Search Results (136)

Background and Objectives: Alzheimer’s disease (AD) has become a serious health problem. Agomelatine (Ago) is a neuroprotective antidepressant. This study aimed to assess how Ago influences behavioral outcomes in AD-like rat model. Materials and Methods: Forty-eight Wistar albino rats were allocated into four groups: Control (C), Alzheimer’s disease-like model (AD), Alzheimer’s disease-like model treated with Ago (ADAgo), and Ago alone (Ago). Physiological saline was injected intrahippocampally in C and Ago animals, whereas Aβ peptide was delivered similarly in AD and ADAgo rats. On day 15, 0.9% NaCl was administered to the C and AD groups, and Agomelatine (1 mg/kg/day) was infused into ADAgo and Ago rats via osmotic pumps for 30 days. Behavioral functions were evaluated using Open Field (OF), Forced Swim (FST), and Morris Water Maze (MWM) tests. Brain tissues were examined histopathologically. Neuritin, Nestin, DCX, NeuN, BDNF, MASH1, MT1, and MT2 transcripts were quantified by real-time PCR. Statistical analyses were performed in R 4.3.1, with p < 0.05 deemed significant. Results: In the FST, swimming, climbing, immobility time, and mobility percentage differed significantly among groups (p < 0.05). In the MWM, AD rats exhibited impaired learning and memory that was ameliorated by Ago treatment (p < 0.05). DCX expression decreased in AD rats but was elevated by Ago (p < 0.05). Nestin levels differed significantly between control and AD animals; MT1 expression varied between control and AD cohorts; and MT2 transcript levels were significantly lower in AD, ADAgo, and Ago groups compared to C (all p < 0.05). Conclusions: Ago exhibits antidepressant-like activity in this experimental AD model and may enhance cognitive function via mechanisms beyond synaptic plasticity and neurogenesis. Full article

Background/Objectives: Urolithin A (UA), a gut-derived metabolite of ellagitannins or ellagic acid, has recently gained attention for its potential benefits to brain health. The present research aimed to assess the antidepressant-like properties of UA in both in vitro and in vivo models and explored the molecular mechanisms underlying these effects. Methods: We investigated the antidepressant effects and mechanisms of UA in a model of corticosterone-induced damage to PC12 cells and in a model of chronic socially frustrating stress. Results: Our results demonstrate that UA treatment (5 and 10 μM) significantly alleviated cellular damage and inflammation in corticosterone (CORT)-treated PC12 cells. Furthermore, UA administration (50 and 100 mg/kg) significantly reduced immobility time in the mouse tail suspension test (TST) and forced swim test (FST), indicating its antidepressant-like activity. Additionally, treatment with UA led to the activation of the cAMP response element-binding protein (CREB)/brain-derived neurotrophic factor (BDNF) signaling cascade and triggered the activation of adenosine monophosphate-activated protein kinase (AMPK) during these processes. Importantly, pretreatment with AMPK-specific inhibitor Compound C abolished UA’s cytoprotective effects in PC12 cells, as well as its behavioral efficacy in the FST and TST, and its neurotrophic effects, highlighting the critical role of AMPK activation in mediating these effects. Furthermore, in the chronic social defeat stress (CSDS) mouse model, UA treatment (50 and 100 mg/kg) significantly alleviated depression-like behaviors, including reduced sucrose preference in the sucrose preference test, increased social avoidance behavior in the social interaction test, and anxiety-like behaviors, including diminished exploration, in the elevated plus maze test, suggesting the antidepressant-like and anxiolytic-like activities of UA. Moreover, UA treatment reversed elevated serum stress hormone levels, hippocampal inflammation, and the decreased AMPK/CREB/BDNF signaling pathway in the hippocampus of CSDS mice. Conclusions: Together, these results provide compelling evidence for UA as a viable dietary supplement or therapeutic option for managing depression. Full article

