Design, synthesis, and biological profiling of novel aryl-spirocyclic diamine derivatives with potential antidepressant-like properties.

Honghua Xiaoyao tablets ameliorate premenstrual syndrome by modulating HPA axis and restoring ovarian estrogen synthesis to attenuate hippocampal neuroinflammation.

High-dose subacute and acute thymoquinone treatments alleviate LPS-induced depressive-like behavior in mice by reducing inflammation via the IDO/KYN pathway.

Simultaneous modulation of 5-HT6 and SERT by MM394: a dual-target ligand providing neuroprotection against amyloid-β toxicity, memory preservation, and alleviation of BPSD symptoms.

Synergistic effects of capsaicin and ketamine on the depression-like behaviors of animals subjected to the chronic unpredictable mild stress protocol.

Fine-tuning 5-HT7 receptor selectivity, inverse agonism, and metabolic stability of new (aryloxy)ethyl-piperidines toward antidepressant and pro-cognitive properties.

Stress-type specific changes of VIP signaling in limbic regions of the rat brain.

Native to tropical and subtropical regions, Moringa oleifera, often known as Moringa, is a member of the Moringaceae family. It can be found in northwest India and Pakistan's sub-Himalayan regions. The phytochemical makeup of the methanolic extracts of M. oleifera seeds (Met-Ext-M.O.) was examined using GC-MS analysis, followed by molecular docking studies for the determination of the most potent ligands. A UV spectrophotometer was used to analyze the extracts for in vitro DPPH scavenging activity at different doses (1000, 500, 250, 125, 62.5, and 31.05 μg/mL), with ascorbic acid serving as a reference standard. The extract was further assessed using two in vivo antidepressant tests: the tail suspension test (TST) and the forced swim test (FST). Mice were administered 125 mg/kg and 250 mg/kg body weight of M. Oleifera Met-Ext. In the meantime, the standard group received an oral imipramine dosage of 10 mg/kg/day. An hour before the test began, imipramine and plant extracts were administered orally. The molecular docking study revealed that certain phytoconstituents (50 phytochemicals) identified by GC-MS analysis are capable of binding serotonin 1A receptor with favorable affinity, potentially, ensuring an interaction with neuroreceptors systems, which mediate mood regulation. GC-MS profiling provided a preliminary characterization of the phytochemical components of M. oleifera seed extract, but some of the compounds identified e.g. those based on phthalates could have been due to environmental or laboratory contamination and therefore were handled with care in the context of their possible biological activity. These phytochemicals were grouped based on their molecular weight at various retention periods, and constituents like Benzo[c]phenanthrene, 5-methyl- showed the best binding affinity (-8.5 kcal/mol), Benzo[1,2-b:5,4-b']difuran-4,8-dione, and 1,3,5-Triazin-2(1H)-one derivatives with Serotonin-bound Serotonin 1A receptor-Gi protein complex (7e2y) by molecular docking studies, suggesting potential for antidepressant effects and novel therapeutic agents. M. Oleifera Met-Ext also showed a great in vitro antioxidant activity, which can lead to neuroprotective effects, but this antioxidative activity cannot be directly related to antidepressant effects. Compared to ascorbic acid (91±0.5; IC50 = 30μg/mL), Met-Ext-M.O. at 1000μg/mL (82±1.5***; IC50 = 90μg/mL) considerably reduced the percentage suppression of DPPH free radicals. Consequently, it was discovered that the extract was a potent antioxidant that also performed well in vivo. Mice administered imipramine and Met-Ext-M.O. in both test models had shorter durations of immobility on days 1, 7, and 14 of the experiment compared to the control group. In contrast to the normal group, which experienced 197.76±4.42 on day 1, 199.08±2.29 on day 7, and 200.28±3.17 on day 14, the immobility period for 125 mg/kg was 131.63±3.79, 117.85±2.47, and 107.09±2.24 on days 1, 7, and 14. The immobility period for 250 mg/kg was 112.19±2.69 on days 1, 7, and 14, 105.49±2.55, and 90.21±2.21 on days 14, respectively. Days 1, 7, and 14 following imipramine injection showed a significant reduction in immobility time (86.64±1.66,72.35±1.75, and 54.75±1.69). In vivo behavioral studies (tail-suspension test and forced-swim test) demonstrated that there was a significant decrease of immobility time thus, exhibited anti-depressant-like effect in mice. These findings, when allied, suggest that these behavioral effects can possibly be explained by the active presence of phytochemicals, but there is still a need to conduct further mechanistic and clinical studies to determine a definite antidepressant mechanism. These effects, which could have a major impact on both in vitro and in vivo research, could be caused by physiologically active phytonutrients in the plants.

