYLP-326: Antidepressant-like effects on CUMS-induced depressed mouse model and alleviation of gut microbiota dysbiosis

BackgroundDepression affects a significant portion of the global population and has emerged as one of the most debilitating conditions worldwide. Recent studies have explored the relationship between depression and the microbiota of the intestine, revealing potential avenues for effective treatment. MethodsTo evaluate the potential alleviation of depression symptoms, we employed a depression C57BL/6 mice model induced by chronic unpredictable mild stress (CUMS). We administered Lactiplantibacillus plantarum JYLP-326 and conducted various animal behavior tests, including the open-field test (OFT), sucrose preference test (SPT), and tail-suspension test (TST). Additionally, we conducted immunohistochemistry staining and analyzed the hippocampal and colon parts of the mice. ResultsThe results of the behavior tests indicated that L. plantarum JYLP-326 alleviated spontaneous behavior associated with depression. Moreover, the treatment led to significant improvements in GFAP and Iba1, suggesting its potential neuroprotective effects. Analysis of the hippocampal region indicated that L. plantarum JYLP-326 administration upregulated p-TPH2, TPH2, and 5-HT1AR, while downregulating the expression of pro-inflammatory cytokines IL-1β, IL-6, and TNF-α. In the colon, the treatment inhibited the TLR4-MyD88-NF-κB pathway and increased the levels of occludin and ZO-1, indicating improved intestinal barrier function. Additionally, the probiotic demonstrated a regulatory effect on the HMGB1-RAGE-TLR4 signaling pathway. ConclusionsOur findings demonstrate that L. plantarum JYLP-326 exhibits significant antidepressant-like effects in mice, suggesting its potential as a therapeutic approach for depression through the modulation of gut microbiota. However, further investigations and clinical trials are required to validate its safety and efficacy for human use.

Pharmacological and computational analysis of the involvement of the 5-HT4 receptor in the antidepressant-like effect of N-(3-(phenylselanyl)prop-2-yn-1-yl)benzamide in mice

The serotonin type 4 receptor (5-HT4R)shows promise as a target for treating major depressive disorder (MDD). Studies have demonstrated that 5-HT4R agonists have a faster antidepressant-like effect compared to conventional medications. Developing drugs that modulate this receptor could lead to faster and more effective MDD treatments. The compound N-(3-(phenylselanyl)prop-2-yn-1-yl)benzamide (SePB) induces an antidepressant-like effect in mice. The present study explored if the 5-HT4R mediates SePB's antidepressant effect. For this, male Swiss mice were treated with GR113808 (0.1 mg/kg, intraperitoneally – i.p.), a 5-HT4R antagonist, and SePB (10 mg/kg, intragastrically – i.g), and then subjected to the tail-suspension test (TST) and open-field test (OFT). In silico tests were conducted to analyze SePB's binding affinity to the 5-HT4R and identify participating amino acid residues. The administration of GR113808 blocked the antidepressant-like effect of SePB in the TST without changing locomotor activity in the OFT. Moreover, SePB exhibited a high binding affinity between the 5-HT4R (−7.9 kcal/mol) and the amino acid residues Leu298, Asp100, Thr97, Arg96, Glu80, Leu81, Cys184, Val185, and Phe186 seem to be important for this interaction. The involvement of the 5-HT4R in the antidepressant-like effect of SePB suggests potential for novel therapies in MDD.

The antidepressant-like effect of doxycycline is associated with decreased nitric oxide metabolite levels in the prefrontal cortex