Background/Objectives: Major depressive disorder (MDD) is a debilitating illness, and chronic stress is a contributing factor for depressive symptoms. However, despite intense research, the mechanisms of MDD remain substantially unidentified. Quercetin is a powerful flavonoid and could be used as a possible therapeutic strategy for depression. Acknowledging the potential benefits of quercetin, this study investigated its effect alone or in association with the standard drug tranylcypromine (TCP) in a rodent model of chronic restraint stress (CRS). Methods: Adult male rats were subjected to a CRS model consisting of an immobilization session of 4 h daily during 14 consecutive days. Quercetin (50 mg/kg, gavage) was administered for 45 days. TCP (10 mg/kg, gavage) was administered for 14 days. Behavioral tasks were conducted to assess locomotor functions, memory, anhedonia, depression-like behaviors, and anxiety-like behaviors. The activity, gene expression, and protein density of acetylcholinesterase (AChE) were investigated. Results: Behavioral tasks showed that the CRS model effectively induced stable behavioral changes. CRS did not alter locomotor function assessed by the open field test (OFT) or anhedonia behavior assessed by the sucrose preference test (SPT). CRS increased total fecal count, which was prevented by quercetin administration in rats. TCP and the association of quercetin and TCP increased the recognition index in comparison with the CRS group in the novel object recognition (NOR) test and improved the swimming and immobility times in comparison to stressed animals in the forced swim test (FST). All treatments were able to decrease the anxiety index assessed by the elevated plus maze (EPM) test. The activity, gene expression, and protein density of AChE were increased in the CRS model compared to control males. Overall, quercetin and TCP proved to reverse CRS-induced alterations in these parameters. Conclusions: Quercetin mitigated cognitive deficits, behavioral impairments, and neurochemical alterations induced by the CRS model, especially in association with TCP, supporting its potential as a promising therapeutic agent for depression. Full article

In West Africa, Paullinia pinnata (P. pinnata) alcohol leaf extracts are used to treat disorders such as depression and anxiety with no documented scientific justification. We have therefore evaluated the potential anxiolytic and antidepressant effects of Paullinia pinnata methanol leaf extract (PPME) in mice, along with probable underlying mechanisms. Adult Swiss albino mice were administered 100, 200, and 400 mg/kg of PPME orally before subjecting them through elevated plus maze (EPM) and hole-board tests to assess the anxiolytic effect. The tail suspension test (TST) and the forced swim test (FST) were used to assess the antidepressant-like effects. Reserpine, labetalol, and risperidone were used to investigate probable mechanisms of action. In both FST and TST, the duration of immobility was considerably reduced by PPME. Conversely, PPME had no significant effect on the number of mice who dipped their heads into the hole-board or entered the EPM’s open arm. Mechanistic analysis revealed that in mice given labetalol or risperidone beforehand, PPME dramatically reduced the length of immobility and reversed ptosis and akinesia caused by reserpine. Our findings suggest that PPME possesses antidepressant-like, but not anxiolytic-like, effects in mice, and antidepressant action may involve enhancing noradrenergic and serotonergic mechanisms. Full article

Muscle atrophy, a physiological decline in muscle mass and strength due in ageing, occurs through an imbalance between protein breakdown and synthesis. The purpose of this study was to verify whether amino acid complex supplementation (ACS) can prevent and treat muscle loss in a dexamethasone (Dexa, 800 μg/kg)-induced rat model of sarcopenia. Sprague Dawley rats (6 weeks old) were assigned to seven groups: (i) normal control, (ii) positive control (high-dose ACS, 500 mg), (iii) Dexa only, (iv) Dexa + high-dose ACS (500 mg), (v) Dexa + medium-dose ACS (300 mg), (vi) Dexa + low-dose ACS (100 mg), or (vii) Dexa + liquid amino acid complex formulation (LF, 2 mL), administered orally for 4 weeks. Exercise capacity tests were performed five times using a treadmill test (TT) and forced swimming test (FST). The body weight increase in each group was less than that of the normal group. The blood biochemical indices, AST levels, and AST/ALT ratio significantly increased in the Dexa-treated medium-dose ACS group. The total muscle protein also significantly increased in all ACS groups. In the Dexa-treated LF group, CK decreased below the normal level. Exercise capacity, assessed by TT and FST, increased the most in the positive control and Dexa-treated high-dose ACS groups. In the TT, the Dexa-only group increased by about 18%, but the Dexa-treated high-dose ACS group increased by about 110%. Additionally, in the FST, Dexa-treated rats receiving a high dose of ACS demonstrated significantly increased exercise time and capacity. Electron microscopic (EM) and hematoxylin and eosin (H&E) observations of muscle tissue revealed muscle fiber atrophy in the gastrocnemius muscles of the Dexa-only group. In the EM findings of the Dexa-treated high-dose ACS group, the M-line and Z-line were clearer than in the Dexa-only group, and the mitochondria were partially preserved. In conclusion, the ACS-treated rats showed a clear recovery from muscle damage based on serum indices, total muscle protein mass, and the microscopic findings on muscle tissue. Notably, a high dose of ACS demonstrated the most effective protection and recovery of muscle tissue in the Dexa-induced sarcopenia rat model. Full article

