Search Results (302)

The role of the endocannabinoid system (ECS) in the development of depression and anxiety is being actively studied, with evidence suggesting that elevation of ECS signaling can have anxiolytic and antidepressant properties. The current study explored the therapeutic potential of Oleoyl Serine (OS), an endocannabinoid-like lipid, and HU-910, a synthetic selective Cannabinoid type 2 (CB2) receptors agonist, in depression and anxiety, using both sexes of the depressive-like genetic model: Wistar Kyoto (WKY) rats. The aim was to investigate behavioral and molecular mechanisms associated with acute and sub-chronic intraperitoneal administration of these compounds. We showed that, in females, acutely administered OS yielded antidepressant-like and anxiolytic-like effects in the Forced Swim Test (FST) and Open Field Test (OFT), respectively. In males, OS yielded acute and sub-chronic anxiolytic-like effects. HU-910 yielded an acute anxiolytic-like effect in females and an acute antidepressant-like effect in males. Sub-chronic administration of imipramine (IMI), used as a positive control, yielded an antidepressant-like effect in both sexes but an anxiogenic-like effect in females. Sub-chronic administration of all the treatments increased hippocampal Cannabinoid Receptor 1 (CNR1) mRNA expression (but not Fatty Acid Amide Hydrolase (FAAH)) in males. Exploratory in silico absorption, distribution, metabolism, and excretion (ADME) profiling suggests that sex-dependent pharmacokinetic variability may partly underlie the observed behavioral differences, in addition to possible pharmacodynamic factors. Our study provides a lead towards unraveling the putative sex differences in response to both conventional antidepressants (e.g., IMI) and emerging pharmacological agents (e.g., OS, HU-910). Further, our study helps advance the field of neuropharmacology by elucidating the anxiolytic-like and antidepressant-like effects of OS and HU-910. Full article

Alzheimer’s disease (AD) is the most prevalent neurodegenerative disorder in the aging population. Drug repurposing provides a cost-effective strategy to identify novel therapeutics that may mitigate age-associated pathologies. Here, we report the therapeutic potential of fluoxetine, a selective serotonin reuptake inhibitor commonly used as an antidepressant, in alleviating cognitive impairment and AD-like pathology in 5xFAD mice, a transgenic model of familial AD. Chronic fluoxetine administration significantly ameliorated anxiety-like behavior and cognitive deficits in 5xFAD mice, as assessed by open field, Y-maze, and novel object recognition tests. Fluoxetine treatment was associated with reduced amyloid plaque deposition in the hippocampus and cortex, attenuation of microglial activation, and decreased expression of inflammatory cytokines. At the molecular level, fluoxetine increased phosphorylation of GSK3β at Ser9, which was associated with enhanced CREB phosphorylation and upregulation of the α-secretase ADAM10. These effects were further examined in SH-SY5Y neuronal cells, where CREB phosphorylation and ADAM10 expression were significantly modulated by GSK3β inhibition, whereas CaMKII inhibition had no detectable effect under our experimental conditions. Our findings suggest that fluoxetine modulates amyloid-associated signaling pathways in the 5xFAD model, in part through regulation of the GSK3β-CREB signaling framework. These results provide mechanistic insight into how fluoxetine may influence APP processing in an amyloid-driven pathological context, although further studies are required to clarify its translational implications in human AD. Full article