Stress is a common factor that can lead to various health issues, including depression and anxiety. Aged garlic extract (AGE) has been suggested to have potential therapeutic benefits, including antidepressant and anxiolyticlike effects. This study aimed to investigate the effects of AGE on depressive and anxiety-like behavior induced by chronic restraint stress in mice using both in vivo and in silico approaches. In vivo experiments involved subjecting mice to chronic restraint stress to induce depressive-like behavior. The mice were then treated with AGE, and their behavioral outcomes were assessed using the forced swim test and tail suspension test, open field test, and elevated maze plus. Additionally, an in silico analysis was conducted to explore the potential mechanisms of action of AGE compounds, focusing on their interactions with the monoanime oxidase-A (MAO-A) enzyme. The in vivo experiments demonstrated that the administration of aged garlic extract significantly ameliorated behavioral deficits in mice subjected to chronic restraint stress. Specifically, AGE treatment led to reduced (p<0.05) immobility time in the forced swim test, with AGE125-treated mice showing (91.12 ± 4.94) seconds and AGE250-treated mice (73.0 ± 7.25) seconds, compared to (119.25 ± 7.13) seconds for the CRS group. Similarly, in the tail suspension test, immobility time was reduced to AGE125 (69.25 ± 5.65)s and AGE 250 (55.0 ± 6.74)s compared with CRS group (102.75 ± 6.84)s, thereby demonstrating antidepressant-like effects. Additionally, AGE-treated mice exhibited increased time spent in the periphery of the open field arena and spent more time in the open arms of the elevated plus maze, suggesting improved exploratory and anxiety-related behaviors compared to other groups. Additionally, in silico investigation suggested that compounds found in AGE may antagonize the MAO-A enzyme. This study provides evidence supporting the potential of AGE as a therapeutic agent for stress-related depressive disorders. AGE's ability to improve behavioral outcomes in stressed mice may be related to the modulation of neurotransmitter systems, reduction of oxidative stress, and anti-inflammatory effects of its compounds, including its potential interaction with the MAO-A enzyme. Further research is needed to fully elucidate the mechanisms of action and confirm the efficacy and safety of AGE in humans. Dhaka Univ. J. Pharm. Sci. 24(2): 157-176, 2025 (December)