Inflammatory bowel disease is a risk factor for brain dysfunction; however, the underlying mechanisms remain largely unknown. In this study, we aimed to explore the potential molecular mechanisms through which intestinal inflammation affects brain function and to verify these mechanisms. Mice were treated with multiple cycles of 1% w/v dextran sulfate sodium (DSS) in drinking water to establish a chronic colitis model. Behavioral tests were conducted using the open field test (OFT), tail suspension test (TST), forced swimming test (FST), and Morris water maze test (MWM). Brain metabolomics, transcriptomics, and proteomics analyses were performed, and key target proteins were verified using qPCR and immunofluorescence. Four cycles of DSS administration induced colitis, anxiety, depression, and spatial memory impairment. The integrated multi-omics characterization of colitis revealed decreased brain chenodeoxycholic acid (CDCA) levels as well as reduced stearoyl-CoA desaturase (Scd1) gene and protein expression. Transplantation of the colitis microbiome resulted in anxiety, depression, impaired spatial memory, reduced CDCA content, decreased Scd1 gene and protein expression, and lower concentrations of monounsaturated fatty acids (MUFAs), palmitoleate (C16:1), and oleate (C18:1) in the brain. In addition, CDCA supplementation improved DSS-induced colitis, alleviated depression and spatial memory impairment, and increased Scd1 gene and protein expression as well as MUFA levels in the brain. The gut microbiome induced by colitis contributes to neurological dysfunction, possibly through the CDCA–Scd1 signaling axis. CDCA supplementation alleviates colitis and depressive behavior, likely by increasing Scd1 expression in the brain. Full article

Background/Objectives: Diabetes mellitus is often accompanied by mental health complications, including anxiety, depression, and cognitive decline. Recent research suggested that capsaicin, the active component of chili peppers, may influence mental health. This study aimed to determine the effect of dietary capsaicin on mental disorders in a type 1 diabetes (T1D) mouse model, while also exploring the potential involvement of the microbiota-gut-brain axis. Methods: We induced T1D in mice using streptozotocin (STZ) and administered a diet supplemented with 0.005% capsaicin for five weeks. Behavioral assessments, including the open field test (OFT), tail suspension test (TST), forced swimming test (FST), elevated plus maze (EPM) test, and Morris water maze (MWM) test, were conducted to evaluate depressive and anxiety-like behaviors as well as cognitive function. Targeted and untargeted metabolomics analyses were performed to assess neurotransmitter levels in the hippocampus and serum metabolites, while 16S rRNA sequencing was utilized to analyze gut microbiota composition. Intestinal barriers were determined using western blot detection of the tight junction proteins ZO-1 and occludin. Results: Dietary capsaicin exacerbated anxiety and depressive-like behaviors along with cognitive declines in T1D mice. Capsaicin reduced gut microbiota diversity and levels of beneficial bacteria, while broad-spectrum antibiotic treatment further intensified anxiety and depression behaviors. Metabolomic analysis indicated that capsaicin disrupted metabolic pathways related to tryptophan and phenylalanine, leading to decreased neuroprotective metabolites, such as kynurenic acid, hippurate, and butyric acid. Additionally, capsaicin diminished the expression of ZO-1 and occludin, indicating increased intestinal permeability. Conclusions: Dietary capsaicin aggravates gut microbiota and metabolic disturbances in diabetic mice, thereby worsening anxiety, depression, and cognitive decline. Full article