Depression-related mood disturbances are increasingly recognized as nutrition-sensitive conditions associated with chronic stress-induced neuroinflammation and metabolic imbalance. Polygonatum sibiricum, Poria cocos, Lilium brownii, and Radix Glycyrrhizae Preparata are edible medicinal plants commonly used in functional foods. In this study, we evaluated the antidepressant effects of a Polygonatum sibiricum-based functional formula (PSF) in a chronic restraint stress (CRS) mouse model. CRS induced prominent anhedonia and behavioral despair, accompanied by microglial overactivation, activation of the NLRP3 inflammasome, and dysregulated tryptophan metabolism. PSF supplementation significantly alleviated depressive-like behaviors and inhibited NLRP3–caspase-1–GSDMD-mediated pyroptosis, leading to reduced hippocampal IL-1β and IL-18 levels. Importantly, PSF restored tryptophan metabolism toward serotonin production, stabilized monoaminergic and glutamate/GABA neurotransmission, and protected hippocampal neurons. Moreover, PSF partially reversed stress-induced gut microbiota dysbiosis. Collectively, these results demonstrate that PSF acts as a neuroimmune–metabolic modulator that improves mood-related behaviors by regulating inflammatory signaling, tryptophan metabolism, and neurotransmitter homeostasis, supporting its potential development as a functional food intervention for stress-induced depression. Full article

Depression remains a major global health challenge, with a significant proportion of patients failing to respond to conventional antidepressants. This study aimed to evaluate the potential antidepressant effects and toxicological profile of a novel tetrodotoxin (TTX) oral film formulation in a mouse model of chronic unpredictable mild stress (CUMS). Male C57BL/6J mice were subjected to CUMS and treated daily with TTX oral film at doses of 10, 20, and 40 μg/kg, with fluoxetine (18 mg/kg) serving as a positive control. Behavioral assessments, including sucrose preference test, open field test, forced swimming test, elevated plus maze, and novel object recognition, demonstrated that TTX oral film administration alleviated depression- and anxiety-like behaviors and improved cognitive function. Furthermore, TTX oral film treatment restored hippocampal serotonin levels, which were depleted in CUMS mice, and showed no adverse effects on organ indexes after long-term use. Toxicological evaluation through acute toxicity testing revealed an oral LD₅₀ of 919 μg/kg, indicating a substantially improved safety profile compared to pure TTX and a wide therapeutic window. These findings suggest that the TTX oral film possesses significant antidepressant activity with favorable toxicological properties, supporting its potential as a novel and safe treatment for depression. Full article

Background/Objectives: Baichuan Baile (BCBL), a novel functional dietary formula, has been shown to exert antidepressant-like effects through modulation of the 5-HT system in our prior studies. Given the close neurobiological connections between depression and insomnia, along with its pharmacodynamic profile guided by TCM theory and nutritional assessments, BCBL is likely to possess beneficial effects against insomnia. However, this hypothesis and its underlying mechanisms require further validation. Methods: The chemical constituents of BCBL were analyzed by UPLC-Q-TOF-MS, and network pharmacology was applied to predict potential sleep-relevant targets and pathways. Subsequently, BCBL was evaluated for sedative-hypnotic effects using pentobarbital-induced hypnosis, locomotor activity, and polysomnography (EEG/EMG). Its therapeutic efficacy was further assessed in insomnia models induced by environmental stress, serotonin depletion, and rotarod-based sleep deprivation. The rotarod-induced chronic model was selected for mechanistic studies due to its sustained insomnia-like phenotype. Finally, key network-predicted targets were validated in this model through histopathology, Western blotting, and ELISA. Results: Pharmacological evaluation confirmed that BCBL significantly promoted sleep at both behavioral and EEG levels, confirming its sedative-hypnotic properties. BCBL mitigated environmental stress-triggered impairments in NREM sleep continuity and duration, and exerted protective effects against body weight loss and sleep disturbances in a serotonin depletion-induced insomnia model. In the rotarod sleep deprivation model, BCBL treatment increased spontaneous alternation rates and recognition indices, ameliorated hippocampal pathological alterations, and reduced hippocampal levels of HIF-1α, TNF-α, and IL-1β. Furthermore, BCBL elevated the p-GSK3β/GSK3β ratio and enhanced SIRT₁ expression in the hypothalamus. It also modulated the activity of key sleep–wake neurotransmitters/neuromodulators (serotonin, dopamine, adenosine, and glutamate) and key circadian rhythm regulators (BMAL₁, PER₂, and CLOCK) in this region. Conclusions: BCBL exhibits significant therapeutic efficacy against insomnia, indicating its potential as a dietary supplement for managing insomnia. Its mechanisms appear to involve anti-inflammatory effects, rebalancing of neurotransmitters/neuromodulators, and stabilization of circadian rhythm gene expression. Full article