Doxycycline is an antibiotic that has shown neuroprotective, anti-inflammatory, and antidepressant-like effects. Low doses of doxycycline revert the behavioral and neuroinflammatory responses induced by lipopolysaccharide treatment in a mice model of depression. However, the molecular mechanisms involved in the antidepressant action of doxycycline are not yet understood. Doxycycline inhibits the synthesis of nitric oxide (NO), which increases after stress exposure. Inducible NO synthase (iNOS) inhibition also causes antidepressant-like effects in animal models sensitive to antidepressant-like effects such as the forced swimming test (FST). However, no direct study has yet investigated if the antidepressant-like effects of doxycycline could involve changes in NO-mediated neurotransmission. Therefore, this study aimed at investigating: i) the behavioral effects induced by doxycycline alone or in association with ineffective doses of a NO donor (sodium nitroprusside, SNP) or an iNOS inhibitor (1400 W) in mice subjected to the FST; and ii) doxycycline effects in NO metabolite levels in the prefrontal cortex and hippocampus these animals. Male mice (8 weeks) received i.p. injection of saline or doxycycline (10, 30, and 50 mg/kg), alone or combined with SNP (0.1, 0.5, and 1 mg/kg) or 1400 W (1, 3, and 10 µg/kg), and 30 min later were submitted to the FST. Animals were sacrificed immediately after, and NO metabolites nitrate/nitrite (NOx) were measured in the prefrontal cortex and hippocampus. Doxycycline (50 mg/kg) reduced both the immobility time in the FST and NOx levels in the prefrontal cortex of mice compared to the saline group. The antidepressant-like effect of doxycycline in the FST was prevented by SNP (1 mg/kg) pretreatment. Additionally, sub-effective doses of doxycycline (30 mg/kg) associated with 1400 W (1 µg/kg) induced an antidepressant-like effect in the FST. Altogether, our data suggest that the reducing NO levels in the prefrontal cortex through inhibition of iNOS could be related to acute doxycycline treatment resulting in rapid antidepressant-like effects in mice.

Nebulized and intraperitoneal ketamine have equivalent antidepressant-like effect in the forced swim and tail suspension tests in mice

Major depressive disorder (MDD) is a debilitating illness that affects millions of people worldwide. Currently available antidepressants often take weeks to months to reach their full effect, which leads to an increased risk of suicidal behavior in patients with MMD. Intranasally, esketamine has emerged as an alternative to current antidepressants because of its rapid onset and long-lasting effects in patients with MDD. Animal models are useful for the initial pharmacological screening and for a better understanding of the mechanisms underlying the effects of new drugs with potential against MDD. There is a lack of data on alternative routes of drug administration, either oral or injectable, that can be used in preclinical studies. This study aimed to test whether ketamine has antidepressant-like effects in mice when administered via nebulization using a low-cost apparatus. When mice whose depressive-like behavior was induced by corticosterone were treated with nebulized ketamine at concentrations of 1.3, 2.6, and 5.2 mg/mL, immobility was reduced by 38.6 %, 62.0 %, and 61.1 %, respectively, in the forced swimming test (FST) and 43.6 %, 42.1 %, and 57.9 %, respectively, in the tail suspension test (TST). When depression-like behavior was induced by dexamethasone, nebulization with ketamine reduced immobility by 79.7 %, 49.2 %, and 44.4 % in the FST and 80.9 %, 71.4 %, and 80.4 %, respectively, in the TST. When depression-like behavior was induced by the association between dexamethasone and unpredictable chronic mild stress (UCMS) exposure, immobility was reduced by 26.1 %, 55.3 %, and 19.1 % in FST. Mice treated with nebulized ketamine did not show significant changes in the distance covered or in the time spent moving in the open field test. The efficacy of intraperitoneal and nebulized ketamine is equivalent, which shows that nebulization can be an alternative inexpensive route of drug administration for behavioral studies in rodents.

Cucurbitacin B Exerts Significant Antidepressant-Like Effects in a Chronic Unpredictable Mild Stress Model of Depression: Involvement of the Hippocampal BDNF-TrkB System.

Although depression has been a serious neuropsychiatric disorder worldwide, current antidepressants used in clinical practice have various weaknesses, including delayed onset and low rates of efficacy. Recently, the development of new antidepressants from natural herbal medicine has become one of the important research hotspots. Cucurbitacin B is a natural compound widely distributed in the Cucurbitaceae and Cruciferae families and has many pharmacological activities. The present study aimed to investigate whether cucurbitacin B possess antidepressant-like effects in mice. The antidepressant-like effects of cucurbitacin B on mice behaviors were explored using the forced swim test, tail suspension test, open field test, sucrose preference test, and a chronic unpredictable mild stress model of depression together. Then, western blotting and immunofluorescence were used to examine the effects of cucurbitacin B on the brain-derived neurotrophic factor (BDNF)-tyrosine kinase B (TrkB) signaling cascade and neurogenesis in the hippocampus of mice. Furthermore, BDNF-short hairpin RNA, K252a, and p-chlorophenylalanine methyl ester were adopted together to determine the antidepressant mechanism of cucurbitacin B. It was found that administration of cucurbitacin B indeed produced notable antidepressant-like effects in mice, which were accompanied with significant promotion in both the hippocampal BDNF-TrkB pathway and neurogenesis. The antidepressant mechanism of cucurbitacin B involves the hippocampal BDNF-TrkB system but not the serotonin system. Cucurbitacin B has the potential to be a novel antidepressant candidate.