Major depressive disorder (MDD) was long framed as a single clinical entity arising from a linear stress–monoamine–hypothalamic–pituitary–adrenal (HPA) axis cascade. This view was shaped by forced swim and learned helplessness tests in animals and by short-term symptom-based trials using scales such as the Hamilton Depression Rating Scale (HAM-D) and the Montgomery–Åsberg Depression Rating Scale (MADRS). This “unitary cascade” view has been dismantled by advances in neuroimaging, immune–metabolic profiling, sleep phenotyping, and plasticity markers, which reveal divergent circuit-level, inflammatory, and chronobiological patterns across anxiety-linked, pain-burdened, and cognitively weighted depressive presentations, all characterized by high rates of non-response and relapse. Translationally, face-valid rodent assays that equated immobility with despair have yielded limited bedside benefit, whereas cross-species bridges—electroencephalography (EEG) motifs, rapid eye movement (REM) architecture, effort-based reward tasks, and inflammatory/metabolic panels—are beginning to provide mechanistically grounded, clinically actionable readouts. In current practice, depression care is shifting toward systems psychiatry: inflammation-high and metabolic-high archetypes, anhedonia- and circadian-dominant subgroups, formal treatment-resistant depression (TRD) staging, connectivity-guided neuromodulation, esketamine, selected pharmacogenomic panels, and early digital phenotyping, as endpoints broaden to functioning and durability. A central gap is that heterogeneity is acknowledged but rarely built into trial design or implementation. This perspective advances a plasticity-centered systems psychiatry in which a testable prediction is that manipulating defined prefrontal–striatal and prefrontal–limbic circuits in sex-balanced, chronic-stress models will reproduce human network-defined biotypes and treatment response, and proposes hybrid effectiveness–implementation platforms that embed immune–metabolic and sleep panels, circuit-sensitive tasks, and digital monitoring under a shared, preregistered data standard.

Throughout time, there has always been a trend connecting stress and tangible damage to one's physical well-being. However, there's a lack of research that elucidates the physical and molecular traits of this stress on organ integrity. Chronic stress disrupts homeostasis, causing oxidative stress, mitochondrial dysfunction, inflammatory markers, and histological damage. In this study, a repeated forced swim stress (FSS) was used to induce stress in the C57BL/6 mice model and analyzed its effects on the brain and liver at behavioral, biochemical, histology, and genetic marker levels. Behavioral analysis showed reduced mobility duration in experimental mice. This was further supplemented by histopathological data, which revealed mild brain deterioration and moderate liver damage. Biochemical analysis revealed upregulated levels of aminotransferase (ALT) and alkaline phosphatase (ALP) and decreased levels of mean corpuscular haemoglobin (MCH), pointing towards the existence of liver dysfunctionality due to stress. Moreover, we reported the gene expression analysis of stress biomarkers (Bdnf, Fkbp5, Npy, Comt, Ppm1f, Adra2b, and Slc6a4), with a particular focus on Fkbp5, which is associated with depression and cognitive impairment. Similarly, we also studied the expressions of Crp, Cyp2e1, and Irs-2 to gauge liver damage. Results revealed significantly upregulated expression of Npy, Fkbp5, and Ppm1f in stressed mice. Our study identifies that chronic stress shows physical and molecular realizations. Additionally, this offers further incentive to look closely at Fkbp5, Npy, and Ppm1f under similar conditions and highlights their possible roles as markers of stress-induced damage.

Chronic administration of berberine attenuates depressive-like behavior in rats subjected to chronic unpredictable mild stress combined with ACTH treatment: Role of nitrergic system.

Depression is a debilitating psychiatric disorder with high prevalence and suicide risk, imposing significant burdens on global health. Against this global health burden, the active ingredients of Gekko gecko Linnaeus (AIGG), a traditional Chinese medicine (TCM), have shown empirical antidepressant effects. However, their specific pharmacological mechanisms remain unclear. This study systematically elucidated the antidepressant mechanisms of AIGG by integrating GC-MS-based component analysis, network pharmacology, molecular docking, and a corticosterone (CORT)-induced depressive mouse model. GC-MS identified 10 bioactive compounds (including fatty acids) in AIGG. Network pharmacology screening of 51 potential targets revealed significant enrichment in synaptic transmission and cAMP pathways. Molecular docking confirmed strong binding affinities between AIGG-derived compounds and key targets. In vivo experiments demonstrated that AIGG significantly reversed depression-like behaviors in both forced swim and tail suspension tests, suppressed Interleukin-6 (IL-6), tumor necrosis factor α (TNF-α), and elevated β-nerve growth factor (β-NGF) levels, attenuated neuroinflammatory infiltration and neuronal apoptosis in brain tissue, and upregulated protein expression of protein kinase cAMP-activated catalytic subunit alpha (PRKACA), brain-derived neurotrophic factor (BDNF), and postsynaptic density protein 95 (PSD95). The study confirmed that AIGG alleviates depression by activating the cAMP-PRKACA-BDNF axis to restore synaptic plasticity, providing a novel natural product-based strategy for treatment of the resistant depression.