Background/Objetives: Menopause increases anxiety and depression risk, linked to gut microbiota changes. Probiotics show psychobiotic effects that could therapeutically alleviate these symptoms in menopausal women. However, this potential and its mechanism of action involving estrogen receptors remain largely unexplored. To investigate whether Lactobacillus reuteri RC-14^® and Lactobacillus rhamnosus GR-1^® exert anxiolytic-like and antidepressant-like effects in ovariectomized rats via estrogenic receptor (ER) activation. Methods: Ovariectomized adult female Wistar rats were divided into four groups: vehicle, probiotics (4.9 × 10⁹), 17β-estradiol (0.09 mg/kg), and their combination. All treatments were administered for 28 days. Three additional groups (probiotics and 17β-estradiol) received tamoxifen (5 mg/kg) to block estrogen receptors. The elevated plus maze (EPM), open field test (OFT), and forced swim test (FST) were conducted to evaluate anxiety and depression-like behaviors. Data were analyzed using one-way ANOVA. Results: In the EPM, all active treatments enhanced open-arm exploration and reduced the anxiety index compared to the vehicle and tamoxifen groups. Similarly, in the FST, these treatments increased swimming behavior and decreased immobility regarding the same control groups. The anxiolytic- and antidepressant-like effects of all treatments were reverted by tamoxifen. No significant changes were observed in the OFT. Conclusions: The combination of probiotics and 17β-estradiol produces anxiolytic-like and antidepressant-like behavioral effects in this preclinical model, suggesting potential relevance for menopause-related affective symptoms by acting via estrogen receptors and the possible participation of serotonergic pathways. These preliminary findings are hypothesis-generating and require validation through long-term preclinical studies and carefully designed clinical trials before any therapeutic recommendations can be made regarding the use of probiotics for menopause-related affective symptoms. Full article

Background/Objectives: As the prevalence of depression and the use of antidepressants have risen steadily in the last decade, new treatment options are needed. Aloysia gratissima var. gratissima ethanol extract has previously shown antidepressant-like activity, and the present study was conducted to identify the active fraction and clarify the possible mechanisms of action. Methods: Tail suspension (TST) and forced swimming (FST) behavioral tests were performed, and possible mechanisms of action were elucidated using serotonergic, dopaminergic, adrenergic, and GABAergic system antagonists. UPLC-DAD-MS analyses were performed to identify compounds in active fractions, and molecular docking studies were carried out to determine the binding affinities of these compounds to serotonergic and dopaminergic receptors (5-HT_1A, 5-HT_2A, 5-HT₃, and D₂R). Results: Ethyl acetate and butanol fractions were found to decrease immobility time in FST. The reduction in immobility time during the FST caused by the ethyl acetate fraction was reversed by pretreating mice with WAY100635 (5-HT_1A antagonist), ketanserin (a 5-HT_2A antagonist, ondansetron (5-HT₃ antagonist), or haloperidol (D₂ antagonist). UPLC-DAD-MS analysis revealed a similar composition for the ethyl acetate and butanol fractions of A. gratissima var. gratissima. Pharmacokinetic predictions suggest that only a few of the identified compounds have the potential to permeate the blood–brain barrier, and molecular docking simulations showed that compounds such as 13-oxooctadecadienoic acid, ferulic acid, and coumaric acid have binding affinities to the druggable site of serotonergic and dopaminergic receptors. Conclusions: These results suggest that the Agg ethyl acetate fraction possesses antidepressant-like activities, altering dopaminergic and serotonergic system functions. Computational simulations also suggest that some of the identified compounds have binding affinities to the 5-HT_1A, 5-HT_2A, 5-HT₃, and D₂R receptors. Full article