The connexin hemichannel inhibitor D4 produces rapid antidepressant-like effects in mice.

Depression is a common mood disorder characterized by a range of clinical symptoms, including prolonged low mood and diminished interest. Although many clinical and animal studies have provided significant insights into the pathophysiology of depression, current treatment strategies are not sufficient to manage this disorder. It has been suggested that connexin (Cx)-based hemichannels are candidates for depression intervention by modifying the state of neuroinflammation. In this study, we investigated the antidepressant-like effect of a recently discovered selective Cx hemichannel inhibitor, a small organic molecule called D4. We first showed that D4 reduced hemichannel activity following systemic inflammation after LPS injections. Next, we found that D4 treatment prevented LPS-induced inflammatory response and depressive-like behaviors. These behavioral effects were accompanied by reduced astrocytic activation and hemichannel activity in depressive-like mice induced by repeated low-dose LPS challenges. D4 treatment also reverses depressive-like symptoms in mice subjected to chronic restraint stress (CRS). To test whether D4 broadly affected neural activity, we measured c-Fos expression in depression-related brain regions and found a reduction in c-Fos+ cells in different brain regions. D4 significantly normalized CRS-induced hypoactivation in several brain regions, including the hippocampus, entorhinal cortex, and lateral septum. Together, these results indicate that blocking Cx hemichannels using D4 can normalize neuronal activity and reduce depressive-like symptoms in mice by reducing neuroinflammation. Our work provides evidence of the antidepressant-like effect of D4 and supports glial Cx hemichannels as potential therapeutic targets for depression.

Isoalantolactone relieves depression-like behaviors in mice after chronic social defeat stress via the gut-brain axis

RationaleThe management of depression continues to be challenging despite the variety of available antidepressants. Herbal medicines are used in many cultures but lack stringent testing to understand their efficacy and mechanism of action. Isoalantolactone (LAT) from Elecampane (Inula helenium) improved the chronic social defeat stress (CSDS)-induced anhedonia-like phenotype in mice comparable to fluoxetine, a selective serotonin reuptake inhibitor (SSRI).ObjectivesCompare the effects of LAT and fluoxetine on depression-like behaviors in mice exposed to CSDS.ResultThe CSDS-induced decrease in protein expression of postsynaptic density (PSD95), brain derived neurotrophic factor (BDNF), and glutamate receptor subunit-1 (GluA1) in the prefrontal cortex was restored by LAT. LAT showed robust anti-inflammatory activity and can lessen the increase in IL-6 and TNF-α caused by CSDS. CSDS altered the gut microbiota at the taxonomic level, resulting in significant changes in α- and β-diversity. LAT treatment reestablished the bacterial abundance and diversity and increased the production of butyric acid in the gut that was inhibited by CSDS. The levels of butyric acid were negatively correlated with the abundance of Bacteroidetes, and positively correlated with those of Proteobacteria and Firmicutes across all treatment groups.ConclusionsThe current data suggest that, similar to fluoxetine, LAT show antidepressant-like effects in mice exposed to CSDS through the modulation of the gut-brain axis.

Intranasal Administration of Resolvin E1 Produces Antidepressant-Like Effects via BDNF/VEGF-mTORC1 Signaling in the Medial Prefrontal Cortex.