With a global prevalence of 3.8% and affecting approximately 300 million people, depression remains a global burden calling for renewed efforts including novel antidepressants to address treatment gaps. Stigmasterol, an unsaturated naturally abundant phytosterol with reported neuropsychiatric activity in preclinical studies, was studied for potential antidepressant-like activity and mechanism of action using computational and experimental approaches. Using network pharmacology, we identified potential key targets of major depressive disorder and stigmasterol (STG) by analysing intersection genes for protein-protein interaction, Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses. We subsequently carried out molecular docking of stigmasterol with key targets identified to confirm antidepressant activity and potential mechanism(s) while the forced swim test (FST) and tail suspension test (TST) were used for experimental validation. To experimentally validate the involvement of monoaminergic mechanism(s) in STG’s action, mice were pretreated with selective inhibitors of monoamine synthesis and storage after which the antidepressant-like effects of STG was re-evaluated in FST. Forty intersection target genes were obtained with AKT1, TP53 and IL1B as well as MAOB, MAOA and SLC6A4 being identified as key targets. GO and KEGG enrichment analysis further reinforced the involvement of monoamine regulation, especially serotonin. Molecular docking showed STG interacts with SLC6A4 (-9.732 kcal mol-1), MAOA (-12.471 kcal mol-1) and MAOB (-14.614 kcal mol-1) further buttressing monoaminergic involvement. STG demonstrated significant antidepressant-like effects similar to fluoxetine-treated mice in both FST and TST. This antidepressant action was significantly influenced by serotonin neurotransmission. Overall, we confirmed the antidepressant-like activity of STG and its possible multitarget potential in depression management.

Binge drinking during adolescence is associated with a higher risk of developing Alcohol Use Disorders and impaired stress reactivity in adulthood. The hypothalamic-pituitary-adrenal axis matures during adolescence and is under strict GABAergic control. Yet, how early binge drinking alters GABAergic signaling in this region, and whether these changes contribute to later-life disruptions in stress reactivity, remain unknown. Our goal with these set of experiments was to test the hypothesis that adolescent binge drinking would impair maturation of GABAergic signaling in the paraventricular nucleus (PVN) and lead to aberrant behavioral and neuroendocrine stress reactivity. Adolescent male and female C57BL/6J mice were given access to 20% ethanol or tap water under Drinking in the Dark-Multiple Scheduled Access paradigm from PD28 to PD42 and went through abstinence until adulthood. At adulthood (PD60+), the behavioral and endocrine response to two stressors, forced swim stress and social defeat stress, were evaluated. Only females with a history of adolescent drinking showed abnormal behavioral reactivity to stress, with increased immobility in the forced swim stressor task. Females with a history of adolescent binge drinking displayed a hypo-corticosterone response after social stress and males showed delayed negative feedback to the forced swim stressor. PVN-enriched tissue from these mice showed no changes in transcription of Gabrg2, but males showed a significant increase in expression of Slc12a5, which encodes for the chloride potassium co-transporter, KCC2. These males showed no change in KCC2 protein when evaluated by immunohistochemistry. Taken together, these data show that adolescent binge drinking in pair-housed mice is associated with male-specific potential vulnerability in hypothalamic inhibitory signaling and disrupted adult stress reactivity in a sex- and stressor- dependent manner.