The objective of this study was to assess the antidepressant efficacy of a novel imipramine–magnesium (IMI–Mg) complex in comparison to the administration of imipramine and magnesium individually. The study utilized adult male albino Swiss mice. Behavioral assessments were conducted using the forced swim test (FST) and the tail suspension test (TST). A locomotor activity test was conducted to exclude false positive results in the FST and TST. Moreover, the study assessed oxidative stress levels in the mice subjected to acute environmental stress by measuring glutathione peroxidase, glutathione reductase, total oxidant status, and total antioxidant status. The administration of the IMI–Mg complex at doses of 5, 10, and 20 mg/kg resulted in a reduction in immobility time in both behavioral tests, thereby indicating the antidepressant-like potential of the tested complex, which was similar to the one observed after the administration of these two compounds as separate drug forms. The efficacy of the novel IMI–Mg complex represents a significant advancement and provides a foundation for future research. This innovative agent has the potential to enhance the safety profile of the therapy, streamline the treatment protocol, improve patient satisfaction, and promote adherence to the therapeutic regimen. Full article

Cichorium intybus L. oligo-polysaccharides (CIOs), obtained from Cichorium intybus L., is a mixture of oligosaccharides and polysaccharides. This study explores the antianxiety and antidepressant effects and mechanisms of CIOs by using acute behavioral despair and chronic unpredictable mild stress mice models and measuring the levels of 5-HT and the expression of proteins related to the BDNF/ERK and PI3K/Akt/mTOR pathways. Moreover, 56 male C57BL/6N mice were used to test behavioral despair. They were randomized into seven groups (Control, Citalopram, CIO 12.5 mg/kg, CIO 25 mg/kg, CIO 100 mg/kg, and CIO 200 mg/kg) based on body weight; they were administered with the corresponding medication daily for 7 days; and behavioral tests were conducted on them (forced swimming test (FST) and tail suspension test (TST)) after 7 days. Seventy male C57BL/6N mice were adopted in the next part of the experiment and randomly divided into seven groups (Control, CUMS, Fluoxetine, MOO, CIO 25 mg/kg, and CIO 100 mg/kg) based on the sucrose preference index. Except for the control group, the other groups were subjected to 6 weeks of CUMS. From the fifth week of stress, the corresponding drugs were administered by gavage until the end of the behavioral tests. In the behavioral despair tests, the immobility time was significantly reduced in the FST and TST after the CIO (25 and 100 mg/kg) treatment of 7 days. After 6 weeks of chronic unpredicted mild stress (CUMS) treatment, CIO (25, 50, and 100 mg/kg) administration significantly reduced the number of buried beads in the marble burying test (MBT), decreased the latency in the novelty-suppressed feeding test (NSFT), and shortened the immobility time in the FST and TST. CIO administration significantly increased the sucrose preference index in the sucrose preference test (SPT). Additionally, CIO treatment increased hippocampal 5-HT levels while upregulating the expression of BDNF, P-PI3K/PI3K, P-ERK/ERK, P-Akt/Akt, and P-mTOR/mTOR. In summary, CIO exerted promising antidepressant effects in behavioral despair and antianxiety and antidepressant effects in CUMS-induced depressive mice. Moreover, CIO therapy was facilitated by increasing the 5-HT content, alleviating the damage of hippocampal neurons, and upregulating the BDNF/ERK and PI3K/AKT/mTOR cascade. Thus, CIO is a substance with the potential to treat anxiety and depression. Full article