Intracerebroventricular infusion of resolvin E1 (RvE1), a bioactive metabolite derived from eicosapentaenoic acid, exerts antidepressant-like effects in a mouse model of lipopolysaccharide (LPS)-induced depression; these effects are blocked by systemic injection of rapamycin, a mechanistic target of rapamycin complex 1 (mTORC1) inhibitor. Additionally, local infusion of RvE1 into the medial prefrontal cortex (mPFC) or dorsal hippocampal dentate gyrus (DG) produces antidepressant-like effects. To evaluate the potential of RvE1 for clinical use, the present study examined whether treatment with RvE1 via intranasal (i.n.) route, a non-invasive route for effective drug delivery to the brain, produces antidepressant-like effects in LPS-challenged mice using tail suspension and forced swim tests. Intranasal administration of RvE1 significantly attenuated LPS-induced immobility, and these antidepressant-like effects were completely blocked by an AMPA receptor antagonist or L-type voltage-dependent Ca2+ channel blocker. The antidepressant-like effects of both i.n. and intra-mPFC administrations of RvE1 were blocked by intra-mPFC infusion of a neutralizing antibody (nAb) for brain-derived neurotrophic factor (BDNF) or vascular endothelial growth factor (VEGF). Intra-mPFC infusion of rapamycin completely blocked the antidepressant-like effects of both i.n. and intra-mPFC administrations of RvE1 as well as those of intra-mPFC infusion of BDNF and VEGF. Moreover, i.n. RvE1 produced antidepressant-like effects via mTORC1 activation in the mPFC of a mouse model of repeated prednisolone-induced depression. Intra-dorsal DG infusion of BDNF and VEGF nAbs, but not rapamycin, blocked the antidepressant-like effects of i.n. RvE1. These findings suggest that i.n. administration of RvE1 produces antidepressant-like effects through activity-dependent BDNF/VEGF release in the mPFC and dorsal DG, and mTORC1 activation in the mPFC, but not in the dorsal DG. Thus, RvE1 can be a promising candidate for a novel rapid-acting antidepressant.

Recovery of Naringin-Rich Flavonoid Extracts from Agroresidues with Anxiolytic- and Antidepressant-like Effects in Mice

Citrus paradisi species belong to the Rutaceae family, and it is commonly known as grapefruit. Grapefruit consumption involves a large amount of waste that goes to landfills and produces significant pollution affecting the human health. To examine this phenomenon, we designed an efficient chemical method that recovers naringin-rich flavonoid extracts from the fresh waste of grapefruits, by using the solvent impregnation resin method (SIR) with XAD-4 amberlite and either methanol or water as elution systems. Additionally, we focused on evaluating these extracts' anxiolytic- and antidepressant-like effects in behavioral predictive paradigms in mice. According to direct Principal Component Analysis (PCA) by NMR, and Direct Injection Electrospray Ionization-Mass Spectrometry (DIESI-MS), methanol extracts obtained after resin treatment were free of coumarin compounds and evinced had a high content of naringin. Poncirin, phenylalanine, chrysin 5,7-dimethyl ether, 5,7-dimethoxy-4'-hydroxyflavanone, 2,3-dihydro-2-(4-hydroxyphenyl)-5,6,7,8-tetramethoxy-4H-1-benzopyran-4-one, tetrahydrocurcumin, corchoionoside C, 6'-coumaroyl-1'-O-[2-(3,4-dihydroxyphenyl) ethyl]-β-D-glucopyranoside were also detected. Naringin-rich methanol extract caused a clear anxiolytic-like effect in the Elevated Plus Maze (EPM) and the Hole-Board (HBT) Tests, increasing oral doses of this extract did not produce a sedative effect. A single oral dose caused an antidepressant-like effect in the Tail Suspension Test (TST), while repeated administrations of the methanol extract elicited a robust antidepressant effect in the Forced Swimming Test (FST) in mice. Our evidence highlights the importance of bioprospecting studies of organic waste with therapeutic potentials, such as anxiety and depression disorders.

Salt-inducible kinase 1-CREB-regulated transcription coactivator 1 signalling in the paraventricular nucleus of the hypothalamus plays a role in depression by regulating the hypothalamic-pituitary-adrenal axis.