Background/Objectives: Apigenin, a naturally occurring flavonoid, has shown promising antidepressant-like effects in previous studies. However, its precise mechanisms remain unclear. This study aims to investigate the underlying neurobiological mechanisms mediating the antidepressant effects of apigenin in chronic unpredictable mild stress (CUMS)-induced mice. Methods: The male mice were subjected to 4-week CUMS, with or without treatment, followed by behavioral testing. Network pharmacology analysis was employed to predict relevant signaling pathways. The mRNA and protein expression levels of the PI3K/AKT/NRF2 pathway were measured. Oxidative stress was assessed through the measurement of malondialdehyde, glutathione, and superoxide dismutase levels. Results: Apigenin significantly ameliorated CUMS-induced depression-like behaviors. The PI3K/AKT pathway may mediate the antidepressant properties of apigenin with both PI3K and AKT emerging as core target molecules. Apigenin restored the activity of the PI3K/AKT/NRF2 pathway and oxidative stress in the hippocampus downregulated by CUMS. Conclusions: The present study demonstrates that apigenin ameliorates depression-like behaviors in mice exposed to CUMS and mitigates oxidative stress in the hippocampus, which is associated with the PI3K/AKT/NRF2 signaling pathway. Full article

The treatment of depression is an uphill battle due to the low efficiency and delayed clinical response of antidepressants and the fact that most of them cause numerous side effects. Psychobiotics, probiotics that affect brain function and confer mental health benefits, emerged as a promising ally showing protective effects against depressive- and anxiety-like behaviors in various animal models of depression. There is rapidly accumulating evidence that psychobiotics show protective effects at the molecular level as well, affecting several pathophysiological processes implicated in depression. This narrative review summarizes preclinical insights into molecular changes related to the hypothalamic-pituitary-adrenal (HPA) axis, peripheral inflammation, neuroinflammation, neurotransmission and tryptophan metabolism underlying psychobiotic-driven mitigation of depressive and anxiety symptoms in stress-based, corticosterone-induced and inflammation-induced animal models of depression. Research evidence indicates that psychobiotics normalize the activity of the HPA axis, decrease levels of inflammatory mediators in the intestine, circulation, and brain, normalize the levels of neurotransmitters and their receptors, and regulate tryptophan metabolism in various animal models of depression. The main setbacks in this field are the extensive diversity of studied probiotic strains, which are often insufficiently characterized, and the lack of mechanistic studies in animal models. However, despite these challenges, further study of psychobiotics in the pursuit of supportive therapies for depressive disorders is firmly grounded. Full article

Major depressive disorder (MDD) is a leading cause of global morbidity and mortality. Although pharmacological treatments are widely used, their effects are often limited, and nearly half of patients show resistance to current antidepressants, including those unresponsive to all available therapies. These challenges highlight the need to better understand the neurobiological mechanisms driving MDD and to develop novel therapeutic strategies, especially those involving natural compounds with multitarget actions. Baicalin, a bioactive flavonoid from Scutellaria baicalensis, exhibits antioxidant, anti-inflammatory, and neuroprotective properties and has recently gained attention for its potential to improve cognitive deficits and mood disorders. In this study, we investigated baicalin’s antidepressant potential and its underlying mechanisms across multiple experimental levels. We found that oral administration of baicalin produced antidepressant-like effects in both naïve mice and those subjected to chronic restraint stress (CRS). CRS impaired hippocampal long-term potentiation (LTP), whereas baicalin restored these synaptic deficits. Importantly, intra-dorsal hippocampal microinjection of the TrkB receptor antagonist ANA-12 abolished baicalin’s antidepressant effects, indicating the involvement of BDNF–TrkB signaling. Baicalin also reduced reactive oxygen species (ROS)/H₂O₂ production in a BDNF-associated manner, demonstrating clear antioxidant activity. Molecular docking further suggested that baicalin binds more effectively to the TrkB receptor than ANA-12, supporting its capacity to activate TrkB-mediated signaling. By integrating in vivo, ex vivo, in vitro, and in silico approaches, our study shows that baicalin exerts robust antioxidant in vitro and antidepressant effects in vivo. These benefits are primarily mediated through activation of BDNF–TrkB signaling, leading to reduced ROS/H₂O₂ accumulation and alleviation of CRS-induced depression-like behaviors. Full article