Background/Objectives: Argemone platyceras Link & Otto, an endemic plant of Mexico, is widely distributed in the central area of the country, mainly in the states of Tlaxcala, Puebla, and the State of Mexico. Ethnobotanical studies in different communities of these states have demonstrated that it is primarily used to treat diabetes and mental illnesses, such as “los nervios” (nerves) and “el ansia” (anxiety); these terms are used in traditional medicine, but it is accepted that they refer to anxiety disorders. This study aimed to validate the traditional use of aerial parts of A. platyceras Link & Otto in treating these illnesses. Methods: a standardized acidic method to obtain alkaloids was used to obtain an extract (AlkExt), which was tested in adult male Swiss Webster mice in the tail suspension (TST) and forced swimming (FST) tests. Results: AlkExt was analyzed using mass spectrometry techniques (DI-ESI and UHPLC-MS) to detect 2,3′,4,5′-Tetramethoxystilbene (m/z 301.14, 3%), scoulerine (m/z 328.16, 19.8%), tetrahydro-columbamine (m/z 342.17, 28.8%), 8-(hydroxymethyl)-2,10-dimethoxy-6,8,13,13a-tetrahydro-5H-isoquinolino[2,1-b]isoquinoline-1,11-diol (m/z 358.17, 22.8%), and glaucine (m/z 356.19, 11.1%); these were assayed in a single oral administration of AlkExt, which caused robust anxiolytic- and antidepressant-like effects without affecting the spontaneous ambulatory activity of the mice. Conclusions: The easy and standardized AlkExt analyzed in pharmaceuticals assays in this study strongly suggest its therapeutic potential to treat the comorbidity of anxiety and depression disorders and support further investigations in people with these diseases. Full article

Background: Lepidium meyenii Walp. (LmW), known as maca, has been shown to increase physical performance. However, the effect size (ES) of LmW on the different manifestations of physical performance has not yet been described. Objectives: To examine and qualitatively describe the studies published up to 2024 that employed LmW supplementation to increase physical performance in animal and human experimentation. In addition, the ES associated with the different interventions was calculated. Methods: The research followed PRISMA^® guidelines for systematic reviews and meta-analyses, using Web of Science, Scopus, SPORTDiscus, PubMed, and MEDLINE databases until 2024. Randomized controlled studies with a pre- and post-test design, conducted both in vitro and in vivo in animals and humans, were included. Methodological quality assessment was performed using the CAMARADES tool for animal studies and the Newcastle Ottawa Scale for human studies. The main variables were the forced swimming test (FST), the rota-rod test (RRT), the grip strength test (GST), blood lactic acid (BLA), and lactic acid (LA). The analysis was conducted with a pooled standardized mean difference (SMD) through Hedges’ g test (95% CI). Results: Twenty-one studies were included in the systematic review and sixteen in the meta-analysis. They revealed a large effect for all outcomes (SMD: FST = 2.26, RRT = 6.26, GST = 5.23, LA = −1.01, and BLA = −1.70). Conclusions: The phytochemical compounds of LmW, mainly macamides, increase physical performance, showing a greater effect at higher doses (dose–response effect). Full article

To investigate the effects of one-week maternal separation (MS) on anxiety- and depression-like behaviors in adolescent and adulthood as well as adult hippocampal metabolomics simultaneously in offspring female and male rats. In the MS group, newborn SD rats were separated from their mothers for 3 h per day from postnatal days (PND) 2 to 8. The open field test (OFT), elevated plus mazes (EPM), novelty suppressed feeding test (NSFT), and forced swimming test (FST) were conducted during adolescence and adulthood. Serum corticosterone, mRNA expression of hippocampal inflammatory cytokines, and hippocampal untargeted metabolomics of offspring adult rats were examined using an assay kit, qRT-PCR, and UPLC-Q-TOF/MS. Both MS female and male rats showed similar behaviors in OFT, EPM, NSFT, and SPT, except for the latency to feeding during adolescence and the open arm entries during adulthood, showed statistical significance only in MS female rats. Serum corticosterone and hippocampal pro-inflammatory cytokines IFN-γ were significantly elevated in both female and male rats, and IL-1β and TNF-α were significantly increased only in female rats. In hippocampal metabolism, the identification of differential metabolites displayed 53 and 37 in female rats and male rats, respectively (with 35 common metabolites), which were involved in 33 and 30 metabolic pathways with 28 common pathways. One-week MS induced sex-specific anxiety- and depression-like behaviors in female and male offspring rats during adolescence and adulthood, as well as sex-differentiated characteristics in the hippocampus inflammatory cytokines and metabolomics of adult MS rats. From the experimental data, the effects of MS on the female offspring rats were more severe than those of the male offspring rats. Full article