Depression being one of the most common psychiatric comorbidities in people with epilepsy. Based on the potent antidepressant and anticonvulsant activities of thiazolidinone moieties, we designed and synthesized a novel series of 5-arylidenethiazolidine-2,4-dione derivatives (11a-h) and (12a-h), and investigated their in vivo anticonvulsant activity using the pentylenetetrazol-induced model (PTZ), along with their antidepressant activity assessed by the forced swim test (FST) and tail suspension test (TST) in mice. The structures of the synthesized compounds were established through 1H NMR, 13C NMR, and LC-MS analysis. The study revealed that compounds 11e, 12e, and 12g exhibited potent antidepressant activity, which reduces immobility time by approximately 50% at 20mg/kg. In addition, compounds 11c, 11e, 11g, 12c, and 12g were identified as potent anticonvulsants, reducing post-convulsion effects such as duration of convulsion, jerking, and Straub's tail by more than 60% at 20mg/kg. Furthermore, key ADMET features were calculated in silico for the most active molecules to determine their pharmacokinetic properties. Molecular docking and MD simulation confirms their binding interactions to target proteins. Based on these findings, the compounds 11c, 11e, 11g, 12c, 12e, and 12g are promising lead candidates for the development of more effective anticonvulsant and antidepressant agents.

This study investigated the effects of coenzyme Q10 (CoQ10) administration on fibromyalgia (FM) symptoms and cognitive functions in a reserpine-induced FM model. It is also aimed to evaluate the role of the PGC-1α/FNDC5/BDNF pathway and oxidative stress in this process. Female Wistar rats were randomly assigned to control, FM, CoQ10, and FM + CoQ10 groups. The FM groups received daily subcutaneous reserpine (1mgkg-1) for three consecutive days. The CoQ10 groups were administered 150mgkg-1 of oral CoQ10 for 7days. Behavioral and sensory assessments were conducted on days 0, 4, and 6. Mechanical allodynia was measured with the Von Frey test, while depressive-like behavior was assessed using the forced swim test. Locomotor activity and anxiety levels were evaluated via the elevated plus maze, and learning/memory performance were tested using the Morris water maze probe test. Reserpine exposure led to increased mechanical allodynia, decreased locomotor activity, elevated anxiety levels, increased depressive-like behavior, and impaired learning/memory (p < 0.05). These behavioral abnormalities were accompanied by decreased hippocampal levels of CoQ9 and CoQ10, increased oxidative stress, and reduced antioxidant defenses (p < 0.05). Additionally, hippocampal PGC-1α, FNDC5 and BDNF expression levels were reduced (p < 0.05). CoQ10 treatment resulted in significant improvements in these neuropathological parameters (p < 0.05). These results imply that CoQ10 can counteract the behavioral, biochemical, and molecular disturbances characteristic of FM. The mechanism is suggested to involve stimulating the PGC-1α/FNDC5/BDNF cascade, which in turn reduces behavioral deficits linked to pain, depression, and cognitive function.