Elucidating the molecular mechanism underlying the hyperactivity of the hypothalamic-pituitary-adrenal axis during chronic stress is critical for understanding depression and treating depression. The secretion of corticotropin-releasing hormone (CRH) from neurons in the paraventricular nucleus (PVN) of the hypothalamus is controlled by salt-inducible kinases (SIKs) and CREB-regulated transcription co-activators (CRTCs). We hypothesised that the SIK-CRTC system in the PVN might contribute to the pathogenesis of depression. Thus, the present study employed chronic social defeat stress (CSDS) and chronic unpredictable mild stress (CUMS) models of depression, various behavioural tests, virus-mediated gene transfer, enzyme-linked immunosorbent assay, western blotting, co-immunoprecipitation, quantitative real-time reverse transcription polymerase chain reaction, and immunofluorescence to investigate this connection. Our results revealed that both CSDS and CUMS induced significant changes in SIK1-CRTC1 signalling in PVN neurons. Both genetic knockdown of SIK1 and genetic overexpression of CRTC1 in the PVN simulated chronic stress, producing a depression-like phenotype in naive mice, and the CRTC1-CREB-CRH pathway mediates the pro-depressant actions induced by SIK1 knockdown in the PVN. In contrast, both genetic overexpression of SIK1 and genetic knockdown of CRTC1 in the PVN protected against CSDS and CUMS, leading to antidepressant-like effects in mice. Moreover, stereotactic infusion of TAT-SIK1 into the PVN also produced beneficial effects against chronic stress. Furthermore, the SIK1-CRTC1 system in the PVN played a role in the antidepressant actions of fluoxetine, paroxetine, venlafaxine, and duloxetine. Collectively, SIK1 and CRTC1 in PVN neurons are closely involved in depression neurobiology, and they could be viable targets for novel antidepressants.

Antidepressant-Like Effect and Phenolic Profile of Brazilian Native and Exotic Species from Psidium Genus.

Depression is one of the disorders involving mental health that most affects the population worldwide. Considering the available pharmacological therapies for the treatment of depression are ineffective in most patients, the search for new alternatives is crucial. In line with this, we investigated the phenolic profile, antidepressant-like, and antioxidant effects triggered by the administration of aqueous extracts from Psidium guajava L. (GUA), Psidium cattleianum Sw. (CAT), and Psidium guineense Sabine (GUI) leaves in mice. Our results show that quercetin is the major compound of GUA and GUI, and o-coumaric acid in CAT extracts. The acute and subchronic administrations of the three plant extracts exerted an antidepressant-like effect in mice exposed to the tail suspension test, without changes on locomotor performance evaluated by the open field test. Furthermore, the GUI and CAT decreased oxidative stress markers, mainly lipid peroxidation and nitrites in the hippocampus, prefrontal cortex, liver, and plasma. Notably, GUA and CAT increased non-protein thiols in all tissues. Therefore, the Psidium extracts demonstrated an antidepressant-like effect in mice, and the antioxidant capacity of the extracts seems to underlie the behavioral effect.

Vortioxetine liposomes as a novel alternative to improve drug stability under stress conditions: toxicity studies and evaluation of antidepressant-like effect.

Vortioxetine hydrobromide (VXT), a new therapeutic option in the treatment of major depressive disorder, is a poorly soluble drug, and instability under stress conditions has been reported. The aim of the present study was to prepare VXT liposomes (VXT-Ls) with an antidepressant-like effect, to improve drug stability and reduce toxicity of the free drug. Liposomes were prepared using the thin lipid film hydration method and properly characterized. Forced degradation studies were conducted in photolytic and oxidative conditions. The cytotoxicity was evaluated in VERO cells through MTT assay and in vivo toxicity was assessed in mice. The antidepressant-like effect in mice was confirmed using the open-field test paradigm and tail suspension test. The optimized VXT-Ls have multilamellar vesicles with an average size of 176.74nm ± 2.43. The liposomal formulation increased the stability of VXT. VERO cell viability was maintained at around 40% when the VXT-Ls were tested at higher concentrations and no signs of acute toxicity were observed in mice. The antidepressant-like effect was effective, for VXT-Ls, at doses ranging from 2.5mg/kg to 10mg/kg, measured by the tail suspension test in mice. The non-liposomal formulation was effective at a dose of 10mg/kg. The open field test was performed and any unspecific changes in locomotor activity were revealed. Liposomes seem to be a promising alternative for an oral VXT formulation at lower doses (2.5mg/kg).

The Sirtuin 2 Inhibitor AK-7 Leads to an Antidepressant-Like Effect in Mice via Upregulation of CREB1, BDNF, and NTRK2 Pathways.