Epidemiological studies have linked fine dust pollution to depression, yet the underlying mechanisms remain unclear. Oxidative stress and endoplasmic reticulum (ER) stress are known contributors to depression, but their induction by particulate matter (PM), particularly PM2.5, in animal models has been limited. This study aimed to establish a rat model of PM2.5-induced depression-like behaviors and elucidate the underlying molecular mechanisms. Adult male Sprague–Dawley rats received daily intranasal PM2.5 for four weeks. Behavioral assessments, including the open field test (OFT), forced swim test (FST), and light-dark box (LDB) test, were conducted weekly. PM2.5-exposed rats displayed depressive-like behaviors, particularly in the FST, reflecting decreased motivation and learned helplessness. Molecular analyses indicated a specific increase in ER stress markers (CHOP, eIF2α, GRP78, and P16) and NOX4 in the hypothalamus, while other brain regions (striatum, cortex, and hippocampus) were not as pronounced. Additionally, PM2.5 exposure reduced tyrosine hydroxylase (TH) levels in the hypothalamus, suggesting impaired dopamine synthesis. These findings indicate that PM2.5 induces depressive-like behaviors via hypothalamic ER stress and oxidative stress pathways, leading to dopaminergic dysfunction. Targeting oxidative and ER stress within the hypothalamus may offer new therapeutic strategies for treating depression associated with environmental pollutants. Full article

Depression is a complex psychiatric disorder that has substantial implications for public health. The lateral habenula (LHb), a vital brain structure involved in mood regulation, and the N-methyl-D-aspartate receptor (NMDAR) within this structure are known to be associated with depressive behaviors. Recent research has identified transcription factor 7-like 2 (TCF7L2) as a crucial transcription factor in the Wnt signaling pathway, influencing diverse neuropsychiatric processes. In this study, we explore the role of TCF7L2 in the LHb and its effect on depressive-like behaviors in mice. By using behavioral tests, AAV-mediated gene knockdown or overexpression, and pharmacological interventions, we investigated the effects of alterations in TCF7L2 expression in the LHb. Our results indicate that TCF7L2 expression is reduced in neurons within the LHb of male ICR mice exposed to chronic mild stress (CMS), and neuron-specific knockdown of TCF7L2 in LHb neurons leads to notable antidepressant activity, as evidenced by reduced immobility time in the tail suspension test (TST) and forced swimming test (FST). Conversely, the overexpression of TCF7L2 in LHb neurons induces depressive behaviors. Furthermore, the administration of the NMDAR agonist NMDA reversed the antidepressant activity of TCF7L2 knockdown, and the NMDAR antagonist memantine alleviated the depressive behaviors induced by TCF7L2 overexpression, indicating the involvement of NMDAR. These findings offer novel insights into the molecular mechanisms of depression, highlighting the potential of TCF7L2 as both a biomarker and a therapeutic target for depression. Exploring the relationship between TCF7L2 signaling and LHb function may lead to innovative therapeutic approaches for alleviating depressive symptoms. Full article

Post-traumatic stress disorder (PTSD) is a debilitating neuropsychiatric condition closely linked to neuroinflammation, with a higher prevalence in women. Cannabidiol (CBD), a non-psychoactive cannabinoid, has shown promise as a potential treatment for PTSD. In this study, we used a PTSD model in which female rats were subjected to a severe foot shock followed by contextual situational reminders (SRs). Testing was conducted one month after exposure. The rats received daily CBD injections for three weeks during the SRs, from days 7 to 28. Two days after the final SR, the rats underwent five extinction trials, followed by the forced swim test (FST). After a five-day rest period, the rats were sacrificed, and brain tissues from the medial prefrontal cortex (mPFC) and ventral subiculum (vSUB) were analyzed for inflammatory markers. Chronic CBD treatment reversed impairments in fear extinction caused by shock and SR. It also reduced learned helplessness in the FST and decreased the upregulation of mPFC-il1β induced by shock and SRs. Additionally, exposure to shock and SRs downregulated mPFC-il6 while upregulating vSUB-il6. CBD treatment further downregulated il6 expression in the vSUB compared to the vehicle groups. Our findings show that CBD effectively inhibited the development of PTSD-like behaviors and suppressed neuroinflammation in the mPFC. Full article