BackgroundSini San (SNS) is a traditional Chinese medicinal formulation originating from the “Treatise on Febrile Diseases”, an ancient text that has been historically employed for treating depression. However, the underlying mechanisms by which SNS potentially ameliorates symptoms of depression remain unclear. This study aimed to elucidate the role of gut microbiota in tryptophan metabolism and examine the involvement of short-chain fatty acids (SCFAs) in the putative antidepressant effects of SNS.MethodsA rat model of depression using chronic unpredictable mild stress (CUMS) was established through simultaneous modeling and treatment for six consecutive weeks. The possible therapeutic effect of SNS on CUMS-induced rats was thoroughly assessed using body weight measurements, open-field tests, and sucrose preference tests. Alterations in rat gut microbiota were analyzed using full-length 16 S rRNA third-generation sequencing. Furthermore, metabolomic analysis was performed on fecal samples. An enzyme-linked immunosorbent assay (ELISA) was used to quantify tryptophan (Trp), serotonin (5-HT), and kynurenine (Kyn) in the hippocampal and colonic tissues. Reverse transcription quantitative PCR (RT-qPCR) was used to measure the mRNA levels of TPH-1 and TPH-2 in hippocampal and colonic tissues. Immunofluorescence was used to assess hippocampal IDO-1 and IBA-1 expression. Finally, gas chromatography-mass spectrometry (GC-MS) was used to analyze the SCFAs content in fecal samples.ResultsAdministration of SNS significantly alleviated depressive symptoms induced by CUMS, as demonstrated by increased body weight, improved sucrose preference, and a statistically significant decrease in immobility time during the forced swim test (P < 0.05). The Shannon and Simpson indices were elevated following SNS treatment, signifying an enhancement in both the quantity and variety of the gut microbiota. Analysis using 16 S rRNA gene sequencing revealed that SNS influenced the composition of the gut microbiome, favorably increasing the presence of beneficial bacteria, such as Firmicutes, Lactobacillaceae, Ruminococcaceae, and Oscillospiraceae, while simultaneously decreasing the levels of potentially detrimental bacteria, such as Muribaculaceae, Prevotellaceae, Lachnospiraceae, and Alloprevotella. Fecal metabolomic studies identified 87 metabolites, of which 57 were differentially expressed, most notably l-tryptophan and phenylalanine. These metabolites were primarily linked to 15 metabolic pathways, with notable enrichment in the biosynthetic pathways of phenylalanine, tyrosine, and tryptophan, as well as the metabolic pathways of arachidonic acid and phenylalanine. Metabolomic profiling indicated that SNS stimulated the kynurenine pathway, leading to increased levels of metabolites with antidepressant properties, such as Trp, 5-HT, and Kyn, in both hippocampal and colonic tissues. In addition, SNS promoted the synthesis of SCFAs, particularly butyrate and propionate, which are known for their neuroprotective properties.ConclusionsThe present study suggests that the antidepressant effects of SNS can be attributed to its ability to modulate the structure of the gut microbiota, consequently regulating tryptophan metabolism and SCFA levels, which ultimately ameliorate symptoms of depression. These findings provide experimental evidence supporting the concept of the brain-gut axis in depression treatment and lay a foundation for further investigation of the underlying antidepressant mechanisms of the SNS.Supplementary InformationThe online version contains supplementary material available at 10.1186/s12906-025-05190-5.

BackgroundIn recent years neuroinflammation hypothesis has emerged as a major player in major depressive disorder. Oxido‐inflammatory stress is known to activate inflammasome NLRP3, an adaptor protein that has been implicated in the pathogenesis of depression.ObjectiveThe current investigation was created with the aim of investigating the effect of flufenamic acid in experimental model of depression like behavour.MethodIn the current study male balb/c mice were used. animals were exposed to forced swim stress for 21 days. Flufenamic acid (10 and 20 mg/kg, per oral) alone and in combination with flouxetine was used as treatment. Further behavioural (forced swim test, and sucrose preference test), Biochemicals (oxidative stress and anti‐oxidant levels), mitochondrial enzyme activities, corticosterone levels and monoamine and their metabolite levels (Norepinephrine, Seretonin, Dopamine, Homovanillic acid, Dihydroxy phenyl aceioc acid and 5‐hydroxyindole acetic acid) were assessedResultsforced swim stress mice showed depression‐like behavioural alterations characterized by increased immobility time in forced swim test and decreased sucrose preference. Flufenamic acid significantly ameliorated depression‐like behavioural alterations. Flufenamic acid also significantly restored antioxidant enzymes, and increased oxidative stress in cerebral cortex and hippocampus showing its anti‐stress and antioxidant property, restored mitochondrial enzyme activities, regained corticosterone levels and attenuated altered monoamine levels and histopathological alterations in cortex and hippocampus.Conclusionthe current study demonstrates the neuroprotective potential of flufenamic acid in experimental model of depression like behavour.

Individual differences in stress coping are linked to working memory performance in male and female F344 rats.