The rise in psychotropic drug use among students, particularly in Veterinary Medicine, correlates with high rates of mental disorders like depression and anxiety, often exacerbated by academic stress. Factors such as high academic demands, emotional exhaustion, and poor sleep quality contribute to the increased use of medications like antidepressants and anxiolytics. However, in Brazil, there is limited research on the profile and factors associated with this drug use among veterinary students. This study aims to assess the prevalence, patterns, and associated factors of psychotropic drug use at the Federal University of Santa Maria. A descriptive-correlational cross-sectional study was conducted using a survey covering sociodemographic data and psychotropic drug use. A total of 245 students participated in this study. The collected data included age, sex, semester, physical activity, sleep quality, drug use, family income, place of birth, and residence. In total, 36.7% of students reported using psychotropic medications during their undergraduate studies, with 77.1% being women and 22.9% men. Additionally, 45.6% reported insufficient sleep, defined as 4 to 6 h per day. Inactive students had a 94.5% higher likelihood of using psychotropic medications. Selective serotonin reuptake inhibitors (SSRIs) and benzodiazepines were the most reported drug classes. The findings highlight the emotional and academic burden of veterinary education, underscoring the need for institutional actions that prioritize student mental health. Full article

Serotonin receptors, in particular 5-HT_1A and 5-HT_2A receptors, are important molecular targets for the central nervous system (CNS) disorders, such as schizophrenia, depression, anxiety disorders, memory deficits, and many others. Here, we present structural and pharmacological evaluation of a serotonin receptor ligand, SERAAK2, identified in a structure-based virtual screening campaign. Molecular docking studies revealed that SERAAK2 binds with its molecular targets via Asp3.32 as the main anchoring point, which is typical for orthosteric ligands of aminergic GPCRs. Molecular dynamics simulations confirmed the stability of the ligand binding poses in the studied receptors. MMGBSA calculations were in accordance with the receptor in vitro binding affinity studies, which indicated that SERAAK2 is a potent ligand of 5-HT_1A and 5-HT_2A receptors. It was also found that SERAAK2 displays favorable ADMET parameters. The demonstrated anxiolytic- and antidepressant-like effects of SERAAK2 in animal models, which may involve its interaction with 5-HT_1A receptors, warrant further studies to confirm these activities and elucidate the underlying mechanisms. Full article

The resin extract of Garcinia nigrolineata (GNR-E), a tropical plant used in Southeast Asian traditional medicine, was evaluated for its antidepressant-like effects in a chronic mild stress (CMS) mouse model, with imipramine as a reference drug. GNR-E dose-dependently alleviated CMS-induced anhedonia (sucrose preference test) and behavioral despair (forced swimming and tail suspension tests). Neurochemical analyses revealed that GNR-E increased serotonin (5-HT) and norepinephrine (NE) levels, reduced expression of their transporters (SERT, NET) and receptors (5-HT1A, 1B, 2A, 2C, 7; α2A, 2C) in the frontal cortex and hippocampus, and normalized HPA-axis hyperactivity by lowering serum corticosterone and modulating glucocorticoid receptor (GR) and SGK-1 mRNA expression. In vitro, GNR-E inhibited monoamine oxidase (MAO)-A and -B (Ki = 2.33 and 1.55 µg/mL, respectively). Phytochemical analysis identified xanthones, particularly cowanin, as key constituents. These findings highlight GNR-E’s potential as a novel plant-based antidepressant, warranting further investigation into its active compounds and clinical applications. Full article