Depression is one of the most important and serious health problems in developing countries which affects millions of people. It is associated with the decrease of the quality of life as well as suicides and mortality. The disease may show recurrent episodes in some patients. Obviously, not all the patients with depression could be treated properly, because some individuals are drug-resistant and the options for the therapy are limited. Therefore, it is crucial to investigate new molecules and pathways that may have possible antidepressant activity. Sirtuin (SIRT), known as a class III histone deacetylase, which is regulated by nicotinamide adenine dinucleotide (NAD +), is one of these molecules. In the current study, we investigated the possible antidepressant-like effect of SIRT2 inhibitor AK-7. For this purpose, behavioral tests were performed in chronic AK-7-treated mice, and the expression levels of BDNF, NGF, NTF3, CREB, NTRK2, ERK1, ERK2, and GAP43 genes were evaluated by qRT-PCR analysis in brain tissues. Protein levels for BDNF, CREB1, and NTRK2 were determined by western blot. Our data showed that AK-7 significantly decreased immobility time and showed antidepressant-like effect. In addition, AK-7 treatment significantly increased mRNA levels of CREB and NTRK2 and protein levels of CREB1, BDNF, and NTRK2. Finally, our results suggest that SIRT2 and AK-7 may have a potential role in the cellular mechanisms of depression.

Antidepressant Low Doses of Ketamine and Melatonin in Combination Produce Additive Neurogenesis in Human Olfactory Neuronal Precursors.

Melatonin (MEL), an indolamine with diverse functions in the brain, has been shown to produce antidepressant-like effects, presumably through stimulating neurogenesis. We recently showed that the combination of MEL with ketamine (KET), an NMDA receptor antagonist, has robust antidepressant-like effects in mice, at doses that, by themselves, are non-effective and have no adverse effects. Here, we show that the KET/MEL combination increases neurogenesis in a clone derived from human olfactory neuronal precursors, a translational pre-clinical model for effects in the human CNS. Neurogenesis was assessed by the formation of cell clusters > 50 µm in diameter, positively stained for nestin, doublecortin, BrdU and Ki67, markers of progenitor cells, neurogenesis, and proliferation. FGF, EGF and BDNF growth factors increased the number of cell clusters in cultured, cloned ONPs. Similarly, KET or MEL increased the number of clusters in a dose-dependent manner. The KET/MEL combination further increased the formation of clusters, with a maximal effect obtained after a triple administration schedule. Our results show that the combination of KET/MEL, at subeffective doses that do not produce adverse effects, stimulate neurogenesis in human neuronal precursors. Moreover, the mechanism by which the combination elicits neurogenesis is meditated by melatonin receptors, CaM Kinase II and CaM antagonism. This could have clinical advantages for the fast treatment of depression.

Intracerebroventricular Administration of Dermorphin-Dynorphin Analogs Producing Antidepressant-Like Effects through Activation of μ1- and κ-Opioid Receptors in Mice.

The opioid system in the central nervous system regulates depressive-like behavior in animals. Opioid receptors and their endogenous ligands have been focused on as novel therapeutic targets for depression. We synthesized dermorphin (DRM)-dynorphin (DYN) analogs (DRM-DYN001-004) using the message-address concept concerning interactions with opioid receptors. It has previously been reported that DRM-DYN001, 003, and 004 have shown high affinities for μ- and κ-opioid receptors, whereas all analogs had a lower affinity for the δ-opioid receptor than for other receptors using a receptor binding assay. However, it remains unknown whether these analogs show antidepressant-like effects in mice. We examined the effects of DRM-DYN analogs on the duration of immobile behavior in a tail suspension test. Intracerebroventricular administration of DRM-DYN001 in mice shortened the duration of immobile behavior, but did not affect locomotion. The DRM-DYN001-induced antidepressant-like effect was inhibited by co-administration of naloxone (non-selective opioid receptor antagonist), naloxonazine (selective μ1-opioid receptor antagonist), or nor-BNI (κ-opioid receptor antagonist), but not naltrindole (δ-opioid receptor antagonist). These data suggest that DRM-DYN001 exerts an antidepressant-like effect via activation of the central μ1- and κ-opioid receptors in mice and may represent a new lead peptide for further investigation for the development of novel therapeutic approaches for depression.