Background: Thunbergia alata is employed in traditional medicine to treat culture-bound syndromes such as “susto” (fright) or “espanto” (fearfulness). These conditions may correlate with depressive disorders. However, there is no evidence that this species has antidepressant properties. Aims: To characterize the antidepressant-like effect of an aqueous extract of T. alata in different paradigms and to analyze the role of brain monoamines in such actions. Methods: Independent groups of mice were treated with saline or the extract (1, 5, 10, 50, and 100 mg/kg; p.o.) and evaluated in the tail suspension (TST) and forced swimming tests (FST). Biochemical mechanisms were analyzed using inhibitors of monoamine synthesis, ligands of serotonergic receptors, and in vitro assays of MAO-A and MAO-B activity. Acute and sub-acute toxicity was evaluated. Results: The extract significantly reduced the immobility time of mice in both the TST and the FST, without affecting locomotor activity, as did the prototypical antidepressant desipramine. PCPA, AMPT, and NAN-190 abolished the extract’s effects on despair, while serotonergic ligands (8-OH-DPAT, fluoxetine, and pindolol) facilitated their antidepressant action. T. alata inhibited MAO-A and B activity. High doses of the extract produced no change in organ morphology; LD₅₀ was >2000 mg/kg. Conclusions: This is the first study to demonstrate that an aqueous extract of T. alata produces antidepressant effects mediated by the monoamine brain levels, especially serotonin. In addition to its use in culture-bounded syndromes, the present findings of safety and efficacy give support to the proposal that T. alata may be used in the treatment of depression. Full article

Background/Objectives: Baihe Dihuang Tang (BDT), a classical herbal formula from Zhang Zhongjing’s Han Dynasty work Jin Gui Yao Lue, is widely used to treat depressive disorder by nourishing Yin, clearing heat, and tonifying the heart and lungs. However, its pharmacological mechanisms remain unclear. This study aims to explore BDT’s antidepressant effects via MAOA-regulated serotonin (5-HT) metabolism and synaptic plasticity, supported by experimental validation, while using network pharmacology to predict MAOA-targeting active components. Methods: Active components and targets of BDT were screened using TCMSP, TCMID, and other databases, and then a component-target-pathway network was constructed. A chronic restraint stress (CRS)-induced depressive mouse model was established. Behavioral tests, including open field test (OFT), elevated plus maze (EPM), forced swimming test (FST) and tail suspension test (TST), were conducted to evaluate antidepressant effects. ELISA, qRT-PCR, and Western blot were employed to assess hippocampal 5-HT metabolism (MAOA, 5-HT/5-HIAA ratio) neurotrophic signaling (BDNF, TrkB) and synaptic plasticity-related proteins (PSD-95, SYN1). Results: BDT significantly reduced FST/TST immobility time and improved anxiety-like behaviors in OFT/EPM. BDT treatment downregulated MAOA expression, elevated hippocampal 5-HT/5-HIAA ratio, activated BDNF/TrkB pathway, and upregulated PSD-95/SYN1. Network pharmacology confirmed MAOA’s central role, identifying MAOA/serotonergic synapse modulation as BDT’s main mechanism and pinpointing Ferulic acid, Caffeate, Stigmasterol, (−)-nopinene, Eugenol, and cis-Anethol as MAOA-targeting bioactive components. Conclusions: BDT ameliorates depressive-like behaviors. This effect is mechanistically linked to suppression of MAOA-mediated 5-HT catabolism—a key validated target. This suppression elevates hippocampal 5-HT bioavailability, thereby activating BDNF/TrkB signaling and promoting synaptic plasticity. Network pharmacology confirmed MAOA as a primary target and identified specific modulatory bioactive components. Full article